Mind & Matter
Mind & Matter
Ketamine: Opioid System, Sex Differences, S- vs. R- Isomers, Depression & Ultrasound Imaging Technology | Tommaso Di Ianni | #147

Ketamine: Opioid System, Sex Differences, S- vs. R- Isomers, Depression & Ultrasound Imaging Technology | Tommaso Di Ianni | #147

Download, watch, or listen to M&M episode #147

About the guest: Tommaso Di Ianni, PhD is an Assistant Professor in the Departments of Psychiatry & Behavioral Sciences and Radiology & Biomedical Imaging at the University of California, San Francisco. His lab uses ultrasound technology and deep learning to study the brain.

Episode summary: Nick and Dr. Di Ianni discuss: the current state of scientific understanding of ketamine; S-ketamine vs. R-ketamine isomers; the antidepressant effects of ketamine; ketamine's known mechanisms of action; sex-dependent effects of ketamine action in the brain; involvement of the opioid system in ketamine's effects; addiction; and more.

*This content is never meant to serve as medical advice.


Full AI-generated transcript below. Beware of typos & mistranslations!

Tommaso Di Ianni 3:59

Reaching out I was actually listening to your podcast quite a bit when I was commuting to Stanford. So that was

Nick Jikomes 4:05

ah, which which ones did you listen to?

Tommaso Di Ianni 4:08

Oh, I listened to Alex Kwan. Listen to Gul Dolan more recently. I listen to Christian Luschiar. Oh,

Nick Jikomes 4:19

yes. Yes, I am. Maybe going to ask you about some of that work and how it connects.

Tommaso Di Ianni 4:24

Yeah, yeah. I listen to quite a few.

Nick Jikomes 4:28

Excellent. Yeah, no, I'm glad to hear it sometimes. I'm starting to hear that more. Which is, which is a nice surprise. Yeah, yeah. That's nice. Yeah. Because sometimes because you know, when I first started, I was you know, essentially emailing people, and they have no idea who I am. But sometimes now they're like, Oh, yes, yes. I listened to this episode. So I already know you. Nice. Yeah. Do you want to just start off by introducing yourself telling people a little bit about your your scientific background and what your lab is doing now?

Tommaso Di Ianni 4:57

Sure. Yeah. So I am the master of the art. Me I, I'm an electrical and biomedical engineer by training. And then I did a postdoc at Stanford, I was in the Department of Radiology. But I was really working at the interface of ultrasound and neuroscience. So my background is mostly in ultrasound. So both ultrasound imaging and therapeutic ultrasound. And when, during my postdoc at Stanford, I started applying these modalities to neuroscience. And more recently, I started, we started develop both developing and applying kind of develop developing technological innovations and applying this modality called functional ultrasound imaging to studying pharmacology and studying how drugs act on the brain and more specifically Academy, which is what we're going to talk about today.

Nick Jikomes 5:59

Yeah, let's, let's start off by talking about some of the technology here. So you're using ultrasound to do imaging. Normally, when people hear ultrasound, they think about a pregnant woman going in for her ultrasound to get those first images of the baby. Can you give us an overview of how exactly ultrasound technology works? And what some of these other applications are beyond? Beyond the familiar one? Yeah.

Tommaso Di Ianni 6:23

So the imaging is really not much different than what happens when when Yeah, the one of the applications, the one you mentioned, for fetal imaging. But what we're really looking at here is blood flows. So ultrasound is also imaged. So people may also be familiar with applications like color flow mapping, like when you're imaging an organ like the liver, for example, or the the neonatal brain, or the arteries, for example, in the neck, and you see those blue and red colors, overlaid on the image, those those colors show a measure of blood flows. And so in the application that we are using there is again called functional ultrasound imaging, we are the kind of the underlying technique is called Power Doppler. So we are doing Doppler imaging and imaging blood flows. Now, if we have one single image of the blood vasculature like that blood flow, that's just giving us a snapshot of the vasculature at that specific time point. But what do we do here, we track those blood flows over time. And there is a principle that is the principle that is underlying all this is called neuromuscular coupling, which is telling us that essentially, the brain has no intrinsic ways to store energy and oxygen, and therefore if there is an increase in activity locally, the way these cells can get the supply of oxygen and glucose that they need is by recruiting more blood. So if we track those blood flows, we can indirectly infer neural activity. So this is not dissimilar to what happens with other modalities like fMRI for exam functional magnetic resonance imaging. Yeah, so

Nick Jikomes 8:25

a chunk of neuronal tissue becomes more active. It could be excitatory cells, it could be inhibitory cells could be both, but they're becoming more active, they require more energy to sustain that activity. So blood flow increases to that region to supply them with oxygen and nutrients and this and that. So it's similar to fMRI in that way.

Tommaso Di Ianni 8:46

In that sense, yes, we are looking at in it similar to fMRI in the way that we are looking at blood flows as an indirect measure of neural activity. fMRI more specifically looks at the rate, it looks at oxygenated and deoxygenated hemoglobin, while in this case, we're looking at three blood blood volume, but the two are highly correlated. And indeed, people have looked at both functional ultrasound imaging and fMRI back to back with optogenetic stimuli, for example. So like stimulating neural activity in a very well controlled way, and imaging with using the two modalities and they are, what they saw is that functional ultrasound is indeed very highly correlated to fMRI. So they're giving us pretty much the same information but functional ultrasound. The nice thing about functional imaging is that it is much more sensitive than fMRI. So for studying these, these, kind of, like neural activity and how, for example, how the brain reacts or how the brain responds to drugs in animals. function offers on imaging is gives you a kind of a better, better resolution and better effect sizes

Nick Jikomes 9:59

Okay, so So just for people listening, when we look at this data, and we talk about it, you guys are measuring a proxy for neural activity, which has to do direct blood flow, but you're not directly measuring the action potentials that the cells are sending out. That is

Tommaso Di Ianni 10:13

correct. Yes. And so yes, exactly. There is there a caveat that we are not measuring spiking activity. But it's, it's somewhere in between. So I like to think of it as kind of a translational tool in that whatever we find in animals, we can possibly translate into humans with fMRI, for example, or we can look at correlative measures in humans with fMRI because it's, the underlying mechanism is very, is very similar. So it's, I think it's a nice bridge between the, the animal world and the human world.

