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Psychedelics, Microdosing Psilocybin, Stress Resilience, Anxiety & OCD | Mikael Palner

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

Mikael Palner 3:53

thank you so much for having me on the show.

Nick Jikomes 3:56

Where are you joining me from?

Mikael Palner 3:59

So I'm joining you from from Denmark and more closely in Copenhagen where I live but my my research lab is in Windsor in the central part of Denmark.

Nick Jikomes 4:12

And what what's your scientific background and what is your lab study?

Mikael Palner 4:19

So my lab study is anxiety and obsessive compulsive disorder and neuronal circuits related to that. And it's actually a quite a, quite a journey from where I started out. I started out as an organic chemist and did my bachelor's in organic chemistry. And then I did a master's in bio bioengineering. So bio technology engineering. And from there on, I then took neuroscience and became interested in PET imaging and other kinds of whole brain imaging methods.

Nick Jikomes 4:59

What are some of the methods like what are some of the main technologies and methodologies that your lab is using today?

Mikael Palner 5:05

So we're the main overall method we're using is PET imaging of small animals.

Nick Jikomes 5:14

And so that's positron emission. tomography.

Mikael Palner 5:17

Yes, exactly. So you have a radio labeled drug, so a drug that has a radio isotope on it, that decays into electrons. And then when two electrons meet, they shoot out to positrons, and then we are two photons. And then we can measure those are the case with a positron shoots out these two photons that you can measure,

Nick Jikomes 5:44

I see so So at a high level, what would be an example of how you use that experimentally in animals?

Mikael Palner 5:50

Exactly as in humans. So that's the beauty of the technique is that it's completely translate translational, you use it a lot in humans, mostly in cancer research at the moment, because they we have some very good tracers to discover cancer when persons comes in, and they get scanned. But you can also use other compounds to study the whole brain and the brain function. And one of the most used tracers is a radio lab labeled glucose derivative. So it's just sugar with a radio isotope on it. And because the brain uses so much sugar, then you can actually inject this and then in people, you can see how much sugar are you using in different areas of your brain? And then that correlates into how active is that brain area compared compared to other areas.

Nick Jikomes 6:43

So in the case of like a drug, if you had a radiolabeled drug and you give it to an animal, you can, you would be able to see to visualize where exactly in the brain that drug is going.

Mikael Palner 6:55

Yes, so I spent a good time of my PhD actually developing one of the first or being part of the team that developed one of the first two of the first pet tracers for the serotonergic, five HTT to a receptor. So we had, the first one we developed was called M H M set, which is an antagonist of the five HTT to a receptor. So that's serotonergic receptor. And the second one we helped develop was called simpIe, 36, which is another, an agonist of the of the five HTT to a receptor. So then you can visualize where are all these serotonergic receptors in the brain, if you inject this drug, it will bind to these receptors, and you can get a map of the of the brain? Where are these receptors in the brain?

Nick Jikomes 7:47

And so what kind of like, what kind of spatial resolution do you get with PET imaging? Can you see down to level individual synapses? Or? Or is it more coarse grained than that? No, it's

Mikael Palner 7:59

more coarse grained, we can get down to about one millimeter at best. And then so and my lab and I, we study rodents and rats, primarily. So it, the resolution is, isn't super great, but it's, it's more functional and molecular than other techniques. So when we can see when we can see, for example, the five AC to a the serotonergic receptors, we can also compete with other drugs. And then you can actually see, if I have this drug that binds to the receptor, and I give this other drug that also binds to this receptor, then they will compete for binding and then you will see a decrease in binding over time if you if you if they compete with each other. So that's, that's actually really useful. If you want to figure out is this drug going to the brain? Is it binding to the right socket in the brain?

Nick Jikomes 8:56

I see so so by so by giving both of those things and using the PET imaging, you can see to with some resolute spatial resolution, where the drug is going, but then you can also measure how much it's occupying a given receptor.

Mikael Palner 9:11

Exactly. Yeah. And and if you have the big regions like frontal cortex, you don't really need a lot of resolution, you will still be able to quantitatively measure how many receptors that are and how much is this drug occupying different kinds of receptors.

Nick Jikomes 9:30

And so you said your lab studies anxiety from a neuro biological perspective, can you just talk a little bit about the what is anxiety? And what what sort of purpose what why do animals feel anxiety?

