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Ep #8 Transcript | Katrin Preller: Empathy, Addiction, MDMA, Psychedelics & Social Cognition

Full episode transcript below. Beware of typos!

Nick Jikomes

Dr. preller, thank you for joining me. Oh, thank you so much for the invitation. I'm really glad to be here. Yeah, we're glad to have you. Where are you? Where are you sitting in today?

Katrin Preller 2:16

I am sitting in my home office in Zurich right now.

Nick Jikomes 2:21

What time is it there?

Katrin Preller 2:23

It's 6pm. So pretty late on a Friday evening.

Nick Jikomes 2:27

Okay. Well, thank you very much for taking the time on a Friday. Can you start off by just telling everyone what you do and what your scientific background is?

Katrin Preller 2:36

Yeah. So I'm a neuro clinical psychologist by training. And after graduating from college, basically, I joined a research department at the University of Zurich where I did a lot of research on addiction. So looking at the long term consequences of drug use. And after that, I switched gears a little bit to investigate the acute and long term effects of psychedelics in healthy participants to gain a more mechanistic understanding of what exactly these substances do, as well as in clinical populations. I've had I spent some time at UCL in London, as well and at Yale University. And I'm now leading a small research lab at the University of Zurich, where we're investigating the effects of psychedelic substances.

Nick Jikomes 3:35

And are there any particular psychedelic substances that you guys focus on?

Katrin Preller 3:41

Most of our work has been in waves, so Simon and LSD at the moment.

Nick Jikomes 3:47

And so these are classical psychedelics that people often talk about in the context of serotonin. So I thought maybe we could start out by just discussing serotonin a little bit and get people up to speed on the basic biology there. So broadly speaking, what is serotonin? And what role does it play in the regulation of things like emotion, plasticity and social behavior?

Katrin Preller 4:10

Yeah, that's a really good question. And it won't be very easy to answer to be honest, because serotonin plays such a big role in, in some people say in everything and nothing at the same time. Um, but in general, serotonin itself is a neurotransmitter that is in everyone's brain. It's not only in the brain. But obviously in the in the context of psychedelics, we're mainly looking at the brain. So in the brain, it regulates a lot of functions, and they range from appetite and sleeping to other functions like emotional processing, etc. So it's really involved in in a lot of things. And it's a pretty complicated system because the effects of serotonin itself depend on Which receptor they activate in the brain. So basically, serotonin is just the transmitter, but it has to activate certain things and which are the receptors docking station so that they will have an effect on, you know, emotion processing, for example, and there are several subtypes of this receptor and depending on where exactly the serotonin acts in the brain, and then what receptor the effects may be different.

Nick Jikomes 5:28

And so where can you talk a little bit about the receptors and serotonin in terms of distribution in the brain is this a transmitter that's being used everywhere, or in particular places,

Katrin Preller 5:40

it's pretty much everywhere in the brain. So obviously, in some places, the density of certain receptors is a bit higher than others. But it's not like it's some kind of localized system. So really, serotonin acts all over the brain.

Nick Jikomes 5:57

And people often talk about the serotonin to a receptor when discussing psychedelics. So why why is that? What is the to a receptor? specifically? Is that one localized at all? And what do we know about that receptor?

Katrin Preller 6:11

So Well, first of all, when we're talking about psychedelics, usually they are substances, which are not necessarily super specific for the serotonin receptors. So there are other receptors involved as well. But it's most of them are rather specific to the, to the serotonin system. And except for maybe LSD, which has a little bit of affinity to the dopamine system as well. But and here comes the important part. And when we block the serotonin to a receptor system by, for example, giving people another drug first, that blocks these types of receptors, and then add LSD or psilocybin, and the prayer, the participants basically don't have any effects anymore. And that tells us that the effects of psychedelics are highly dependent specifically on the serotonin to a receptor. And with that receptor as well, it is you can find it basically all over the brain. So it's not that, you know, we can point to one brain region be like, yeah, this is where, where psychedelics act, right, it's really all over the brain. But again, in some areas with a little bit higher density than in others.

Nick Jikomes 7:23

I see. So the to a receptor is really important for the action of classical psychedelics. Because if you give people another drug that blocks that receptor, and then you give them something like LSD, pretty much nothing happens.

Katrin Preller 7:37

Exactly. So we've done exactly those kinds of experiments. And I mean, if you're familiar with what LSD for example, does, it's a highly altered state of consciousness, right? It's very different from your usual reality. But if you administer this other substance first, which blocks these receptors, and then basically, our participants couldn't distinguish between a placebo. And you know, this combination of this other substance plus LSD, even though you know, they had ingested a medium dose of LSD, but there's really nothing happens, they don't feel any alterations at all. And I think that is pretty remarkable given that, you know, usually you have this really highly altered state of consciousness. So we need this specific receptor for the effects of psychedelics to take place.

Nick Jikomes 8:24

And when you and your colleagues are administering LSD or psilocybin, what are the participants doing? Where are they?

Katrin Preller 8:32

So all of our studies are conducted at the psychiatric University Hospital in Zurich. And so it is obviously a hospital environment and medical environment. But we have, we have decorated the rooms in a way that is more of a living room like setting so it's not, you know, the usual hospital atmosphere that you you know, you encounter when you visit someone in the hospital. So we've really tried to make it as pleasant as possible. And, but of course, when we are trying to find out what happens in the brain of our participants while they are on the substance, then of course, we need to do you know, a little bit more technical measurements, and one of the things we do is, for example, fMRI. So if you put people in a brain scanner, and look at what exactly is happening in the brain, while or after they have been administered LSD or psilocybin, so obviously, that is not necessarily a very living room, like setting and being in a brain scanner, but people tend to tolerate this really, really well. So when when we started doing these types of experiments, we were worried in the beginning, you know, if people you know, would feel comfortable in the scanner environment that people usually really do. Um, and well, after we've done you know, the mess of measurements that we are interested in, then we take them back to the living room. Like setting, and that is, of course a little bit different when we're talking about, about clinical studies, where it's really more about the therapeutic aspect instead of the mechanistic one, they are most of the measurements really take place in this living room like settings, so we're not exposing them to any kind of like eg or FMI experiments usually, while they are on the substance.