Nick Jikomes 10:50

And you said something earlier about Doppler imaging is this has to do with the Doppler effect. Sort

Tommaso Di Ianni 10:57

of Yes, I mean, the idea, so kind of, in the, in the kind of at the origin of ultrasound, blood flow imaging, there is the Doppler effect. And that's because kind of so so for, for people listening, the Doppler effect is essentially that effect when an ambulance is approaching, and then you hear the pitch is increasing. And then when the ambulance is kind of going away from you, you, you hear a lower pitch, so you have that, but the ambulance is emitting the same tone all along. So that modulation, that you that you perceive is called the Doppler Effect, which is essentially squeezing the pressure waves when the ambulance is approaching. So you hear when you hear a higher pitch, pitch, a pitch, because the waves are closer together. And then when the ambulance is leaving is dilating those pressure waves and so you hear a lower pitch. Similarly, when you send an officer on pulse, and you have a scatter, moving away from you, it will modulate the ultrasound that you receive. And if it's moving towards you, it will tell you will have either a higher or lower frequency. And then therefore, by looking at those frequencies, you can you can kind of infer the velocity of the scattered.

Nick Jikomes 12:22

Yeah, and let's, let's just be really explicit for people. So when you use an ultrasound device, how exactly is it working to ultimately generate the data that that we're going to talk about?

Tommaso Di Ianni 12:33

So there's a lot f coming in there. So I'm trying to Yeah, squeezing in as much information without as possible without making it too confusing. So we are sending ultrasonic pulses. And then we are so every time we send the pulse, then we start listening.

Nick Jikomes 12:53

So that's it's altra sound, are you talking about a physical vibration that's generating good sound wave,

Tommaso Di Ianni 13:00

exactly, it's a pressure wave that is not dissimilar to sound, the only difference is that so we define ultrasound whatever is beyond 20 kilohertz, because the, the spectrum of the kind of the audible sound in humans is between 20 hertz and 20 kilohertz. Almost nobody can get to 20 kilohertz, but that's like the textbook definition. So

Nick Jikomes 13:25

ultrasound is basically just referring to sound waves beyond what you possibly perceive. Exactly.

Tommaso Di Ianni 13:33

So in our case, we are looking at we're talking about mega hertz here. So, the higher the frequency, the better the resolution. So, we want to use a frequency as high as possible, because then we get a better kind of a smaller pixel, a higher spatial resolution. But then, so essentially, we signed up not just on pass, we listen. And then we use some smart array signal processing. So in the ultrasound probe, that is the one that is that is in contact with with the body in contact with the brain in our case or in contact with the, with the skin in other, you know, the other clinical applications. That's what we call an ultrasound probe, and the probe is nowadays is almost never made of one single ultrasound transducer. So it's really made of an array of transducers and so, in the back ends are what happens in the scanner, we are detecting the the pressure waves that are backscattered that are returned like scattered back by the tissue from an array of sensors, and then we use some signal processing to essentially refog us artificially, if you will. So create electronic lenses. So we we refocus in all the pixels in our image.

Nick Jikomes 14:58

So it sounds Like there's an analogy between optical forms of imaging. So instead of using photons that go in and come back and they scatter with some kind of pattern, you're just doing this with sound.

Tommaso Di Ianni 15:11

To some extent, yeah. You could Yeah, you could think about it that way. Some, some work. Yeah. I mean, it is not, we're delivering some form of energy inside in this case is ultrasound. And the other case would be optical energy, and then you have something and it's yeah, it has to be scattered in this case, right? Because we are staying outside of the body. So kind of we are sending something in and then listening or watching from the same same location. So where there is a backscattered component. So yeah, so I mean, it's not, it's not dissimilar. The signal processing also kind of the erasing or processing that I was talking about really comes from from radar. And it's not, like in radars, they're, they're these kind of antennas are called phased arrays that are essentially moving the electromagnetic beam, to scan the volume. And in this case, we do something similar as well. So by having access to all those tiny ultrasound elements, we can manipulate the ultrasound that we send in. Because we can we have access, and we can control each of those elements electronically. So everything happens electronically, we're not moving anything mechanically, but then we can manipulate the ultrasound very well and reconstruct the images out of the ultrasound signals that we receive from all these tiny little transducers.

Nick Jikomes 16:48

And last question, on this tech, what kind of, can you say a little bit more about the, the spatial and temporal resolution that you're actually getting? Yes,

Tommaso Di Ianni 16:58

so as I mentioned, the spatial resolution in particular is a function of the frequency. So the higher the frequency, the higher spatial resolution, however, the attenuation is also a function of the frequency. So the higher the frequency, the higher attenuation, we will have to face. And so for applications that are relatively shallow, we can use much higher frequencies because we can still penetrate a few centimeters without losing too much of the of our kind of signal to noise ratio without losing too much energy. So for example, in our case, we are using 15 megahertz in all the our functional imaging studies. And then applications, for example, like in the liver, where you're imaging down to 1520 centimeters, those applications use much lower frequencies. And so that's in kind of as a flip side of the coin is that you can penetrate deeper, but then you get a lower spatial resolution. I see. Just yeah, one caveat, actually, that I wanted to mention, since we're talking about penetration depth, compared to optics is that the nice thing of ultrasound is that we can penetrate deep. So we can in our case, for example, we can image the whole body. Yeah.

Nick Jikomes 18:26

So when you use a microscope, to do like calcium imaging or something, you can image, the cerebral cortex, you can go down, you know, a little bit in the brain and collect photons back to create an image that way. So what you're saying is you can go much deeper in the brain and get information about deeper structures. Exactly.

Tommaso Di Ianni 18:44

And possibly we can get hold brain imaging, or like going back to optics. The other thing that you could do, you can implant for example, a fiber optic technique that is called fiber photometry. So you can detect photons from deep inside the brain, but then you are so one, you're also causing physical damage. It's amazing. And also, you're biasing in the study in that you are deciding up, you're in where you want to look at it when you look at the whole brain. You

Nick Jikomes 19:13

can survey the whole thing. And then yeah, exactly. Last question. Actually, one more. Is there. What is there any reason to believe that the ultrasound stimulus itself might affect neural activity?

Tommaso Di Ianni 19:28

That's a very good question. So we ourselves in our lab, we are we're working with ultrasound in neuroscience. So we work both on we develop technologies and we use ultrasound imaging as well as another technique that is called Dr. Sonya modulation. So we are using ultrasound to modulate neural activity. So we are actively kind of doing doing that as well. And in that case, kind of the difference is that we need a higher level of intensity or a higher energy at the, at the focus or whatever we want to, in that case stimulate or inhibit neural activity. It requires much higher intensity than what we use in imaging, because in imaging, so to give you an idea, in one case, we are focusing the error. So we are using those elements or a physical or electronic lens to focus the ultrasound energy in one spot, even though the intensity is still much lower than what is called high intensity focused ultrasound, which is essentially upgrading tissue. So we're not in that regimen of very high intensities. But still, the intensity that we deliver for neuromodulation is a lot higher than what the intensity that we subject the tissue to in ultrasound imaging applications, because in office only imaging, we are using plane waves. And actually that goes back to the temporal resolution question, which I haven't really answered yet. But we use plane waves, which means we are in Sonic fine, we are sending off sound into the whole field of view at once. So we're not focusing the energy in any point we are the energy is diluting in the tissue is diluted in the tissue. So the intensity at the kind of in the tissue is is very minimal compared to what we would need to modulate neural activity. I

Nick Jikomes 21:35

see So okay, so it's in that way, it's different from something like two photon microscopy where you're focusing, you're focusing all of your light in one plane. Yeah, exactly.