Mikael Palner 9:45

Yeah, yeah. It's quite interesting because if you look at anxiety and in animals, you actually have neurons sitting that are responsive to different kinds of anxiety. I always use this example or Uh, from people that have been looking at the fear of heights in mice, and they measured the, they lifted up the mouse from the table, and then they saw certain neurons in the amygdala was firing when they lifted it up high. And when they didn't lift it up, they were not firing. So you have these receptors sitting in the amygdala, or neurons sitting in the amygdala that are responsive to different kinds of dangers in your environment. And they try to predict if things are dangerous for you, and then they tell the rest of the brain, this could be potentially dangerous, you have to look out. And then if you go a step further, and you, for example, experienced in post traumatic stress syndrome, then it's a different kind of thing that goes on you have conditioning. So if you have even, even Pavlov, the famous Russian psychiatrist who did this experiment with dogs, where he had wanted to feed his dogs on the same time, or at the same time, he had many dogs, then he was ringing a bell. And then you notice that the dogs were actually starting to cool, before they got fed, just by hearing the bell. And that's a call to conditioning. So we can do that in an anxiety research as well, you can look at something called fear conditioning, wherever then prime an animal to the sound of a noise and to a food shock. And then after a while, it will respond to the sound of the noise as if it had the food shock, but doesn't get the future. And that's kind of some of the same things that are going on with if you get PTSD, for example, if you are a soldier going out and and, and you are in a cab in a stressful environment, and you get a fear response. And then you couple that with something else that goes on, you could be driving past a bakery shop and smell the smell of fresh bread. And then you cobble those two together which are a stimuli that's not not dangerous with a stimulate that it's actually very dangerous. And then they get cobbled together.

Nick Jikomes 12:13

And what are so when we think about things like stress and anxiety in the brain, and how they're generated, what are some of like the the brain regions and the circuits that you've looked at, or that you've studied that are important for either creating or getting rid of anxiety.

Mikael Palner 12:30

amygdala is generally seen as one of the most important areas, but actually, hippocampus we know is a region that is really important in retrieving and storing memories. So that also plays a big role. And then all of the frontal cortex is really, really key. Because you can, you can actually control a lot of your own anxiety just by convincing yourself that there is no monsters under the bed. Because I have never seen a monster. That's what I told my daughter a couple of minutes ago. And then you can reason yourself into believing, okay, if I never seen a monster, why should that be one found on my bed, and then you can actually lower your anxiety in that way. So the frontal cortex has a lot to say.

Nick Jikomes 13:17

I see. So the frontal cortex can provide a different kind of feedback to these other circuits in places like the amygdala that you might say are more responsible for generating the anxiety. But the frontal cortex is maybe involved more in inhibiting that response as you learn what actually is or is not dangerous. It

Mikael Palner 13:39

is also the other way around. It can also be the reason that tells tells you that a lot of things that that that isn't true, for example, how if you have obsessions, you will also get them generated in some areas of the of the cortical regions, and they will go down and never become ruminations and obsessions.

Nick Jikomes 13:59

And that I mean, I think that probably ties into the work that you do for obsessive compulsive disorder and compulsive behaviors and animals. So why is it? How do we start to think about that? Why is it that you? You know, my understanding is animals will often show compulsive behaviors, not always, but oftentimes in response to a strong stressor or in response to chronic stress. And so what is that relationship between stress and anxiety on the one hand, and these repetitive compulsive behaviors that you sometimes see?

Mikael Palner 14:30

You noticed repetitive behaviors in many animals. So if you go to an old school where they don't have enough space, you will see that go around the same circle all the time. But we can also measure that in less stressful ways. They will also broom. So you can if you induce obsessive compulsive disorder, we actually groom so much that their hands are getting, they lose their hair. So you can watch this In a behavior that I kind of put it in the same box, as humans are checking their phone, so, so you, you are checking your phone, you know, there's no notifications, but you do it anyway, because you're bored, and you just check it the same thing, rodents will just if they sit in a corner, and they have nothing to do, they were just the groom that differ and, and have a nice time about it. And then you can see if that goes up, it usually goes up if they're stressed. So if you're stressed them, then they will do more. Or if they are less stressed, they will usually go down.

Nick Jikomes 15:35

I see is this is this really grooming is basically an innate behavior. All animals have different types of grooming behavior. So you know, you we see our cats and dogs doing this all the time, mice do it, we do it, you know. And immediately when you think of something like OCD, right, you think of classic examples, like someone obsessively washing their hands over and over again, or you just thinking about someone who you know, bites their nails when they're feeling anxious. Because we also have

Mikael Palner 16:00

studies that have shown that if, if I start to talk to you about lice or something, then you will start to actually begin to touch your hair and scratch. And you will do that more if I if I talk a lot about that. So, yes, you're gonna induce it in humans as well, actually.

Nick Jikomes 16:19

And how do we start to think about this, this is maybe one way to think about it that like grooming behavior is sort of inherently or innately reduces anxiety, it feels you know, animals presumably feel good, or it feels, you know, feels good when we wash ourselves, we get clean we groom ourselves is is it sort of a natural anxiety lytic behavior. And that's maybe why it gets coupled to stress and anxiety responses. But it's sort of a behavioral attempt of the animal to ameliorate whatever the stressor it's encountering.

Mikael Palner 16:53

That can be that could be really nice if we could ask them and figure that out. It could be Yeah, so if it feels good, and you can know your anxiety by doing something or stress that that feels good, that it could be a natural way of lowering your your own stress level.