Nick Jikomes 10:24

I see. One more thing I wanted to discuss about serotonin is I think the the typical person who hears serotonin, if they know anything about it, they probably associated with mood and emotion, because of SSRIs and how those are prescribed for anti anti depression. So what what exactly are SSRIs? And how do they affect serotonin differently from something like LSD or psilocybin?

Katrin Preller 10:51

Yeah. So what SSRIs do is they inhibit the re uptake of the serotonin that is naturally occurring in your brain. So basically, serotonin is floating around between two, you know, two neurons that need to communicate with each other. And, you know, once they have been activating the receptors at the other side of the next neuron, what happens is that they that the serotonin usually gets re uptake in the first neuron where it gets broken down and then reassembled at one point. And what exercise do is they basically increase the level of serotonin of the naturally occurring serotonin in your brain. And by making it stay longer in what we call the synaptic cleft, so between these two neurons, so they can activate the next neuron for a longer time period. Um, and the difference to psychedelics is that here, we're not working with the serotonin that is occurring in your brain. But the psilocybin and LSD activate the receptor directly, first of all, and so so basically, they do the job that serotonin is usually doing. And the second difference is that, of course, you know, then the serotonin you have in your brain that is just, it's just there, it will stimulate all types of serotonin receptors, we've talked about this before, already, there are a lot of subtypes of these receptors. So it will just activate the whole serotonin system. However, as as seen in these previous experiments that we already talked about, is that psychedelics are really mainly focusing on this one specific receptor subtypes and not so much on the other.

Nick Jikomes 12:45

Gotcha. So an SSRI will essentially increase the total volume of serotonin present in the space between neurons, and that serotonin will then go activate all of the different types of serotonin receptors everywhere that it can, whereas a psychedelic like LSD will act almost in place of serotonin, but in a much more biased way at a particular receptor. Exactly, exactly. So SSRIs are so common, I don't actually know how common they are, just know that they are very common. Is there any interaction that an SSRI would have with a psychedelic say? So if someone was taking prescription SSRIs? And then, you know, in a social setting, or otherwise, they took something like LSD or psilocybin? What would the potential interaction or effect be compared to someone who is not taking an SSRI?

Katrin Preller 13:33

And that's a really good question. And I can not, at this point in time give you a really scientific answer to that. And one of the reasons why these experiments have not necessarily been performed yet is because and people are worried that if you have too much serotonin, so SSRIs plus a psychedelic could lead to basically, you know, too much serotonin activation, and this can cause what is called the serotonin syndrome, which, you know, is is really is not particularly a nice state to be in and could be dangerous. So that's why, yeah, well, that's why these experiments have not necessarily been done quite yet. However, if we look at anecdotal reports of people who are on SSRIs, and have tried to psychedelic, what they usually report is quite the opposite, actually, that they have less effect than then participants or people don't take exercise. And the reason for that could be that by taking exercise, chronically, so over a longer period of time for or every day, right? You change your serotonin system. So your serotonin system, the receptors are adaptive. So if you increase the level of serotonin, it might give You might have a reaction that the receptors themselves internalized. So you have you ever scepters, which could also be the case, why, if you if you don't have that many receptors anymore, and the the psychedelic itself has less to stimulate, that's why you might not feel the effects that strongly. But again, this still needs to be tested in in, in scientific studies.

Nick Jikomes 15:26

Yeah, it's really interesting to think about the adaptive or plastic capabilities of neurons. So with that in mind, what would happen? I'm guessing you don't give patients or participants LSD, two days in a row? And can you comment on why that is?

Katrin Preller 15:44

And so the reason for that is, well, I mean, so far, there has not necessarily been the need to do that. And also people don't know, I mean, psychedelics are a substance with very little abuse potential. And there's obviously a reason for that, because very few people would enjoy, you know, two days of tripping necessarily in a row, right? I mean, it's quite a ride. So it's really, it's really not something that people, if you've taken a psychedelic one day, you hardly want to do that exact same thing the next day. But there's also a biological reason for that, because this overstimulation of the serotonin system leads to this what what I said before, like internalization of the serotonin receptors, so you don't, you will have a much, or at least not as much of a strong effect if you take LSD or psilocybin for that matter, the next day, and so, so you would just not feel that drug, either at all, or at least a lot less. And you need at least a few days, like a week, or maybe 10 days for the system to get back in its normal state. So you can actually feel the effects again, and that is also some kind of, you know, on a biological level, that is another mechanism that prevents psychedelics from being you know, abused on a daily basis, for example.

Nick Jikomes 17:11

Yeah, that's interesting. And that's, that's a normal response, right, this and receptor, so So you take a drug, it could be a psychedelic, or it could be just some other prescription drugs, say, and if it's stimulating a particular receptor a lot, that receptor will tend to go down, it'll be less frequent, but then it comes back in the absence of the drug is that accurate, normal.

Katrin Preller 17:33

And that is, in general, accurate and normal. I mean, it depends a little bit on which receptor system you're stimulating, right. And so sometimes that happens a bit faster. Sometimes that happens a bit slower. In the case of psychedelics and the serotonin to a receptor, that happens pretty fast. Which is also the reason why you don't hear there's no no binge consumption of these drugs, usually. And whereas with other drugs, you know, the recovery is often much faster, which is also why you can basically take them more or less every day. But in the long run, you will still need to increase the dose to get the same effects you had the first time you use the substance.