Tommaso Di Ianni 21:45

So in the old days, ultrasound imaging, that's what happens. So you were, you would focus the energy in one point, and then either build, kind of that kind of build up, meaning like in post processing, right? I mean, you acquire data, and then you you build the image in that specific point where you image where you focus the energy, or you build the line. So you kind of you have a focus, because you're focusing in transmit, receive. So kind of you can do all these different tricks. So basically, you can. Anyway, I mean, what I was, what I was saying, when I was trying to say is that in the old days of ultrasound imaging, or most clinical scanners, still today, you are focusing the energy in one specific point or in a few points for each image line. Okay? While in our case, we are sending the energy in the entire volume at once. And the advantage of that is that every time we send the pulse, instead of sending energy in one point, and therefore imaging that one point or a line, we can image the whole volume. So we have a much higher temporal resolution in the order or in the order of kilohertz. Well, if you have to build an image, point by point, by the time we have built the whole image, the kind of we are already, the tissue has moved, everything is changed. So that kind of gives us a much lower temporal resolution that we will actually need to look at these tiny signals from the brain, the brain vasculature.

Nick Jikomes 23:21

So using ultrasound, you can get information about what's going on in the brain, you're getting a signal back, which has to do with blood flow, which is going to be related to what the neurons are doing in terms of their action potentials. But it's not literally a direct measure of that signal. It's kind of similar to fMRI in that way. But we're using ultrasound, the same thing that a pregnant woman would you know, when she goes into get her ultrasound to see her baby, it's the same type of technology. You can point that at a little rodents brain and actually get information about pretty much all parts of the brain. And you guys use this technology recently to study the effects of ketamine in the brain. Because of that, so many episodes about ketamine and enough people listening will will have some basic education here. I don't want to spend too much time on the basic basics of ketamine. Nonetheless, let's just for those listening who aren't very up to speed on what's going on in the ketamine research world, what is ketamine? What has it been used for historically, and what have we started to use it for more recently from a medical and therapeutic perspective?

Tommaso Di Ianni 24:30

Yes, so ketamine, the textbook textbook definition of ketamine is an NMDA receptor antagonist, which means it is blocking these receptors in the brain that are called methyl D aspartate. receptors. And historically, ketamine was really used as a combat anesthetic in the beginning so it is very safe compared to other anesthetics. Compared to narcotics, for example, it doesn't call significant side effects so it can be used in on the battlefield. And so that's how ketamine was used for historically for a very long time. And then in the early 2000s, it kind of became clear or there started to be evidence that ketamine had antidepressant effects, and at very low doses, so a very solid anesthetic, and somebody said, ik doses, so a very tiny infusion of ketamine has antidepressant effects. And the nice thing is that those effects are very rapid. So it's a rapid acting antidepressant of an antidepressant, which is an advantage compared to let's say, selective serotonin reuptake inhibitors that take weeks to show effects. So that's one advantage. However, the effects, the antidepressant effects are also short lasting. So it starts acting within hours, and then usually the effect fades out between one and two weeks. I

Nick Jikomes 26:16

see. So, immediate effect, rapid antidepressant effect, but not particularly particularly long lasting compared to other drugs. Even things like psilocybin, for example, have a much different time course. You mentioned that you get different effects at different doses. So just to summarize that, at high doses, let's just call it high doses. You get anesthetic effects. That's been a historical use. At lower doses, you get psychoactive effects. So when people are using ketamine recreationally, I guess we can just call that a medium dose. And then the low doses that give the antidepressant effects, are they low enough? Where there's no obvious psychoactive effects either? No,

Tommaso Di Ianni 26:54

there are there are definitely psychoactive effects. I mean, I guess the associative mostly,

Nick Jikomes 27:01

so the antidepressant effects do happen concurrently with some dissociation.

Tommaso Di Ianni 27:07

Yeah, I mean, the dissociation happened. So I believe the the antidepressant effect, outlast the association, so the dissociation is only limited to the half life of the drug, kind of the time when the drug is actually actively inside the body. And then the antidepressant effects Outlast that meaning that, as I mentioned, they lasts for one to two weeks. And at that point, ketamine will be definitely out of the body. So it's not actively causing any, it's not binding to those receptors anymore, because it's been washed out. The antidepressant,

Nick Jikomes 27:45

addressing effect of any adverse effects are triggered by the drug but they outlast the drug. So something's happening that that outlast the drug being in the brain that actually sort of preamps my next question. So before we go into your work, which is going to have interesting things to say about how ketamine is working, you mentioned that the primary mechanism that ketamine is known for is antagonizing the NMDA receptor in the brain is Has that been proven to be the mechanism that causes or as required for the antidepressant effects, or other mechanisms thought to be at work, you know, that are actually responsible for the antidepressant effects or that are also required in addition to the NMDA receptor effect? What's sort of the latest on what's known and what's controversial about the antidepressant mechanism?

Tommaso Di Ianni 28:35

I think that's a very active question right now. Because there is no I don't think there is definitely not necessarily a consensus on the mechanism definitely in humans. Because again, the original idea is that ketamine binds to the, these NMDA receptors preferentially and inhibitory interneurons in the prefrontal cortex, and therefore it is inhibiting inhibitory interneurons and having an excitatory effect can have a net excitatory effect. But there's been evidence recently, preclinical evidence showing that there are also other mechanisms that may be responsible for the mechanism of action of ketamine, at least for the kind of the antidepressant like effects in rodents, for example, on AMPA receptors, so it's another receptor that also is a good glutamate receptor, but different than the NMDA receptors. And then more recently, both in humans and in rodents there. There has been evidence that by blocking the orchid receptors so they Same type of receptors the that seems to modulate the antidepressant effect as well. So now how those are kind of placed in the pipeline. So, where ketamine is binding first and what is happening downstream, at least to my knowledge that is not very clear yet so we don't know exactly what the cascade of events that is leading to the antidepressant effect.

Nick Jikomes 30:26

I see. You know, another way to start to think about this is, you know, there are many other drugs that antagonize the NMDA receptor, some of them are probably much more specific for interacting with the NMDA receptor. Do NMDA receptors, antagonists generally have antidepressant effects? Or is ketamine somehow unique here?