Nick Jikomes 17:12

And so how do you how do you measure in animals something like stress or something like a compulsive behavior? What does that look like experimentally,

Mikael Palner 17:20

we've video record that grooming, and then we assess how much they grew. But then at the same time, we also do other kinds of animal behavior measurements, like having an elevated plus maze, for example, that's a big X where they're lifted up from the ground, and you have two arms that are closed and two arms that are open. And then you can measure how much are they actually venturing out in the open space compared to being in the close space. And then you can can see if they are more or less anxious? The same thing you can do in an a big square, where you can see how much do they venture into the center of the square compared to how much do they venture out in the corners of the square. But then we also use PET imaging and looking at some of these circuits for compulsive behavior. One of the circuits is called the corticostriatal Philando cortical circuit. And you have, as I said before, we have the cortical regions that are giving a lot of signals down to another region in the brain, that's called the striatum. And down in the striatum, you have two kinds, two principal kinds of neurons that respond to dopamine. So they're called the dopamine T one positive neurons and the dopamine D to positive neurons. And they actually sending signals down to the midbrain. And the really interesting thing here is if you turn on one of these, then you will also turn on grooming, but if you turn on the other one, then you will lower grooming. So these two, the ratio between the turning on and shutting down at these two pathways are actually very much involved in grooming behavior. I see.

Nick Jikomes 18:59

So then I would imagine that the levels of stress or anxiety that an animal is facing are going to tune that ratio somehow.

Mikael Palner 19:08

Yeah, you will definitely get some dopamine release. And so that whole thing and then you can actually see how much are they binding to the T two and T one receptors? And how much grooming are they doing and this this dopamine release will be also a kind of a stressor for that animal.

Nick Jikomes 19:25

And so in humans and in animals, when you have something like obsessive compulsive disorder, what are the most effective treatments we have in terms of drugs that are used? How well do they work and what are they doing? What is their what is like their pharmacology?

Mikael Palner 19:41

Right now unfortunately, we don't have very many options. The most prescribed one is co2, serotonin reuptake inhibitors, SSRIs, or antidepressants, and then you give them in a very high dose for obsessive compulsive disorder so they act You have a lot more side effects than reported than people with depression normally do. And a lot of the time, they're not really that effective. So they can lower some of the anxiety. But they don't really do anything about the obsessions and the thought patterns you get, then. So, in the new drug realm we're getting, we're seeing some papers coming out with psilocybin and this psychedelic rock, and seeing that this may be a way to ameliorate some of the other symptoms of obsessive compulsive disorder.

Nick Jikomes 20:42

And so, I mean, have very many studies been done demonstrating that or is that something mostly that people are reporting anecdotally at this point?

Mikael Palner 20:51

There hasn't been a lot of studies, it's mainly anecdotal. But back and back before psychedelics, and psilocybin was a thing. The first clinical study that actually came out was from some people. Moreno, Adele, I can't remember his his first name, but they started OCD with psilocybin and showed showed very good effects on that.

Nick Jikomes 21:17

When was that was that quite a while ago?

Mikael Palner 21:19

It's in 2008, I

Nick Jikomes 21:21

think. Okay. Okay. So there's, there's some indication here in the literature, some hints,

Mikael Palner 21:27

and also two clinical trials going on right now. So there are a little bit of things going on.

Nick Jikomes 21:35

Yep. And so um, so there's some reason to think that psilocybin could be effective for treating compulsive disorders. And and you guys have suddenly started to study it. Yes.

Mikael Palner 21:47

Yeah. But both in high doses, actually, but also, we recently published a paper on on micro doses of psilocybin and looked at compulsive behavior and anxiety and stress levels.

Nick Jikomes 22:01

So what is the phenomenon of psychedelic micro dosing? And what What have people been saying about it?

Mikael Palner 22:10

The phenomenon really took off in Silicon Valley, and 2012 to 14 ish, where a lot of people were trying to get in on this productivity wave of being focused and productive in the tech environment. And then they took up taking small amounts that are non psychedelic, of psychedelic rocks. And that could be both LSD that could be psilocybin, or other types of psychedelic rocks, and they will take them. Often they would take them every second I referred day. And then they will report benefits to focus and stress. And basically, the Internet was starting to blow up with the good things that could happen when you microdose. If it's, if you feel you can get better from this, you can probably find somebody who said they got better from it. So there was a lot of reports, and it wasn't really clear what they was doing. So I got excited about it a little bit. And four, we have to figure out what is what in this story. Usually, when you have so many positive stories and anecdotes, there is some truth to to it, you just have to figure out what it is. So we started to study that in in rats, and then came out with some positive results recently.

Nick Jikomes 23:41

So so before we unpack your work, has any work on microdosing been done in humans? And if so, what has that looked like so far?