Nick Jikomes 18:16

One of the other things that I noticed in your CV in terms of what you've looked at is, you've looked at other drugs, including MDMA, you've looked at things like empathy and social cognition. So I thought maybe we could have a short discussion about those things, and then maybe compare and contrast some different classes of drugs, something like MDMA, something like LSD, and then something like cocaine or stimulant say. So, to start what what is empathy? How do you define it? And what are some of the important parts of the brain or brain networks that we know are important for empathy?

Katrin Preller 18:51

Yeah. And so, we usually tend to distinguish between two different kinds of empathy called the cognitive and an emotional part. So, the emotional part of empathy is really feeling with the other person. So, you see that someone is suffering and that makes you suffer too. Or same obviously, with happiness, right. So, you see someone is being happy, and which usually makes you happy too. So, that is the emotional part and the cognitive part are also called theory of mind sometimes is that you understand what exactly it is that the other person is feeling. So I see someone is smiling, which means I know that he or she is happy. And that doesn't necessarily mean that I have to feel happy to but I know what this other person is feeling. So these are two different things we distinguish. Usually, they also you can distinguish them on a neural basis as well. But there is they are, they have highly overlapping networks. And in general, what we do Look at when we're talking about social cognition or empathy in the brain is usually the so called. And well, yeah, some people really call it the social brain. And this includes a lot of the midline structures. So the structures that we see, basically here in the in between the two hemispheres are in the middle of these two hemispheres, as well as some more lateral parts, like the temporal parietal junction for, for example. So these are like over here. And but these are like the key areas we look at, when we're when we're talking about empathy and social cognition in general.

Nick Jikomes 20:40

And is there any, is there any interaction between serotonin to a receptors and those parts of the brain or these social capabilities?

Katrin Preller 20:50

Absolutely. So we've run quite a few tests with psychedelics and social, various social cognitive measures, and one empathy, for example. So what we've seen there is that it's also been acutely increases emotional empathy. So how much you feel with this other person. And we didn't see any changes in cognitive empathy, though. So it's not like they can name the emotion that another person is feeling any better. But they tend to feel more with this, this other person. And we haven't done that in the Mr. scanner. So we don't know where exactly this originates from in the brain. But we've done other other tests, which were we also gathered from IHS or where we can also localize where this effect is coming from basically, and one was an experiment where we looked at exclusion or rejection processing. Because we also know that a lot of psychiatric patients experience a lot of rejection, right. And, on top of that, they also react more strongly to social rejection. And when we think about, for example, borderline personality disorder patients, they have a very strong reaction to social rejection. And they are what we've seen there is that psilocybin reduces this reaction towards social rejection. And so people are not, they are less emotional about being socially rejected, they are aware of it, but it just, it's not that emotionally important. And when we look at the fMRI data, during this experiment, we see that we have less activation in what is called the anterior cingulate cortex, which is exactly one of those midline structures in the brain. So very much in very much in the middle of, of the brain, between or at the border of the two hemispheres.

Nick Jikomes 22:58

Yet most people probably haven't heard of the singlet cortex unless they're a neuroscientist or something. So can you talk a little bit about the cingulate cortex? Let's be very concrete about where exactly it is, and what do we know about it? I know there's there's a lot that we could probably discuss, but what what would you say are the basic facts about the the cingulate cortex and what it does?

Katrin Preller 23:19

Yeah, so the cingulate cortex is the area. So if you imagine like you have your, your subcortical structures like the thalamus, etc, which are like very early structures, where for you, some of your sensory input is first processed in the brain. And then you have the corpus callosum, which is connecting the two hemispheres. So that is on top of that, and right above the corpus callosum, the first part of the cortex, right above that in the middle of the brain, so where the two hemispheres meet, and that is the cingulate cortex. And, again, it's a pretty complicated brain structure, because it's not, you know, we cannot associated with one single thing that is being processed there. And a lot of research has focused on pain processing in general there. And there's also a lot of research that has associated the anterior cingulate cortex with conflict monitoring. So if you're, if you're seeing something that is or processing on something that is in conflict with your expectations, for example, and, but also and, again, that is important for the experiment that we conducted for social rejection, which some people have also called social pain processing, which kind of led to this idea that because it's processed and overlapping areas that you know, social rejection is basically the feeling a painful social feeling. And therefore, it kind of makes sense that it's processed in similar brain areas, and we know that If we do the same experiments that we conducted with psilocybin, if we do the same thing with, with, for example, borderline personality disorder patients, that we get an increased reaction in this anterior cingulate cortex in these patients.

Nick Jikomes 25:15

Yeah, it sort of makes sense intuitively, I think most people who've studied or, or tried psychedelics, people often describe, describe the experience as almost childlike, in its qualities. And, you know, if you think about what a child is, they're just, they're a very emotionally reactive person. So they're very, very sensitive and reactive, both on the positive and the negative side. So that that actually makes sense to me. So you don't necessarily think about psychedelics as increasing empathy or emotional processing? First, I think most people probably think of them first for the sensory effects, they have bought something like MDMA. That's really I mean, people call it an pathogen, the the empathy and the pro social behavior effects that it has are really the primary thing that are associated with MDMA. So how does MDMA work in comparison to an SSRI and in comparison to something like LSD?