Tommaso Di Ianni 30:46

No, that's actually that's one of the Exactly, yeah, thank you for that question. One of the reason why I believe people have started in first place, I've started investigating other mechanisms for the antidepressant effect of ketamine is that more selective and NMDA receptor antagonists didn't work very well in clinical trials. So they will still work maybe in animal models. But the animal models are models, by definition, so kind of dead on we can only model a very complex disorder like depression in animals, you know, we can only do that much to model that. So because it's a very complex disorder and therefore, anyway, those those NMDA receptor antagonists didn't work very well in clinical trials. And therefore, people started looking at alternative hypotheses for the mechanism of action of ketamine.

Nick Jikomes 31:46

Is there any evidence that ketamine might be metabolized and one or more of its metabolites might be doing something relevant?

Tommaso Di Ianni 31:56

Therefore, so? Definitely, so ketamine is metabolized into nor ketamine hydroxy, nor ketamine, so there are all these metabolites that are created, if you will, mostly by the liver, and then they they're also psychoactive. So they reach the brain and they do something themselves. There is some evidence that those metabolites are actually sufficient to create an antidepressant effect in animals. But there is also evidence that is going against that. So I don't think we have a clear picture yet if specifically hydroxy, nor ketamine, if it is, at least to my knowledge. If that is sufficient to have an antidepressant effect,

Nick Jikomes 32:49

yeah. So this is a very active field of research. It sounds like, you know, there's evidence for some of these things. But then there's also conflicting evidence. So we really are on the cutting edge here. And no one truly knows exactly what's going on yet.

Tommaso Di Ianni 33:01

That's correct. Yes, I think that's the

Nick Jikomes 33:05

one more background piece of information about ketamine that I think is interesting and relevant. So as many people know, there's two ketamine isomers, S and R. What do we know about the differences between them? Do they have different pharmacological properties? Do they have different effects with respect to the anti depression, anti depression effect or anything else?

Tommaso Di Ianni 33:28

Yes, definitely. So. So first of all, maybe let's step back. So we have three compounds here we have really like three, when we talk about cadmium, we are talking really about three different things. One is s ketamine, and our ketamine so these are the two stereoisomers so it's the same molecule, but specular structure, and then the other one is racemic, ketamine. So when usually when we talk about ketamine without specifying anything, we are talking about the racemic compound, which is more or less 50% are ketamine and 50% esketamine. And what for what we know at least now, I think, yes, they are all acting differently and they bind to they have different affinity for different receptors. As ketamine, for example, seems to have a higher affinity for opiate receptors than or for mu and kappa opioid receptors and then our ketamine for example. So they are definitely they act differently and as ketamine is FDA approved for treatment resistant depression, are ketamine. There is it's an active field of research to determine if our ketamine is has antidepressant effects or not. And the safety profile also seems to be different between the two at least in animal moles. So they are definitely different different molecules and they act differently. Yes.

Nick Jikomes 35:06

In the study that you guys did recently that we're going to talk about, did you use one isomer? Or was it the racemic? Ketamine

Tommaso Di Ianni 35:15

so we worked with both. So the study that you're mentioning the one that was published more recently, that's with only with racemic, ketamine, and but we also collaborated with Mike McLean is at the National Institute on Drug Abuse at the NIH. And in that case, we use S ketamine. So we were imaging, the effects of s ketamine in the brain. And in the paper that came out recently, we were only looking at proxemic ketamine so it's, again 50% of our caravan and 50% of s ketamine.

Nick Jikomes 35:53

Yeah, so let's let's talk about the recent study a little bit, can you just give us a basic overview, what was the setup? And then what kind of experimental? What kind of questions were you looking to answer?

Tommaso Di Ianni 36:03

Yes. So our study really kind of the, the way we came up with this, with this idea of testing the opioid receptors, testing kind of what is happening in the brain at the opioid receptor level, was generated by a few, a couple of papers that came up in between 2018 and 2019. That we're showing them that in patients, so patients with treatment resistant depression. And an opioid receptor antagonist called naltrexone was suppressing the antidepressant effect. So in these patients, they were pre treating the patient were not Traxion before administering, administering sub anesthetic, ketamine. And in the other group, they were just administering ketamine, so they were pre treating with saline, it's kind of an inert compound and the GRU in the group that they pretreated with saline. So the group had just received ketamine, they saw as expected an antidepressant effect of Southern State Academy. However, when they pretreated the the patients with naltrexone there were suppressing that effect. So they were essentially deleting at least partly the antidepressant effect of ketamine. So

Nick Jikomes 37:32

the interpretation of that is that somehow the opioid system is involved.

Tommaso Di Ianni 37:37

Yes, that's correct.

Nick Jikomes 37:40

Okay, so what did you guys do in your paper with rodents.

Tommaso Di Ianni 37:44

So in our rodents, we, in our paper, we essentially tried to back translate, kind of reverse translate that into animals. Now, of course, we don't have the breast animals, just as a as a caveat. These are these are rats. So it's not a it's not a tiny human. So we have it's a different animal altogether, but we tried to kind of reverse translate that study. So we use the same compound, there is no tracks on again to unblock the opioid receptors. And then we administered sub anesthetic, ketamine, at a dose that is very, is widely used in the literature, and is known to elicit antidepressant effects in our antidepressant like effects in rodents. And then, we image essentially what happens in the brain, when we administer ketamine alone, or when we are blocking the opioid receptors before we administer ketamine. So and the underlying idea is that if the if ketamine is kind of is not interacting with opioid receptors at all, then the two conditions should look same, should look the same. But if ketamine or if the opioid receptors are responsible, to some extent that we don't know yet, if they are responsible for that effect, then when we block the receptor, so when we take them essentially, out of the picture, we silenced them, then there is something different and that's what we tried to decode here.

Nick Jikomes 39:39

So the question is, basically is the opioid system involved in ketamine is action in the brain? You have this ultrasound technique? You can you can point your little ultrasound at the skull of a rat. You can get information about what's going on in the brain. I'm going to refer just for people listening to connect this with what we were saying earlier about how This technique works. I'm going to say things like brain activity. But you know, you're not measuring spiking activity. You're measuring a proxy for this, but it's related to the, to how active the neurons are. So you're able to look at activity in different parts of the brain using this ultrasound technique. You can give ketamine, you can give ketamine, and simultaneously block the opioid receptor. If that receptor system, if opioids are doing something, then we should see a difference between ketamine versus ketamine plus opioid block. So where did you look in the brain? And then what did you see? Did you see a difference?