Mikael Palner 23:52

It's actually been quite a few studies, but they're mostly retrospective studies. So there have been like questionnaires or looking at Reddit and seeing what people have been have reported. And from those studies, you you have seen a tendency to a positive mood and some have mixed feelings with anxiety. And then a lot of people have also reported positive improvement in compulsive behaviors. Then there has been a few studies where they have looked at one or two doses of very low doses of psilocybin in in humans, and they have measured a lot of things. And that actually seems that if you take a as sub perceptional dose of psilocybin, you actually get impaired working memory so you, it doesn't improve your focus and it doesn't improve your working memory, at least not while the drug is working. It also makes sense in my head, I don't know if People have tried psilocybin and tried to to do a sudoku at the same time, it doesn't work out very well. So if we are going to take the premise that a small dose of the drug does the same as the last dose of the drug, just less than it makes sense that you're not, you're not gaining anything and not gaining focus from this. Yeah.

Nick Jikomes 25:20

But you know, a couple things could could be true. In theory, right? The small dose might not do the exact same thing as a large dose. That's very common with psychoactive drugs, that different doses do very different things. Sometimes. It could also be that, right? If you're chronically administering a low dose of the drug, every second or third day, the benefit might not actually come with the acute drug effects. It could be some other effect that you measure in the in the intervening time.

Mikael Palner 25:47

Yeah, yeah. So what we did in this study was also looking at, we didn't look at the acute effects. So we looked at all the effects that were happening one or two days after we ended the drug treatment. So maybe, but maybe we want to go do one or two, we have explained the study first, and then we can go into the details of what we have done. Because I think,

Nick Jikomes 26:10

yeah, let's do that. So yesterday, so you're gonna give micro doses of psilocybin to rats? You know, what is it? What is a microdose compared to a macro dose for a rat? And how are you guys determining what dose you should be using and whether or not it's a micro dose?

Mikael Palner 26:25

Exactly, we can't ask the rat, if it has a big trip, or doesn't feel the effect of psilocybin. So we actually had to rely on on what we what I developed during my PhD and earlier using the pet tracers. And then we had to give psilocybin and give this drug, a radioactive drug that was binding to the 5HT2A receptor. And if we get a large dose of psilocybin, we can see that it almost competes out the drug or the radio isotope completely. So we don't, we get a really big drop in the binding of the radioisotope and don't see any of that in the brain. So we can calculate how much do we need to occupy the receptor in order to have just a small dose of the drug of psilocybin bindings to the same receptor?

Nick Jikomes 27:17

I see. So yeah, does that make sense, you can you can give this radioactive drug to the animal, it doesn't do anything in terms of like psycho activity, it allows you to see where in the brain this thing is going. In this case, it's a drug that binds to the serotonin to a receptor, which is the same one that's going to be responsible for the psychedelic effects of psilocybin. So then what you guys do is you can give different doses of psilocybin. And the higher the dose, the more it competes with that radio labeled ligand for the five HTT to a receptor. And so by looking at how much of that signal goes away, you can see exactly how much of the receptor is occupied by this drug. And I guess by using that approach, you can you can settle on a dose where the animals don't probably show obvious behavioral signs of tripping or whatever. And also, you can calculate literally like that only a small percentage of the receptors are being occupied by psilocybin.

Mikael Palner 28:14

Yeah, the good thing was that one of my friends, Martin Matson did a did a study in humans in the exact same way. And there, they were looking at the occupancy of the 5HT2A receptor of psilocybin. And then they were asking them questions at the same time, how intense is your psychedelic experience? And then they could correlate the occupancy with the psychedelic experience and figure out what is the threshold of occupancy towards psychedelic experience. And they figured out that if you have below about 20% occupancy of the receptor, then you don't really have a psychedelic experience. So we use that the data from humans and said, Okay, we need to be below 20% occupancy in the rat, in order to not have it as a psychedelic dose.

Nick Jikomes 29:01

I see. So So you give a low dose, it's below 20%, serotonin to a receptor occupancy. When you give that dose compared to a larger dose, What differences do the animals display behaviorally.

Mikael Palner 29:16

So if you give a high dose to rodents, and mice, and particularly, they will make a really nice behavior that is shaking their head called the hatred, Twitch response. Rats do the same, but not to the same extent. But we can still measure it. And if you give a high dose, they will do a certain amount of it's called web pack shakes and rats, and then they will shake their body like a having a with a wet dog that shakes. Yeah. And you can count that. And then when we give a low dose here that we don't see that behavior, so we're not inducing any psycho activity on the breaths at this level.

Nick Jikomes 29:58

I see. So you see, you can measure behavioral difference. directly, you can measure the serotonin to a receptor occupancy of the drug. And then you also know from the human studies that you know, blow approximately 20%. People don't report psychedelic effects. And so all of those things sort of match up.

Mikael Palner 30:15

Yes. And then we have a non psychedelic dose in rats that we can use to treat them with over a period of time, so we chose to treat them for three weeks, because we knew from the literature that they're some of the positive effects of, of micro dosing weren't seen until at least a couple of weeks. So we chose to treat them for three weeks. And then we looked at behavior following the end of the three

Nick Jikomes 30:45

weeks, and is is one micro dose per day. It's one dose every second day, every second day, so every other day for three weeks. And rats are getting a micro doses of psilocybin.