Katrin Preller 26:15

Yeah. And so MDMA is, again, a very difficult drug, because it does a lot of things. And, in a way, it's a little bit closer to an SSRI than a psychedelics or classical psychedelics, because it's not necessarily stimulating the receptors that much itself, but it's rather it's rather releasing serotonin. And so the serotonin you again have in your brain already gets released into the synaptic cleft. So the, the space between the neurons, and then can stimulate the the neurons that are on the other side of the synaptic cleft. However, it is not only doing that to serotonin, but it's also doing that for dopamine, and for a nor epinephrine, for example. So it's a very complicated drug pharmacologically. But it's, it's more of a releaser, than stimulating the receptors themselves. It does that a little bit too, but much less than a classical psychedelic. So again, you know, a pretty different mechanism of action here. And you're perfectly right. So the social aspects are definitely the ones that people look at when we're talking about MDMA, because they are just so prominent, right. But and we have done, you know, not necessarily comparison studies, but I've written a review paper where we compare the studies that have been conducted with MDMA, on the social aspects, and the studies that have been conducted with psilocybin and LSD. And what we see there, when we compare these results is that the social or the increases in empathy and the changes and other aspects of social processing are actually pretty similar in MDMA, and in, in classical psychedelics. So my interpretation here it is that, well, maybe, you know, we just don't talk about the social effects of psychedelics that much, because, you know, when people take them, and the first thing they notice is, obviously, all these alterations in, you know, their visual system, and, and the sensory system that, you know, somewhere underneath the whole social, social changes and social perception happen, but they're just not as obvious. Because, you know, maybe they're just because all this other thing is going on as well. And that is also a lot easier to describe, for example. But yeah, when we look at the data, the the alterations in social processing, are to a degree pretty similar to the to the ones of MDMA.

Nick Jikomes 29:02

Yeah, that's interesting. I think the flip side of that, too, is with MDMA. People focus so much on the the social and empathic behavioral effects that they sometimes overlook. The sensory effects, there definitely are sensory effects. I would say, what, what do we know if anything about that scientifically,

Katrin Preller 29:22

and not so much to my knowledge right now, because usually people have, you know, alterations and sensory experiences, mostly pretty high doses of MDMA. And obviously, we need to make sure in the experiments that we are conducting that yeah, that that we keep our participants safe. So we tend to administer you know, doses which are like in a moderate range, right. And what has there is a bit of research on MDMA and and social touch, so how that you You perceive, you know, the the the touch of another person in a different usually more pleasant way. But I'm not aware of most research going on on like visual effects of MDMA, for example, because you know, they're just not as reliably induced at least in low to moderate doses with MDMA compared to for example, psilocybin.

Nick Jikomes 30:24

Gotcha. So something like LSD or psilocybin is directly stimulating certain serotonin receptors in the brain that's causing all of the psychedelic effects. MDMA is not doing that. It's really dumping serotonin and other transmitters into the synaptic space. More so you've sort of got more of these neurotransmitters in the brain doing stuff. And so in that sense, it's sort of like an SSRI and SSRI and MDMA would put more serotonin into the synaptic space. So is there what's the interaction or the potential danger of having an SSRI in your system when you take MDMA?

Katrin Preller 31:04

Yeah, that's a good question, and can basically only give you the same amounts I gave you before. And that we did right now at least we we just don't know. I mean, there's always you know, the problem that with the serotonin syndrome, right, so too much serotonin really is not good for you. And so it's probably not something that people should try. And even more so with, with MDMA. It's, it's just probably not a good idea to kind of overload your serotonin system that much. But we we just don't know, at this moment, right? There will be I'm pretty sure there are some studies going on, or will be going on in the near future, where we will have scientific data on that, and where people are doing these experiments in the safe setting.

Nick Jikomes 31:56

I see. So when we think about the perceptual or sensory effects of psychedelics, in particular, they're, they're very striking. So there's very strong sensory effects people, you know, literally see stuff that isn't there, or it's or it's moving. So can you talk a little bit about the brain networks that underlie perception? And what, what, how would you define perception as a neuroscientist? And how would you maybe distinguish it from simpler sensory processing?

Katrin Preller 32:28

Yes, your perception for me, and I'm not entirely sure if that is, you know, a common definition of that, or if everyone would share this definition. But in general, you know, we don't usually experience just, you know, your visual input, or just your auditory input. But usually all these inputs that you receive from your environment, as well as the ones you receive from your own body get integrated in one coherent perception. And I think there is where the difference is, right? You can't have a visual stimulation and a visual perception and the visual Yeah, processing. But eventually, you have one pretty broad picture of yourself, and you know, the world around you which is, which is, you know, put together from different senses, right. And with psychedelics, obviously, something happens there. And there are multiple things that happen, and across the whole brain, not only in our, our sensory brain regions, but even before we get to the cortex, there is the thalamus, which I mentioned before, briefly. And the thalamus is usually responsible to filter important from non important information in in the world. So, the world as as you know, is presented to us is not necessarily, you know, the reality, because in reality, obviously, there are no colors, right? And they're just different wavelengths. But not only that, we are largely ignoring a lot of stimuli. And that is good because and this is the way we can function in this highly complex world. Now, under the influence of a psychedelic, what we've seen there is that the thalamus seems to be losing its ability to really filter this information that we're receiving. And again, I'm talking not only about our environment, but also about the information that we receive from our own body. And so this seems to lead to more information being sent to our sensory brain region. So from the thalamus this information gets to the primary sensory brain regions and we have different ones for all of our senses for our visual system. For example, this is in the occipital cortex which is in the back of our brain. For our auditory system, this is, you know, on the sides of our brain. And yeah, so we have more connectivity, more information flow, do these sensory cortical brain areas. But of course, you know, as I said before, you need to integrate all these things into, you know, a coherent perception. And we see that these sensory brain regions, they're highly connected under the influence of a psychedelic to the rest of the brain. However, the brain areas which are supposed to make sense of the percepts, that we have, and to integrate all this information that we are receiving from about the current state of the world, the current state about ourselves, as well as integrating that these percepts with, you know, what we know about the world, these, these brain areas are loosely connected to the rest of the brain. So our interpretation of that is that we have a sense, a state of heightened sensory perception, but the integration of these, these sensory perceptions is different. So basically, we bring together this information differently than we usually would. And that could explain on the one hand, why we experienced things like you know, these illusions that you've been describing, but also why people, for example, say that, you know, psychedelics allow them to break out of, you know, the usual thinking patterns by they allow them to sees themselves in a new world in a new way, or see the world in a new light. Because the way we put information together seems to be different in in the psychedelic state.