Tommaso Di Ianni 40:35

So we looked at, to kind of we limited our because we didn't have a fully volumetric imaging setup. At the time, we looked at two slices in the brain, but we tried to pick slices where we knew from the literature that something interesting could happen. So the one slice we have the prefrontal cortex that is been has been has been shown to be involved with the mechanism of action of ketamine broadly for different different models of disease and also more mechanistically. The prefrontal cortex seems to be very heavily involved with the mechanism of action.

Nick Jikomes 41:26

I think it's it's fair to say right that like the prefrontal certain circuits in the prefrontal cortex, certain chunks of the brain in that region, seem to play an outsized role in depression, generally speaking, and in the action of things like ketamine and answer to nergic. psychedelics. That's

Tommaso Di Ianni 41:42

correct. Yes. I mean, it seems that exactly. But honestly, all those regions that we are going to talk about they are they were they're both interesting for both depression and ketamine. And so kind of that that was interesting for us to see that that was actually the case. So the other region in that in that same slice is the nucleus accumbens, which is a regional that is very important for reward processing. So also important for depression, for example, for the anionic aspects of depression, so kind of lack of lack of pleasure from rewarding stimuli. So, there's implements also, again, like a very, very important region.

Nick Jikomes 42:29

Yeah. And that's also like, when we think about things like drug addiction or addiction generally, that's a kind of alteration of reward processing and the nucleus. nucleus accumbens is a very important, certain part of the brain circuits and that are very important for addiction. Before we go further, in your paper, actually, can you give people a short summary of what do we know about ketamine addictive potential relative to other drugs of abuse?

Tommaso Di Ianni 42:58

Well, just full disclosure, I'm not a psychiatrist, but I will just Yeah, so I don't I don't see patients with either depression or addiction. But I think in general, there is the idea is that ketamine is not already kind of the mainstream idea is that ketamine is not very addictive, it is abused. So it is a substance that is, it is a controlled substance. So it's regulated by the Drug Enforcement Administration. And the reason is that it is it is used recreationally it is abused as a drug. But kind of the general consensus, at least to my understanding is that it's not very addictive. But again, this is something that is very much an object of research right now. And there again, seems to be a difference also between the different molecules like our ketamine versus as ketamine versus racemic, ketamine versus hydroxy or ketamine and so on. So you don't know exactly what is happening and we don't know exactly if it is addictive or not.

Nick Jikomes 44:19

Yeah, I mean, we don't have the mechanism of action fully worked out. That's part of what your papers about, you've got our ketamine event s ketamine, you know, sort of my my take on this just for those listening is, on the one hand, you've got animal research from people like Kristian Lucia, who I've had on the podcast before, if you want to go learn about that, and what they show fairly compellingly is that ketamine is certainly less addictive in a rodent than something like cocaine, but doesn't mean it's not addictive at all. And it's also important to keep in mind, right? Even though it's obvious, it's easy to forget, a lot of times that you know, rats and mice aren't humans, because even though that research and animals shows that there seems to be quite a low addiction liability for it I mean, if you've spent any time around people who take ketamine recreationally there are people out there who get addicted to ketamine for sure. So we kind of Yeah, we don't know exactly how addictive yet, but it's probably less addictive than something like cocaine, which is quite addictive.

Tommaso Di Ianni 45:18

That's correct. But then on that note also worked by Mike MC lead is our collaborator at NIDA. NIDA is the National Institute on Drug Abuse, they have looked at our ketamine versus S ketamine, and also in the other paper that I mentioned, where we looked at functional ultrasound imaging with esketamine in the nucleus accumbens again they showed that rats are self administering esketamine which means that they are kind of self administration is one of the is a behavioral model is that is thought to recreate some of the aspects of, of addiction in rodents. And rats do self administer s ketamine at least in in their lives in the papers.

Nick Jikomes 46:18

I see. So there could there could be a difference between SNR and there's some evidence that S is reinforcing in rodents, which would imply some addictive potential in humans.

Tommaso Di Ianni 46:27

Exactly, exactly. And racemic ketamine again is made of both so we also have that as ketamine component.

Nick Jikomes 46:33

Okay, so you looked at nucleus accumbens, in your paper, you looked at parts of the frontal cortex, what did you guys see, when

Tommaso Di Ianni 46:41

we also look at the more posterior slice, where we have some other interesting regions, like the lateral habenula, for example, which is a region that has been implicated heavily both with ketamine and with opioid receptors. It is also a region that is part of the reward circuit, it's not been studied. A lot, definitely less than the prefrontal cortex and the amygdala components, but what we know is that it is also implicated with the reward circuitry in the brain. And in that slides, we also have the retrosplenial cortex, which is also another region that has been recently shown to be involved with mechanism of action of Somerset Academy and specifically for the dissociative effects of Somerset Academy. Interesting.

Nick Jikomes 47:35

Alright, so you looked at several brain regions using this technique. We've got the ketamine condition, we've got the ketamine plus blocking the opioid receptor condition, what was the basic result that you saw.

Tommaso Di Ianni 47:49

So, essentially, we saw that when we are pre treating the animals with opioid receptors, it is modulating the neural activity evoked by its sub anesthetic, ketamine. So, in some regions, it is suppressing at least partially that neural activation in some other regions, it is enhancing the response to ketamine. So, it appears to have divergent effects in different regions, which is also somewhat expected because some, some of these regions are acting differently, for example, in that reward circuit, and in other circuits as well. So that was expected, but there seems to be definitely an effect that is mediated by opioid receptors, because when we take them out of the picture, something is changing in the brain. However, something that was very, very surprising and unexpected to us was that this was only the case for male rats. When we did these experiments in female rats, we did not see any, essentially any differences, at least in these two slices that we looked at. So there seems to be a sex divergence in kind of this awkward mediated component in the response to the second study Academy. What

Nick Jikomes 49:15

exactly was the difference between males and females?

Tommaso Di Ianni 49:19

Well, in males, we saw all these different regions showing significant statistically significant effects in females with almost did not see anything. So we almost we saw some minor clusters of differences, but they were not. I see. So definitely, definitely, they are not to the extent of what we seen in males.

Nick Jikomes 49:46

I see. So in male rats, you give ketamine, it causes activity, activity to change and a bunch of different parts of the brain. If you give them ketamine, and simultaneously block parts of the opioid system, you see big difference It says significant differences in what's going on in the brain. So the opioid system is somehow involved in ketamine effects. When you do that, in females, the difference between the opioid block and non opioid block condition is much smaller. So there's less of an effect coming through the opioid system and females, it seems, if

Tommaso Di Ianni 50:17

at all, yes, there is there are very minimal effects, we still see a response to ketamine itself, that things are slightly different than what we see in males. But still, there is a substantial response to ketamine itself. Just it doesn't change. When we block the opioid receptors in female rats,

Nick Jikomes 50:37

did you guys go into the study intentionally aiming to look at males and females? Because there was some reason to believe there might be a sex difference? Or did you stumble onto this in the process of just studying the drug effect itself?