Mikael Palner 30:56

And that was basically also just, we had to choose between every second day and every third day, and the rats have a little bit faster metabolism. So we thought that every second day would be good.

Nick Jikomes 31:09

And then so so in what context, are you doing this? What kinds of experiments did you do? And what did you see,

Mikael Palner 31:16

following the three weeks, we did the elevated plus maze that I was just talking about before where you're going to have to look at anxiety. And then we were looking at the open field test where the animals are running around in the corners or venturing into the middle. And we can also measure how much they're grooming at the same time. And then we did another test, that's called a shook sucrose preference test. That means that you, you present that and you teach it to like sucrose for that is 1% sugar in normal drinking water. And they tend to really like it once they get to know it. But then you present two bottles to them, you and then you present them for 12 hours, and they have free access to the two bottles of water. And then you can see how much do they drink. And usually they drink 70% of the sucrose water and 30% of normal water. If they then start to not drink sucrose, water, so go go down and sucrose water preference over normal water, then we say that they have an ad hedonic phenotype, that means that they are they're not feeling pleasure in the same way as they used to.

Nick Jikomes 32:34

I see. So Anhedonia would be Yeah, not seeking out pleasure as much as you normally do. And that would be that's something that's associated with like major depression. So

Mikael Palner 32:43

yes, exactly as if, or stress in general, or other types of psychiatric diseases as well.

Nick Jikomes 32:57

And so what were the basic results in terms of the effects of this three week, every other day microdose treatment.

Mikael Palner 33:03

So here, we we didn't see anything, actually, when we gave them a microdose. And that was good, because we we hope they wouldn't get wouldn't get an Atlantic. But what we did see was that in the control animals, were we. So you've got to remember, we are injecting psilocybin or Ceylon, under the skin, because we're not feeding them through the mouth. So we are stressful. That is a stressful experience. So if you have, every second day has an injection under the skin, it will hurt a little bit, it will be stressful. It's not something they like. But then we see that the animals that are getting settled in actually getting an hedonic and doesn't prefer the sucrose, the sugar, sugar water over the normal water anymore. And the microdosing animals doesn't care, they actually prefer them at the same mount all over the time. So they don't get the same effect from the stress that we are introducing to the animals as the control animals do I see

Nick Jikomes 34:07

so so in your hands, the micro dose of psilocybin seem to protect against just the stress of the experimental conditions themselves.

Mikael Palner 34:15

Exactly. Yes. And that why that may also be why we don't see anything when you when you do this and annum on people. So you don't get less stressed. But you don't get as stressed from stresses.

Nick Jikomes 34:29

Yeah. Right. So it's a subtle but important difference. Yeah. Yes. I see. Yeah. So you would have to, you know, if this is a robust effect, you would have to when you make these measurements, whether in humans or animals, you actually have to give them some kind of stressor to see how resilient they are.

Mikael Palner 34:46

Yes, exactly.

Nick Jikomes 34:49

Did you have any other differences between the two groups?

Mikael Palner 34:52

And then following that we were looking at the compulsive behavior and particularly we're looking at the grooming because we know that that It was a part of the, the compulsive actions of a rodent. And here we saw that they had an a lower frequency of grooming, but they groomed the same amount of time actually. But they were just not doing it as often as the as the control animals I

Nick Jikomes 35:17

see. So like a normal animal, you know, every so often every few seconds or whatever it will groom, it'll scratch itself, I don't know, 12 times on average, and it might do 10 Little 12 Scratch bouts per hour or something. And so every time they groom the groom to sort of the same way, the same amount, but the frequency of events, grooming events decreased in the microdosing. Exactly,

Mikael Palner 35:41

yes. And that is very tied to, as I said, we had dopamine before, but also to stress. So we know that if they are more stressed, they will grow more, if they're less stressed, they will groom less. So it could be an effect of distress. But it is also an effect just a positive effect on compulsive actions of the red that we see a very light kind of compulsive action. So we haven't measured the repetitive tapping, you can measure that on a on a lever press. So if they learned to press a lever press and you can measure how many times do they do that? They can go around and just press it compulsively at the end, or run in circles or some mice I actually doing somersaults just all the time? Yeah, but those are really bad, big compulsive behaviors that you can induce with drugs and stuff like that. But here we were just looking at normal animals actually. And sorry, reduction.

Nick Jikomes 36:41

And then you have these behavioral differences that you can see that are related to things like stress and anxiety. Did you look at anything inside the brain? Like what was it was anything changing inside the brain? Yeah, that's

Mikael Palner 36:54

that's, that's the good thing about working with animals is that we can actually take out the brain afterwards and limited look at specific markers in the brain. And we looked at all the most of the serotonin receptors and the receptor levels in the brain. So we looked at the five SC to a receptor. Because we know if we give a drug repeatedly, if you take high doses of a psychedelic drug repeatedly, then you will have a downregulation of the five, eight others, five AC to a receptor that they are targeting. So it will down regulate over time.