Nick Jikomes 36:45

This reminds me of Aldous Huxley, who famously speculated about how the brain worked. Basically, in the context of psychedelics, he described the brain as perhaps acting as a reducing valve, basically a giant filter, it's actually filtering out information, mostly, before it actually comes into our conscious awareness. And it sounds like you're, you're saying that something like that is actually happening. So on a psychedelic, there's at least two things happening, if I heard you correctly, one is, relatively early parts of the information processing stream, like in the thalamus, are actually being relaxed. So you're filtering out less, there's actually more sensory information coming in and getting to the cortex. And then after that, the cortex itself, the association areas in that the higher order areas are behaving differently, they're, they're stitching that stuff together differently, we can just say that, so. So there really does seem to be a filtering mechanism that is reduced when you're on a classical psychedelic.

Katrin Preller 37:47

Yeah. So that is, at least what the data tells us so far, right? I mean, it's, it's obviously hard to test this in, in humans directly. So we, we have to, you know, find ways to work around that we cannot necessarily just stick electrodes in the human brain usually, and and just, you know, watch the information flow. And so we're working with other techniques, like, for example, connectivity measures in the brain. And there'll be seeing exactly that. So we have a stronger connectivity between the thalamus in certain parts of the cortex, there are other paradigms that we use as well, where we can test how information is, is processed, and basically all of these different measures that we have applied during a psychedelic state point towards a reduced filtering mechanism in the brain.

Nick Jikomes 38:45

And then I would imagine, I mean, anyone who's tried these things will know firsthand that the dose really matters. So a very high dose versus a medium dose versus a low dose, you're gonna have extremely different effects. And in many cases, right now, something that's very trendy, you can you know, people are talking about this in magazines, in the grocery store, micro dosing LSD, and you know, it's really marketed, it's really being marketed literally as almost a kind of stress ball or supplement, you know, that you would take as part of your normal healthy living, because it's going to make you supposedly more creative, a little bit more functional or whatever. So do we actually know anything about the effects of micro dosing something like LSD? And are there any potential risks in doing something like that even at a very tiny dose day after day after day?

Katrin Preller 39:41

Yeah. So unfortunately, we know very little, so there are various question marks around that. But let's look at the safety issue first. And again, you know, there are many unknown so I won't be able to answer that question. Really. But we also know that LSD is stimulating the serotonin to be receptor and there are a lot of those receptors involved in your cardiovascular system. And, and we know that stimulating this receptor chronically so over a long period of time might have negative effects on your cardiovascular system. Now, obviously, we don't know if a microdose off of LSD will be enough to induce any kind of adverse effects there. But it is an open question. So we have no scientific data on the safety of, you know, a chronic application of off psychedelics. So this is just something to keep in mind. You know, I'm not saying that it is necessarily dangerous, and but it could theoretically be. So this is something we really need to keep in mind when we're talking about, you know, daily administration of LSD, for example, I hope that there will be some safety data in in the future, but right now, we don't have them. And coming back to the potential, the potential mechanisms have beneficial effects of a low dose of, of LSD. And again, we don't we have very little data on that yet. And most of the studies that have been conducted are not looking at chronic administration, but they are just administering low dose ones, and then look at the acute effects. And, and compared to a placebo, we see relatively little effects, to be honest. So some studies have tried to do some, like creativity tests and things like that are concentration and things that people describe anecdotally, and we haven't been able to find that effect, yet.

Nick Jikomes 42:00

It's probably very difficult to detect something like that anyway,

Katrin Preller 42:05

it is, I mean, it's a bit harder, or it's a bit easier to to test things like, you know, attention span or concentration and like these more cognitive measures, whereas obviously, testing creativity is a much harder task to do in the lab, right. But yeah, in all these tests, we haven't, we haven't seen the beneficial effects of a single dose of, of LSD, or a single low dose of LSD. Now, that being said, when we looked at the brains of participants under the influence of low dose, we have seen changes in the connectivity between the prefrontal cortex and the amygdala. And the amygdala is basically, to put it very simply, is like the emotional center of the brain. And what we've seen there is that we we, a low dose of LSD seems to change the interaction with the prefrontal cortex, which is kind of controlling this emotional response. And what that might mean is that someone who has some kind of issues with regulating emotion, for example, because they are in a slightly depressed state, and this could theoretically be helpful to, to normalize this change in emotion regulation. And obviously, that probably, you know, getting rid of, you know, this, this, you know, maybe not pathological but kind of, you know, depressed state will obviously also make you, you know, more creative and might also make you, you know, may make makes it easier to focus on your work, etc. So there are mechanistic hints that microdose of LSD might be helpful in people who are maybe not, you know, not performing at, you know, the level that they theoretically could, because of some kind of underlying, underlying problem like Mark depression or something like that. But there is not necessarily any evidence for now that, you know, someone who's already performing at an optimal level, will gain a lot from a small dose of LSD. Again, that being said, There's way too little research at this moment to be able to, you know, answer this question really.

Nick Jikomes 44:41

How so in your opinion, like right now, a very hot topic in the research world and also in the private sector, is the potential therapeutic application of things like LSD or psilocybin? at a very high level, are you excited or opt mistake that there will be some major positive outcomes there? Or do you think maybe things are being exaggerated somewhat?