Tommaso Di Ianni 50:50

Honestly, we stumbled on on this, it was rather surprising that is that we saw such a strong sex difference we only like when we did. The we did a preliminary analysis of the data, like an interim analysis of the data that we had collected with about half the animals. Then we started seeing these very strong sex differences. And then it began to so we had to essentially repeat the studies and to have to have a better statistical power in females, because then at that point,

Nick Jikomes 51:31

yeah, when you pull them all together, it would have diluted the effect you saw in males. No, we

Tommaso Di Ianni 51:35

would still see significant effects, even with males alone. So male alone, males alone, where it's definitely driving statistically significant effects in the brain. So when we pulled males and females, we would still see effect, but when we specifically use statistical tests to to address that question, which is pretty much almost these days a routine thing to do, like you poor use 50% males and 50% females. Just as a as a caveat, there's a historical background, males have been used, much more than than female animals in in research, it's only recently that people have started looking at kind of using both both sexes. But anyway, when we do that, at some point, we run statistical tests, to see if there are sex differences. And so when we did that, we had still a good, good statistical power. So we had a significant effect. But then we saw this very strong difference between males and females. And so at that point, we had to kind of repeat the experiments to, to validate that and to verify that that was the case that indeed, only males were showing these opioid mediated effects.

Nick Jikomes 52:55

Yeah. So earlier, you know, we were discussing, you know, whether or not or what the evidence is that ketamine might be addictive to some extent. And we mentioned that, well, it's actually important to think about s versus r ketamine, because there's some evidence to suggest one of them might have more reinforcing properties than the other. Is there the potential for a sex difference here? In other words, does the involvement of the opioid system being stronger, and males imply that they might have higher levels or potentially lower levels of addiction liability or reinforcement here?

Tommaso Di Ianni 53:32

Again, this is just this is rats. So there's quite a bit in between, you know, between what we show in rats and assessing the abuse liability in humans. Also, I don't think that we can necessarily see that the opposite system is stronger in males. That's not necessarily what we're seeing here.

Nick Jikomes 53:54

It's just involved. It's, it's involved

Tommaso Di Ianni 53:57

in some way. And it's different between males and females. But I don't think we have evidence to say that the at least in our case, that the opioid receptor system is stronger in males. And indeed, I think there is evidence in the literature that it is quite the opposite, that females have a stronger have kind of a Yeah, I mean, let's say stronger, it's simplifying here, but they have a stronger opioid receptor system. And also in our case, when we look now I'm jumping a little bit at the end of the paper with the one we were looking at opioid binding of ketamine. Also, there, we saw differences between males and females in the nucleus accumbens, but it doesn't necessarily indicate that males have a stronger awkward system. Actually, our evidence seems to be going in the opposite direction that females are somewhat overcompensate not over but compensating for that blockage that Don't do so we've logged into this app. There's been a few more. Yeah,

Nick Jikomes 55:03

I guess, I guess the fact that you're seeing differences at all here, both the sex difference and, and with respect to the opioid system, it's probably worth someone out there explicitly testing the the level of reinforcing properties you see in males versus females, and then probably breaking that up by by s versus our isomer.

Tommaso Di Ianni 55:22

Yes, absolutely. Absolutely. And yeah, I mean, even even the the antidepressant effect, so without going in the direction of one of the reinforcing effects, but even just the antidepressant effects of sub anesthetic, ketamine, we, as as relates to the opioid receptor system. We don't know exactly if there are any sex differences there. Because all the studies that have been done in humans, they are underpowered, too, which means they don't have enough enough subjects, to split them into groups and statistically compare males versus females. Yeah. So we don't have the statistical power to do those those assessments. estroux For what relates to the opioid receptor says that not to somebody said ketamine alone.

Nick Jikomes 56:13

Yep, yep. Um, so you saw, I mean, ketamine is doing stuff in the brain. It's got this interesting, sex dependent effect here. The opioid system is involved, at least in males. Can you talk a little bit about some of the experiments that you did to look at the nature of how the brain activity changes, you did some eCOGRA experiments where you're looking at patterns of brain activity.

Tommaso Di Ianni 56:37

So the EEG of experiments they were. So as you mentioned earlier, we're looking at blood flows, right. So as a caveat, here, we are not looking at neural activity. Strictly speaking, we're looking at a proxy for neural activity. So to task or like to, to address that, that concern that actually what we're seeing is indicative of anything happening at the neural level, as opposed to just something that happens in the cardiovascular system. We did experiments with Electrocorticography. So we implanted electrodes on the surface of the brain, and we recorded electrical signals in response to 70 Study Academy, and then we correlated those signals with our functional ultrasound imaging responses, but that was with ketamine alone and without the opioid without blocking the opioid receptor. So it was more way to validate that what we are measuring here, it is actually correlated to what happens at the neural level. And what we found was actually very interesting. Also, because it confirms what other people have seen as well. So functional ultrasound imaging is still a relatively new modalities, or we're still to some extent, trying to really understand the signals that we are measuring what they're what's the underlying mechanism. But other other another group have looked, they have looked at kind of electrophysiological Carpe Diem is doing a similar study, but in a different part of the brain and with different stimuli. And they saw correlation between the function ultrasound imaging signal or the cerebral blood volume signal, where gamma power, so when we record these electrical signals from the brain, we split them into frequency bands, and then we can analyze those bands differently. And those bands gave us different information. And so they in that case, they observed a very strong correlation between the function offers on signal and gamma band gamma activity in, I believe it was the visual cortex and the hippocampus but and with different stimuli. And in our case, we saw converging evidence that also functional ultrasound imaging was correlated to very strongly correlated to the electrophysiological signal in the gamma band. I

Nick Jikomes 59:16

see. So and when you say gamma band, so So basically, there's a lots of patterns of like electrical activity in the brain. If by analogy, we think about like looking at the surface of the ocean, right, you might have very fast little waves coming and you might have big slow waves from like a big ship going by. You guys can sort of measure how much of all of the different wavelengths there are in the signal. And you're saying that you see certain changes in certain bands. So the gamma band would be relatively fast rhythms in the brain, right? That's correct. Yes, that's,

Tommaso Di Ianni 59:49

in our case, it was between 30 and 80 Hertz. Everyone uses different kind of limits for those bands, but it's usually between 20 and 30. And 50 to 80 hertz, the upper band.