Nick Jikomes 37:25

And that's presumably why, you know, people who take psychedelics recreationally, if they take a psychedelic dose of psilocybin say, they need to take a look, they report that the effects are diminished for some number of days afterwards, then presumably, that's because of this effect, where the large dose causes your cells to get rid of some of those serotonin receptors for a while.

Mikael Palner 37:46

Yes, yeah, it's called tolerance, you build up tolerance to the drug, and you need more and more and more in order to but we measure that and with this microdose regime that we see here, we didn't see any of this buildup, they actually had the same amount of receptors afterwards, they also had the same amount of head switches. If the gateway, if we gave them a high dose afterwards, we're fairly certain that there was no tolerance build up at this level. Then we looked at other kinds of receptors as well, I didn't really see much until we looked for the 587 receptor in the thalamus. So inside the thalamus region, it's also part of this corticostriatal thalamocortical circuit that I talked about before. So that's why we went and looked in the thalamus. And we know that it's involved in sorting out what to do and what to act on and sorting out what kind of sensors come into the brain and what kind of sensors Should we do something about. So it's kind of like a filter for the brain. And here, we actually saw an increase of these 587 receptors, and the five SC seven receptors is sitting. So if you have two neurons that are connected, then you will have the transmitting neuron ends up in an axon that then meets in a synapse, and the five HT seven receptors are sitting on the end feet of these axons, and then controlling how much is released.

Nick Jikomes 39:20

So as opposed to the serotonin to a receptor is different in that respect, it tends to be on the dendrites on the receiving neuron. You're saying the five G seven receptor tends to be on the sender neuron, the axon terminal of the neuron sending a signal to another one. And what do we know about 5g? Seven receptors, what are they linked with?

Mikael Palner 39:41

And we don't know much about them, other than some of the new antidepressant drugs actually also have five st seven effect affinity, so they also binding to these, these receptors, and they do seem to be better than the old generation of antidepressant drugs. But other than that, We don't know a lot about it other than it's highly expressed in the thalamus. And not a lot of other places in the brain.

Nick Jikomes 40:09

Okay, and you said after the microdose, so after the every other day three week micro dosing psilocybin protocol, you saw, did you say you saw reduction of expression of this result,

Mikael Palner 40:18

we saw an increase in everies. Okay.

Nick Jikomes 40:22

And is that we did, were you able to tie that to behavioral changes at all,

Mikael Palner 40:26

we didn't look at correlation between these two things. I don't think we have enough animals to actually say something about the correlation between those things. We have, in this experiment 16, and the biggest group of animals where we did both measurements, but we did tie it to another marker of synaptic plasticity, that's called the SB two a, which is synaptic vesicle, to a, which is sitting in the axons as well and help put neurotransmitter back into the vesicles, before it's going to be released into the synaptic cleft. And this can, this target is, is also upregulated in these animals in the thalamus, but not in the cortex and not in the hippocampus. So we actually see that the effect Yeah, and the thalamus actually pretty robust, because we have two magnets that are going in the same direction.

Nick Jikomes 41:24

And so I would say overall, it sounds like, so you've, you've established a sort of bonafide microdose in rats, it doesn't give the behavioral effects that that a larger dose does, it doesn't result in tolerance, you've measured the receptor occupancy of the drug, and you've kept it under a certain amount. So it's so it's a real microdose, it seems, and doing that chronically for three weeks every other day gives you both behavioral changes, that you can measure in what the animal's doing, as well as these molecular changes, changes in receptor expression at synapses. And so something is clearly happening in the brain in response to microdose. What do you think that makes it more plausible than it was before that something is actually happening when humans or microdosing

Mikael Palner 42:13

thinks something is happening? It's, it's a matter of, if you if you can feel it, I think. So. Think about it like this, if you are perfectly happy and going around your day, and not really getting a lot of stresses on your life and your your yet just normal, quote, or happy, then I don't think you will see a big effect because you're not getting all this stress into your life and getting the stressors and but maybe if we find some patient population or some population of people where they are really they're feeling a lot of stress, and maybe they're feeling the stress are small and other people, I think in that portion of people it may be effective to a higher degree than in other people.