Katrin Preller 45:09

Well, um, so I do think that, you know, there's definitely a potential. So the studies we know in which are published right now, definitely showed that, especially in addiction, as well as in depression, people are getting better. And that, you know, and that is a that is super interesting, that is super promising. But the studies that have been conducted so far, are often not necessarily well controlled, and they have, they just included a few patients. So to be able to, you know, eventually determine whether we can use the substances as medication. And there are a lot more a lot more questions that we need to answer. And first of all, we need to conduct well controlled trials, we need to conduct trials with a lot more participants, we need to figure out what the best therapeutic approach is that basically comes with the therapy because usually psychedelics in a therapeutic setting are not just, you know, you don't just give it to the participant, and then leave them alone and hope that they will magically get better, but it's usually embedded in some kind of psychotherapy. So we need to figure out what the best approach is to conduct this therapy that, you know, comes along with the psychedelic administration. And we need to figure out who actually benefits from this treatment and to not, because as it usually is, in general, in in psychiatry, and in therapy, it's it's highly unlikely that, you know, this will be the magic bullet for everyone, there will be people who benefit from from the experience and from the administration of the psychedelic, but there will be others who don't. And, you know, one of the major questions to figure out, well, who are these people who respond well to this treatment? And who, you know, might not be really, where Shouldn't we administer that substance. So there are a lot of open questions that need to be answered. But the results that we have so far are very promising.

Nick Jikomes 47:22

So one thing that you've mentioned so far, is that the effects of classical psychedelics like LSD depend, if not entirely, then in very large part on the five htt to a receptor alone? And another question that people have discussed in the literature and elsewhere is, well, to what extent can the therapeutic effects of psychedelics be dissociated from the psychedelic effects, because on the one hand, some of these results with LSD and psilocybin are very striking. On the other hand, he to put it, to put it one way, it's very inconvenient that a doctor has to administer something, and stay with the patient in the room for six or eight or 10 hours. So it would certainly be nice. If doctors could prescribe something, and it doesn't last that long. It doesn't have hallucinations, or very strong sensory effects that the patient, you know, might have an adverse reaction to, let's say, so but but on the other hand, you've already told us that the the major psychedelic effects depend very strongly on this one receptor. So do you have any thoughts? Or is there any data on how plausible it is that we can dissociate the psychedelic sensory and perceptual effects from the potential therapeutic effects?

Katrin Preller 48:42

Yeah. And right now, we can't. And this comes back to you know, another open question when we when we're talking about you know, using psychedelics as medication is that we really don't know why exactly, they have these beneficial effects. And I think we really need to answer this. We trying to do that in the clinical trials that we are currently running. So on top of just looking at whether people get better or not, we're also trying to find out why they get better. So what is it really that, you know, makes them makes them feel less depressed or reduces their drinking behavior after the administration of the substance? And there are so many hypotheses out there which range from changes in the serotonin to a receptor system to changes in neuroplasticity? And do you know more biological factors like insight into dysfunctional behavior, social connectedness, etc. So for the time being, it's really hard to dissociate these things, but we're trying to find out and once we have clarified what exactly it is that helps people get better then And we know for example, that is then your plastic you face or it's the long term changes in the receptor system, then of course, if we know that it's just that, that the the actual experience itself doesn't have much of an impact, and then we know it's the biological factors, and then we maybe can also design something that is just targeting this specific mechanism of action. But for For now, we just don't know.

Nick Jikomes 50:27

So we've discussed how, not only that LSD and psilocybin have quite a low abuse potential, but they might actually turns out to be useful for treating addiction to other substances. So you've done some research on cocaine, that's a very different type of drug. So you can you talk a little bit about about cocaine, what is it? What kind of drug is it? How does it behave differently from MDMA and LSD? The things we've already talked about? And how does that inform why it has a very different abuse potential than that.

Katrin Preller 51:01

So the main difference between psychedelics and almost all other drugs of abuse is that the that basically all drugs that you know, will that have some kind of addiction potential act on the dopamine system. And this is the same for for cocaine, it's not, you know, it's not just the dopamine system, there is serotonin and norepinephrine and these things involved as well. But the main action is on the dopamine system, that's why you have very different effects you're feeling you know, very much awake, you're feeling like cognitively very sharp and things like that, but you don't go into a necessarily an altered state of consciousness, like, like psychedelics usually induce. But obviously, due to its action on the in very fast action on the dopamine system, it's much more addictive than then classical psychedelics.

Nick Jikomes 52:02

I see so so it has to do with the relative difference in which neurotransmitter systems the drugs are primarily acting on? Yes. Gotcha. So, what can you go into a little bit more? What What do we know what studies have been done so far about classical psychedelics and addiction? What what sorts of addiction have people done pilot studies on and where, where are we with that research.

Katrin Preller 52:27

And so there are two studies published currently one in alcohol use disorder and one in tobacco and nicotine addiction. And both of them, again, very low numbers of participants. And, and not not in a controlled setting, so meaning no comparison condition. But both of them have shown really, really nice results. So people drink a lot less. And in the nicotine addiction study, a lot of people stopped smoking. And I think it was 10 out of 12 participants or something like that, or 12 out of 15, who stopped smoking. And I mean, these are incredible numbers, I have no treatment that is comparable to that. But of course, you know, the studies are their first studies, they're basically feasibility studies, again, not necessarily well controlled. And and we need these larger trials on these well controlled trials to confirm that. But these studies are currently underway. And so there, we and several other groups around the world are conducting these types of studies with a larger number of participants with a placebo or an active placebo control condition, which will help to find out if we can actually replicate the findings from these early studies. And it's also being extended to not only alcohol and nicotine. So as far as I know, there is one study being conducted for treating cocaine addiction. And another one for opioid use disorder. So we'll see if the these early results generalize to other forms of addiction or to addiction to other substances as well. And and whether, you know, we can replicate these early results, but again, you know, the ones we have so far are really promising.