Nick Jikomes 1:00:03

Um, you know, I know that there's, you know, a lot of people have a lot of different opinions in the neuroscience world about what all of these rhythms and frequency bands mean. But just to give some people a sense for, for, for something a bit more concrete here, what would be like, what would be like a naturalistic behavior? Like do you see do you see high gamma band activity in awake animals and sleeping animals and animals that are like doing a task and animals that are eating food? How do we think about high gamma band activity?

Tommaso Di Ianni 1:00:33

Well, I mean, that's not really my field of studies. I kind of Yeah, that's just, you know, a big caveat there. But, but high gamma is mostly kind of indicative of kind of an awake and aroused response. So I see. Yeah,

Nick Jikomes 1:00:52

okay. Yeah, I guess that would make sense. I mean, the doses of ketamine you're using here, are, you know, by design, not putting they're not anesthetic.

Tommaso Di Ianni 1:01:00

Exactly, exactly. So, so that's expected. Yeah. And also, interestingly, there is. And again, this is kind of it will be object of further further studies, because I think it's something very exciting that kind of the, the inter neurons where ketamine binds at the NMDA receptors that we mentioned earlier, is one of the hypotheses of sub anesthetic, ketamine, they're also involved with generating gamma oscillations in that part of the brain. So I think that was a very interesting kind of point of contact between the two, which I thought was very, very exciting, but we don't have evidence to, to show that those are related. But I just thought it was very interesting that we did see those patterns converging between two modalities in in that part of the brain, which was the prefrontal cortex again.

Nick Jikomes 1:02:00

And you know, based on this study, or other studies that are out there, when you give ketamine to a rodent, a freely behaving rodent, what are the behavioral effects? What are they a sub anesthetic, antidepressant dose? What are they what do they do? How does their movement and their behavior change?

Tommaso Di Ianni 1:02:19

Um, they, I mean, there are different different parents, or at least in rats, they definitely become wobbly a little bit, I mean, they show kind of their behavior changes their patterns of, of behavior changes change in a way that they are kind of less in control, like so to speak of their of their, of their environment, and I'm just anthropomorphic icing the rat here, but they seem to be kind of less aware of what's what's happening around in their environment, there is a hyper local motion response. So they are actually

Nick Jikomes 1:03:12

moving around more moving around more,

Tommaso Di Ianni 1:03:15

which is actually something that we also also tested and that is also something that has been shown quite quite a bit in the literature that ketamine has, causes hyper locomotion in, in rodents. So they're, they're moving more, but kind of less able to move overall. They also sometimes show stereotypical responses, like they are maybe grooming more or they can do different stereotypical behaviors, but it's usually shortlist that. So within a few minutes, they are pretty much back to normal. So it is usually very quick. Yeah,

Nick Jikomes 1:03:59

I see. Yeah, I would. Yeah, and Academy doesn't last that long, like in humans, right, it lasts for a shorter period of time than something like psilocybin say. And because of the metabolic differences between rodents and humans, I imagine that the drug is basically in their system for just minutes.

Tommaso Di Ianni 1:04:15

Right? Yeah, it's very sure. I mean, just also another thing that we should mention is that the dosages is very different between humans and rodents. And that's, again, because of the differences at the metabolic level, the way that drug is metabolized in the two animals is very different. And rodents have a much faster metabolism. So usually we give, the doses that we give in animals are much higher than what is actually used in humans. But those are kind of the doses that have been shown to have antidepressant like effects in growth. And so there is a lot of literature showing that at that specific dose Um, you have you have antidepressant like effects, which is 10 milligrams per kilo of body weight.

Nick Jikomes 1:05:07

So what are you guys doing to followup on this? Or more broadly speaking, you know, what do you think are some of the next steps for the field to get a better handle on ketamine some mechanism of action of the brain?

Tommaso Di Ianni 1:05:23

Well, I think, at the rodent level, one thing that we are actively investigating right now is trying to understand better that circuit. So now we got these snapshots of regions in the brain where something interesting is happening when we block the opioid receptors, but we don't know exactly how they relate to each other. And we don't know exactly what is happening. When these regions, how these regions talk to each other, essentially. And now those patterns change. We then without the opioid receptors, we also there are some other regions in the brain that are definitely interesting to look at that we left out in our study, because also there was, we have to kind of decide because of the setup that we had at the time. So now again, since we have access to volumetric imaging, we're also expanding that so there is a there's a paper essentially a preprint, that just came out a few weeks ago, where they also show interesting effects in the central amygdala, also with opioids and ketamine, so that's also another region that they could definitely be interesting to look at. But in general, I mean, I'm interested in having this whole brain picture of what's going on with them without pocket receptors, but that's all in rodents. And then in humans, it will be, I think, it'd be very nice to see if there's a kind of defects that we found, or this kind of ketamine opioid interaction. And the sex differences translate into humans. So there, we don't have a whole lot of fMRI literature with ketamine. So it's only that we there's definitely some, but it's not, not a lot. So we don't know exactly how those patterns may may change in humans, but I think would also be very interesting, try to understand, essentially, the question is, if opioid opioid receptors are a thing at all, and if there are those strong sex differences, we need to try to understand if that is the case, before deciding what to do with it essentially, before kind of steering the field in one direction or the other, but I don't think we have a clear picture yet of what's happening.

Nick Jikomes 1:07:57

Um, you know, on the one hand, you know, obviously, we we have seen that ketamine can have these remarkable, rapid antidepressant effects, they don't last forever, they are short term. On the other hand, you know, there's still a lot of open questions, right, there's, there's still a lot of controversy and and worked a bit on the field to work out things like sex dependent effects, involvement of the opioid system and the full mechanism of action to be worked out. And what exactly the addiction liability is, is it different between the SNR isomer is a difference between males and females? So we've got, you know, we've got all of all of the science that's still ongoing in terms of how ketamine works and what it's doing. And on the other hand, you know, because of the remarkable results with respect to the rapid antidepressant effects, we've seen things like ketamine clinics just pop up all over the place. I see them all over now. To what extent, you know, is that warranted, because we're seeing these rapid antidepressant effects, and they are apparently helping a lot of people people are commonly reporting that it does in fact, help them when they get these doses? And to what extent like should we maybe be a little bit more cautious because we, while we are seeing these rapid antidepressant effects, we also know they don't last forever, and there may be, you know, there may be things we don't understand. That should make us slow down a little bit.