Nick Jikomes 43:04

Yeah, I mean, it might, you know, this is speculation, but maybe that's why this was like a Silicon Valley thing, because, you know, you've got people over there, you know, working all day in a stressful environment and trying trying to do a lots of difficult things. Maybe it's not a coincidence that that was the population that seemed to

Mikael Palner 43:23

exist, it's actually interesting. Now, I'm doing some talks about micro dosing as well. So I picked into when the first micro dosing experiments were actually happening. And I, I believe that it is as old as psychedelics, because if you look at the Native Americans, they were using peyote as, as their psychedelic experience that and those peyote bots, they, they have mescaline in them. And you actually need to have 10, or 12 pod bots to have a full dose of mescaline to have a psychedelic trip. But what they were doing during the day was actually just going around chewing one when they were going hunting and stuff like that. So I think if you're chewing one pod, but that is probably equal to microdose

Nick Jikomes 44:17

Yeah, and if it's having some kind of stress resilience effect, then it might be useful in that kind of context. If you

Mikael Palner 44:25

haven't eaten for a long time and out hunting and trying to find food enough for your family and stuff like that. So they they trace these pod bots and the use of these pod pods back to 5700 BC. So it's been used to

Nick Jikomes 44:43

people been using this stuff for a long time. Wow. So what what are you guys doing now to what sort of how are you going to build on this set of experiments?

Mikael Palner 44:55

Actually doing a we have quite a few studies with that are not part just yet, but with high doses of psilocybin and rats as well, and trying to look at some of the same circuits, and also see, see changes in the thalamus is one of the big regions when we, when we treat the animals with a high dose of psilocybin and then wait a week and then trying to look with, again with pet scannings and see how other circuits developing where the different changes in the brain happening. And we look at the thalamus and see that stuff is going on as well with a high dose. And then we

Nick Jikomes 45:33

are just gonna say, so when you saw these changes in the paraventricular nucleus of the thalamus, Did that surprise you? Were you expecting to see something in that particular region? Or? Or was it was it kind of a surprise?

Mikael Palner 45:48

It was a surprise to us that it was in that region, we were deliberately looking in the regions that were part of this circuit, that compulsive actions were made up, because we know that that was where we were going to look if we saw an effect of compulsive actions. So upfront, we weren't going to look in the thalamus. And then the frontal cortex, the striatum and those regions.

Nick Jikomes 46:14

And then, you know, it sort of sounded like you were saying, you know, you found this change in the five HT seven receptor in this particular region of the brain. It sounded like you guys looked for all sorts of different changes in different receptors, but you didn't see many of them didn't show a change was was that Is that a fair summary?

Mikael Palner 46:32

Yeah, we didn't see changes on the five AC two way or five AC to to see receptors. We also looked for the five St. Four receptors and didn't see anything I don't recall. I don't think that's in the manuscript, but we didn't see anything. We also didn't have any affinity to the five HD for receptors. Yeah, so we looked at a lot of different different things. And then now we have also begin to look at other types of psychedelic drugs and looking at if we can actually figure out because psilocybin is kind of its gained status as the gold standard of psychedelic drugs more or less, right. And if we go on in the world, probably every, if we're going to do a comparison between two drugs, like psilocybin will be one and then you're going to compare to another one and see, which is better. So we are starting to look into some of these drugs and just glue. Yeah, we we just looked into a form of Ayahuasca but doing it with pharmaceuticals. So it's called farmer who Aska. We mix the MAO inhibitor with DMC and then we try and see see the effects on the brain. And see if we get increased DMT in the brain when we mix it with the the mayo inhibitor that is that those two drugs are usually the ones that are combined and ayahuasca. And yeah, for the first first couple of experiments, we did a pilot study, just to see if we could increase DMT in the brain by mixing these drugs together, and it seemed to work fine. So now we can pass on and go on and experience that kind of cocktail a little bit more

Nick Jikomes 48:19

interesting. Are you doing anything with mescaline?

Mikael Palner 48:23

Not yet, I really want to do something with mescaline, we have done studies with LSD, five Meo DMT and DMT and four, four hydroxy tip t also. And mescaline, we we want to because it's a different kind of structural structure, the drug has a different kind of structure. But I don't think we will end up using mescaline because it has a really low affinity for the five HTT to a receptor, and we're going to probably have some therapists that has high affinity for the five HTT to a receptor. And in that regard, actually also a long time ago, we, when we develop these agonist radiotracers, to the brain, we actually found one, one drug that had a really high affinity towards the five HTT to a receptor and was very selective. So the five HTT to a receptor. So one of the N bomb compounds called the 25, c and n bomb. It binds really strongly to the five HTT to a receptor and it's really selective and doesn't bind to anything else. So

Nick Jikomes 49:32

is that the one that gives people very long duration trips? Yes.

Mikael Palner 49:37

And usually also very unpleasant. And there's been a few reports of people also dying from it. So it I wouldn't recommend anyone doing that.

Nick Jikomes 49:49

I see. I see. Interesting. So as opposed to the other psychedelics like psilocybin, that one is very selective for two A Yes. Interesting.

Mikael Palner 49:59

Yeah. psilocybin or citizen basically binds to most of the serotonin receptors, but this drug only binds to one. And yeah, people report that it's quite unpleasant and other people have been dying from it. So don't do that.