Nick Jikomes 54:29

And would that be? Would it be unique in the pharmaceutical world for a drug to be able to treat different forms of drug addiction? My understanding is when you're treating addiction, there's typically you know, maybe one treatment for nicotine, a different treatment for alcohol and so on and so forth. Is that the case?

Katrin Preller 54:47

Yeah, that is indeed usually the case. And that being said, there for some of us for some forms of addiction, we don't even have really good pharmaceuticals to treat them, but in general in General Yes. And this again comes back to the question, what exactly is the mechanism of action, right. And for example, an alcohol use disorder, or inheriting addiction, what you do is basically block the block the receptors where the drug usually acts so that you either don't have an effect when you when you use the drug again, or that you have an adverse effect when you use the drug again. And so that is obviously a very specific to the drug of abuse. However, again, a big question is why would psychedelics be able to help and all these types of addiction, which basically means that if that is true, that the mechanism of action is very different from the one which the pharmaceuticals, which are currently used for the treatment of addiction are targeting? Right? So if, if we have if we think about something like for example, um, neuroplasticity, right, that could be terribly helpful in in addicted patients, because they need to kind of unlearn associations between drug stimuli and their response are the brains response to them. And and if you if you can, if you can, theoretically, combine that with increased insight into dysfunctional behavior. And we could theoretically explain the long lasting effects and why they why psychedelics may act across different substance use disorders. But again, we don't quite know yet what exactly the mechanism is. But or if if we indeed see these positive effects across different substance use disorders, then it is probably something a lot more general than the pharmaceuticals, which are currently used.

Nick Jikomes 56:53

So you're working. And joining us right now from Zurich. I'm curious what the drug regulation is, like in Zurich, compared to the United States. So one point of comparison, that's sort of interesting, or one of the ironies of drug regulation in the US and how it impacts research over here is, for example, something like cocaine is actually less regulated in the United States than these other substances like LSD. So it's actually more difficult to do research on what is arguably the worst, or at least the more addictive drug. And some of the medical benefits, because some of the medical benefits of cocaine are recognized, but they're not formally recognized for something like LSD yet. So what is what is drug scheduling or drug regulation look like in Switzerland compared to the United States for these drugs? And can you comment on, on which which version you think is more appropriate?

Katrin Preller 57:49

And it's actually pretty similar to be honest, is I won't be able to comment on which version especially because it's really it's, it's, it's very, very similar. But there is a difference. And the difference is that research with psychedelics has never completely stopped in Switzerland and has, and we say, so the lab I was working in, has conducted or has conducted the first experiment with psilocybin in humans in, I think 1996. So there's quite a while ago. And so therefore, we we obviously know how to conduct these studies, we know how to get approval for them. And it's obviously a it's a very, it's a strongly regulated space, also in in Switzerland over here. But given this, this long experience, in terms of, you know, us doing this type of research, so we know what exactly we need to do to get approval, but also, on the other hand, you know, the regulatory authorities, and are used to us conducting these studies, and we have been, you know, doing this for 30 years, and you can show that you know, you are be you're able to do that in a very safe way, obviously, and create some mutual trust and the studies and that makes it a lot easier to conduct these studies over here, because we don't have to figure out everything new, but we have this long experience with how to conduct these studies.

Nick Jikomes 59:26

I see so so the regulations are actually similar in Zurich does that how how does that impact the research you guys are doing? Is it take a long time to get approvals to work with these things?

Katrin Preller 59:38

Yeah, it's, it's actually yeah, given the the, the, the experience we have with these trials, and it's not necessarily it doesn't necessarily take too long to get approval. And it just makes things very expensive. And that obviously is an issue. So there is little funding for these types of studies from you know, the Usually usually funding bodies, which are usually governmental where we, where we fund academic research. So it's hard to get, it's hard to get money to do this research and because it is scheduled, and it's schedule one in the US, as well as here, and that makes the research just a lot more expensive. So that is actually the thing that is difficult not necessarily getting approval. I see.

Nick Jikomes 1:00:26

So can you talk a little bit about where your funding actually comes from? Is it coming from private sources?

Katrin Preller 1:00:35

Yeah, a lot is coming from private sources. So private donations, etc. And there is the hefter Research Institute, which is supporting studies with psychedelics, for example, that is also but rely is also relying on private donations, of course, and we are lucky to be one of the few countries in the world if not the only one, where we have actually obtained governmental funding to do studies in humans with psychedelics. And that is really unusual. That is, is I don't think there are many countries in the world, which where that is possible. So we have, we have a bit of governmental funding, but not enough to keep our research program running.

Nick Jikomes 1:01:24

I see. So how did you actually get interested in this stuff? I mean, you do this for a living? How did you? How did you get into that position?

Katrin Preller 1:01:33

Yeah, so for me, I was so when I, when I studied psychology, and then moved on to doing my PhD. I was really, so the questions I had, were really to understand, you know, what happens in in our brain on a neuro chemistry level, that kind of makes us you know, think the way we think makes us feel the way we feel? So, what exactly what is the contribution of, you know, specific receptors or neurotransmitter systems that, you know, makes this makes our brain so complex? Right. And, and, yeah, and obviously, one way to study that is by challenging your drains new brain or changing your brain by, by drugs, right. And, and that's what got me interested in this type of research in the first place. And that's when I started doing the research on the long term effects of, of addictive substances. And I think there was, there was very, very educating and it was a wonderful research project, but it could not necessarily answer the questions about you know, what, what, you know, exactly in the brain happens in a causal way. Like, if you if you tweak, you know, this receptor system a little bit now, what, what, what does that mean, right? And, yeah, during that time, I learned about the research with psychedelics, and I was like, Yeah, wow, this could actually, you know, it's, it's a safe way to put people in and in an altered state of consciousness, so that you can causally investigate the the contribution of the serotonin to a receptor system to, you know, very complex process processes, like, you know, social cognition or emotion processing. And so my fascination for that was really driven by the scientific interest in the neuro chemistry of the brain. And then, obviously, working with these substances, and also thinking about their therapeutic potential. And is, you know, another thing that was highly fascinating for me that we might have something in our hands that is able to, you know, help people where it has been so difficult to find treatment for them.