Tommaso Di Ianni 1:09:23

Yes. So, on that note, I wanted to mention before answering your question that since ketamine has to be essentially administer, over and over again. We also looked at repeated administration, effects of repeated administration of ketamine because we kind of the rationale there was that we did see opioid receptors modulating the response to ketamine in that reward system. And so and also knowing that ketamine needs to be administered In humans, repeatedly, we wanted to try to see if the opioid receptors were also having an effect on kind of in, in that specific behavioral response, like habituation to the response. Exactly. And so we looked at locomotor sensitization. So as I mentioned, rats are and mice, they, they have they showed his eyebrow lokomo locomotion when they are administered ketamine meaning that they behave more they walk around more acutely, so in the first 20 or 25 minutes of ketamine administration, but after ketamine administration, and as we administer the drug repeatedly that response goes up. So the animals show some sort of adaptation in the in that part of the of the limbic system that is ramping up that that behavior over several days of repeated Drug Administration. So we, we also tried to probe that and again, we saw that naltrexone blocked that behavioral sensitization, locomotor sensitization in males and females, we still had behavioral sensitization, meaning that the animals were behaving more and more like the HeLa login model, this role model response was increasing more and more over other American people's record if it was four or five days of repeated administration. And, but we could not block that with naltrexone. So when we block the receptors, in males, we were essentially deleting almost completely that that behavioral sensitization, while in females, that would not be the case. I

Nick Jikomes 1:11:49

see. So So again, there's a sex dependent involvement of the opioid system here. What exactly is going on? We can't say, but behaviorally the males were becoming more sensitive sensitives eyes sensitized to the effects of ketamine, at least with respect to locomotor behavior.

Tommaso Di Ianni 1:12:08

Now that we're both becoming sensitized to ketamine, both males and females, I spot in males, we could block that effect by blocking the opioid receptors, but not in females, but only in females. So in females, whether the opioid receptors were available or not, they will become more sensitized to it, regardless why, but that was not the case in males. Got

Nick Jikomes 1:12:29

it. And so, you know, what, what would this potentially imply that, you know, that potentially you could take lower and lower doses of ketamine and you would still get the same magnitude of effect? How should we start to think about this?

Tommaso Di Ianni 1:12:45

I think it's more of a safety question. I mean, what you are, I think, taking a lower and lower dose of ketamine, that would be more efficacy, like whether it is sorry, go ahead.

Nick Jikomes 1:13:00

So if there's sensitization, and let's say, you know, someone's going into a ketamine clinic, and they have to go back every two weeks because the the antidepressant effects aren't permanent. Would this imply the possibility that, you know, if they're going back once every two weeks, they're actually becoming, they're effectively getting a larger dose because they're becoming more and more sensitive to the dose they're getting?

Tommaso Di Ianni 1:13:22

I'm not necessarily I mean, that because there is also like, a tolerance effect, which means they are kind of the opposite receptors, specifically, they are changing in response to repeated administration. And that's actually something that we showed, both in this paper, but also in the other paper that I mentioned, with s ketamine, we show that the repeated administration of s ketamine is reducing opioid receptor availability in the nucleus accumbens. So basically, when you lower the level of the opioid receptors available, essentially, you need more drugs to get the same at the same level of reward. Exactly. So those are it's not necessarily it's not necessarily like that they're getting kind of a higher effect. I sort of response is not Yeah, it's not necessarily getting that. I

Nick Jikomes 1:14:23

see. But, you know, with repeated dosing, there are differences. So it's not the exact same effect you're seeing with each successive dose.

Tommaso Di Ianni 1:14:34

Exactly, there is a sensitization and there is a tolerance effect mechanism that are going on when you administer the drug repeatedly. So

Nick Jikomes 1:14:45

that would imply the likelihood that if repeated doses of ketamine are given, you know, time after time, the way the person or the animal responds, is going to change over time, potentially Yeah,

Tommaso Di Ianni 1:15:00

that's That's correct. And he might like in the case of, again, like with esketamine, what we were probing there were experiments that were done at NIDA. Again, we did the functional stuff on imaging experiments for that paper. That is, again, like showing the, the animal is developing some sort of tolerance to the drug. So it's reducing the sensitivity to the drug, because they it has less opioid receptors to be activated.

Nick Jikomes 1:15:37

So what are some of the, what are some of the experiments you guys think you're going to do in the near future? What are what are some of the the next steps the next questions?

Tommaso Di Ianni 1:15:46

Well, as I mentioned, for us, we're very interested in trying to kind of go deeper in understanding the circuit level effects, trying to understand how those regions talk to each other. And how that changes in response to the that are period modulation. That is definitely something that we are actively doing right now. In the lab, there are also like, another aspect of this. So the lab where i, where i was before, where I did this work at Stanford, is developing ways to is developing technologies to deliver ketamine in a focused focal way to kind of deliver ketamine orally to specific regions in the brain, also using ultrasound. And therefore, another aspect of this research is trying to understand if there are regions in the brain where we can preferentially elicit, let's say, No, I'm stretching a little bit here. But let's say that we can preferentially elicit their antidepressant response versus other adverse effects. And so if that is the case, we can deliver ketamine only to that region, specifically, I

Nick Jikomes 1:17:05

see. So in principle, you know, the antidepressant effects might come largely from ketamine ZZ effect on you know, one part of the brain or one circuit, maybe other effects come from other places, if you could locally apply it there. The idea would be you get the antidepressant effects without the other stuff that might be undesirable. That's

Tommaso Di Ianni 1:17:23

correct. And then if, like in rodents, people have, for example, delivered, ketamine like that you can micro infuse the drug in specific regions in the brain. So people have shown definitely that ketamine and prefrontal cortex can have an antidepressant effect, we will have shown that ketamine in the lateral habenula This very tiny region where we also saw opioid dependent responses. So, infusing ketamine only in that region also seems to be sufficient to elicit an antidepressant effect. So there are there is there are indications that actually that may be sufficient kind of that you can target regions individually and still have an antidepressant effect. Now, we don't know if their antidepressant effect is, again, mediated by the operator receptors in that region. And if that would be necessarily safer. That's an open? That's an open question. But that is another aspect of this kind of mapping that we're trying to do here.

Nick Jikomes 1:18:27

Interesting. Well, this is this is exciting stuff. Obviously, this is a pretty hot field. There's a lot going on, and it's pretty fast moving. So it's exciting. Is there anything you want to reiterate for people or any final thoughts you want to leave them with about the specific work that you did? Or just this field in general? Oh,

Tommaso Di Ianni 1:18:45

just, again, I think that we are like, as basic scientists, we're putting out evidence, right, that that something is happening then, at least in Rhode Island. So I think these are definitely facts that need to be confirmed in humans. So hopefully, there will be clinical trials to specifically test these questions. Because I think it is an important it is it's critical to try to understand better these mechanisms to improve the safety profile of ketamine. And if we have sex differences that have not been tested, specifically so far, it will be critical to try to understand those better and try to understand if that is actually real in humans, so

Nick Jikomes 1:19:37

All right, well, Professor tomato de Yanni. Thank you for your time.

Tommaso Di Ianni 1:19:41

Thank you so much.

Mind & Matter
Mind & Matter
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