Nick Jikomes 50:15

And like, obviously, right now, all of this work with psychedelics and related compounds, it's getting a lot of attention, people are very excited. People are many people are very hopeful these could be a very effective alternative to the many psychiatric medications that we use today that are not that effective or not effective as we would like them to be. How excited are you in terms of psychedelics or psychedelic derivatives turning into, you know, prescribed and widely used psychiatric medications and humans? Do you think it's a it's a very, are you very excited, Are you skeptical is how much of this is hype?

Mikael Palner 51:00

I'm pretty excited about it. It's actually one of the first times where we have seen improvements in treatment options for psychiatric diseases. But I also think that it comes with a lot of of problems that we may have not seen before. Because for these drugs to be effective, I really believe that you need to have a good therapeutic session as well. So you need to have a therapy, in order for them to actually work. Work in a nice way. And that comes with a problem, right? Because then we need to have a lot of therapists. And that is an expensive way of treating people compared to when you just give them a drug and say go home and take this for two weeks, and then you feel better, then you need to start and incorporate the therapy into treatment. But I also think that is a really good thing, because therapy by itself also helps people, right. So I think it's gonna show some really nice things in the future, if we get if we can get hold of how these two things are going to be matched with one another. And maybe you don't need to give people a super high dose, it could be that they need a micro dose or a small dose that is just a little bit psychedelic. And that will be very effective as well. And maybe there's different doses for different conditions. That could also be

Nick Jikomes 52:28

what what do you think are some of the key questions in psychedelic neuroscience right now that that people are or should be pursuing? What are some of the questions that that will, we'll get answers to, but are still there are still big question marks in terms of how these drugs are working?

Mikael Palner 52:44

I think side effects are one of the really big ones. We simply don't know a lot of the side effects that could happen. So what are the How are this and psychosis related? Is it related at all, we need to know that if we need to start treating people and or not treat people that I endanger in that way, then in case of microdosing, there's a lot more complications, because we give a drug, there's there's a huge difference in giving a drug once and then not giving it again, compared to giving a drug every day or every second day for six months or longer. So people haven't there's not a lot of people who have been doing this. There's a lot of people who have been taking high doses and we know it's relatively safe. But there's not a lot of people who have been doing micro dosing even though it seems so on the internet, but we don't know anything about what are the long term consequences actually of taking micro doses of of psychedelic drugs or psilocybin. On your health, it could be targeting the serotonergic receptors in your heart. It's actually called serotonin serotonin because it was discovered in blood, right? So it's from serum. And that's why we've discovered the serotonin so there is a lot of serotonin in your blood.

Nick Jikomes 54:13

So so like the etymology like serotonin as in serum, or like stereotype or or like that?

Mikael Palner 54:20

Yes, exactly.

Nick Jikomes 54:21

I see. So there's a potential heart issue. Yeah, I've heard about this. Like Apparently, some of these drugs bind the five HT to be receptor, which is in the heart and other drugs that do this have been linked to, but also

Mikael Palner 54:35

just the five HTT to a receptor will. That's a vassal constrictor. So it will, it will increase your blood pressure and your heart rate when you take it right. And we know that from high dose of psilocybin that it will do that. But what are the consequences if you do that? Over a long time, we don't know. And, specifically, the five AC to be receptor is very X breath in the heart. And if you stimulate that, we know that from some of the weight loss compounds in the 80s, that were stimulating this receptor, they got taken off the off the market because they were giving valvular heart disease. So enlarge the muscles in the heart. So it could be a big issue. And people just haven't looked into that a lot. Yeah.

Nick Jikomes 55:29

Is there anything that you want to reiterate? Or see again, based on the conversation we've had so far that you think people should should remember? And take away? Huh? I got on the top of my head. No. So I guess the cliffnotes on your experiments are in rats, you figured out how to give them a micro dose, that's a true microdose you've got clear behavioral effects and changes in the brain. So micro dosing psychedelics in animals and non human animals is doing something. It seems like it's doing something pretty interesting that could be relevant for you know, treating different things like compulsive behaviors, or anxiety or distress, resilience, that whole sort of family of, of issues. And so that sounds like you said, this makes this does make you a little bit more hopeful that microdosing psychedelics in humans may be doing something we haven't we haven't pinpointed that yet. But there could be a there there.

Mikael Palner 56:30

Exactly. Yeah, that's, that would be the take home message of that paper. And but I really also want to stress out that people should really be seeking, seeking counseling or seeking conversations with other people before just throwing themselves out into doing micro dosing or high doses. It may not be a therapist or psychiatrist, it could also be a good friend or something else. But it's really important to go out and talk about your mental health problems, or issues or problems that are with other people, because that will help you in the long run and get better. So I think, Now, yesterday was mental health day and we should really try and be more open about our mental health in general, and be better at talking about I'm feeling stressful, or I have a bit of anxiety or whatever it is, then it we should be better at talking about it.

Nick Jikomes 57:32

All right. Well, Dr. Mikael Palner thank you for your time, welcome.

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