Nick Jikomes 1:03:47

And so remind me your PhD was in neuroscience or psychology.

Katrin Preller 1:03:51

At neuro psychology, is it both actually,

Nick Jikomes 1:03:54

okay. Okay. And then what did you study in college? So we actually have a lot of listeners that are around that age, it seems, and I do get questions fairly often, that are of the form, I'm interested in this area. I'm going to study in college and I've no idea what to study.

Katrin Preller 1:04:11

Yeah. So I studied, I studied psychology with a focus on your psychology and clinical psychology. And so that was basically my, that is my path. And then, you know, during my PhD, and and later on, as well, I focused maybe a little bit more on the neuroscience side of thinking things in terms of you know, brain imaging, and and these these things. I think there are multiple ways, if you if you want to conduct these types of research there, there are a lot of ways of how to do that. Right. So our team is very interdisciplinary. So there are you know, there there MDS, of course, medical doctors, which is probably you know, psychiatry is probably right now the easiest path to get there. But obviously a lot of psychologists as well, and there is a computer scientists, they're their physicians, right? So there are multiple ways of how to enter the field, and there's no right or wrong, but what I am trying to tell people is that, you know, they should think about what exactly it is they want to they want to do, right, in terms of what are your questions? Why do you want to work with these substances? Do you want to work therapeutically, and then maybe computer science is not necessarily the right way to do that. And I mean, if you if you are more interested in, in the philosophy of these, you know, and on all the surroundings of that, I have quite a few friends who are philosophers, and are also working in this field. Right? And but it's really dependent on what exactly it is that fascinates you about that. And then obviously, also, like, Where, where are your general interests, and then you know, then develop these interests and develop the skills you need there. And then you can you have the choice, right, so if you are a highly trained neuro imager, then of course, you can apply these skills to psychedelics, as well as to basically anything else, right, if you're really good therapist, then you can work with psychedelics, probably, but you, you know, obviously can also help patients without without psychedelics, and just, you know, do do whatever therapy you're trained in. So, I think the really important part is to get a skill set that you are good at. And if you're comfortable with that, then you can add psychedelics on top of that. So I would never recommend someone who's a therapist and who's not you know, is not confident to treat a depressed patient, and that they should do that with the help of psychedelics, right. So psychedelics don't make your life easier. In that case, they might even make it a lot more complicated. So, um, you know, get a good training in what you're interested in, and then, you know, maybe then you can add the next layer of complexity to the Add by adding psychedelics.

Nick Jikomes 1:07:19

I see. So you guys mentioned that you were that you were doing some addiction related research. Can you speak to any other studies you have, that are ongoing, that you're particularly excited about? Or, or maybe just areas of investigation that you think are? Maybe the most important to explore next?

Katrin Preller 1:07:39

Yeah. So as I said, we cannot run like 10 studies in parallel. So the the ones which are running currently are the two clinical trials, psilocybin for the treatment of alcohol use disorder and psilocybin for for the treatment of depression. And obviously, what we're looking there is, you know, the, the efficacy of the substances as so are people doing better after the treatment? And, but we are also trying to really understand why. So basically, we have, you know, we do from ice scans and various tests and various questionnaires with our participants before and after treatment, trying to figure out what exactly it is that makes, makes them better eventually. And hopefully, and I think this is a, we won't be able to answer this question within one or two studies, right? Because there are so many hypotheses that we need to test, and why these substances could be beneficial, that will definitely need more work on doing that. And I think this is, you know, the big task for the future, to find out what what the clinically beneficial mechanism of action is. And there will definitely need more studies. And as I mentioned before, the other thing that I think we really should be looking at in the future is a is a way to test which therapeutic approach is best for treating and treating patients and the therapeutic approach itself might actually differ between, you know, substance use disorders and depression or other other illnesses. It might even differ for you know, cocaine versus alcohol addiction, like all these things are things that are unknowns for for the time being and I think if we want to develop these these molecules into, into into medication, then we should target these questions sooner than later. How

Nick Jikomes 1:09:41

common Do you know off the top of your head how common things like alcohol use disorder and depression are globally right now?

Katrin Preller 1:09:50

I don't know. I don't have the numbers on the top of my head, but they are very common.

Nick Jikomes 1:09:55

Yeah, I imagine it's actually gotten worse in 2020.

Katrin Preller 1:10:00

Probably I don't think we have the numbers quite yet. But yeah, it's, in these times, especially depression and substance use disorders are Yeah, are probably rising. Yes.

Nick Jikomes 1:10:13

Well, Catherine, I don't want to take too much more of your time. Thank you for doing this. This is definitely the longest are the furthest away geographically. I've done a podcast so far. Do you have any final thoughts you'd like to leave people with on this general area?

Katrin Preller 1:10:28

Um, well, maybe not necessarily final thoughts. But you know, if there are any questions or anything like, please don't hesitate to get in touch with me. And and yeah, I hope I can, you know, follow up there any questions?

Nick Jikomes 1:10:42

How can people do that?

Katrin Preller 1:10:44

So the easiest way is to is to contact me via Twitter. So I do read the personal message messages there. So and that's definitely the easiest way. But also, if you you know, just want to write an email. That's absolutely possible as well.

Nick Jikomes 1:11:05

All right, well, Katrin preller, thank you for your time, and I look forward to getting this up for everyone. Thank you very much.

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