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Manoj Doss: Psychoactive Drugs & Memory (Sedatives, Stimulants, Cannabinoids, Psychedelics, MDMA)

Full episode transcript below. Beware of typos!

Nick Jikomes

Manoj Doss thanks for joining me. Thanks for having me on here. Can you start off by just describing for everyone who you are and what your scientific background is?

Manoj Doss 4:05

Yeah, so I'm a postdoc at the Center for psychedelic and cautious research at Johns Hopkins University School of Medicine.

My background is essentially in psychopharmacology or neuro psychopharmacology and cognitive neuroscience. So I kind of I call it cognitive neuro psychopharmacology, just to be complicated. And yeah, my training is really an episodic memory research and psychoactive drugs, although now I've sort of focused on psychedelics and other hallucinogens. But, you know, broadly speaking, yeah, my interests are in just various psychoactive drugs and how they impact cognition, especially episodic memory.

Nick Jikomes 4:48

So let's, um, let's break down some of the terminology for people before we get into memory stuff. So psychopharmacology, what is that?

Manoj Doss 4:58

I mean, I think this can mean a lot. Okay, there's a lot of times people will probably refer to how it impacts behavior, how drugs impact behavior. And so are not agency nurses, they have to be you could even look at like the neurotransmitters and how those impact behavior or cognition, so how they affect the mind. And a lot of times from behavior, we can then use that as a readout to infer what's going on in the mind. And so yeah, I think that's, that's approximately what some people would refer to as psychopharmacology. Episodic Memory, I think that was probably one of the things that, you know, I should probably define. So there's been some, you know, debate these days as to how to really section up different aspects of memory. And I think it really helps to describe some other aspects of memory in order to kind of contextualize what episodic memory is, or what we think it might be, but so Endel Tulving, he kind of came up with this distinction between episodic memory and semantic memory. So episodic memory is the is whatever she was like mental time travel, it's reliving, re experiencing an event or information from the past.

Whereas semantic memory is more kind of your fact based information. So to give you a, you know, an example people will always use is that you might remember, you might know that George Washington was the first president of the country of the United States, but you don't remember where and when you learn that information. So you have this magic number, but you don't have the episodic memory. And it does kind of become tricky as to, you know, what is semantic and what's episodic. Because not everybody has the same types of semantic memory. So I might, it might be a fact to me, that I grew up in Texas, but obviously, that's not a fact factual information to other people. And I think one way people have kind of distinguished these things, is if you take out certain regions of the brain that tend to be particularly important to episodic memory, does the memory of some of this semantic like information still remain. And so people could show that if you take out the hippocampus, people might still know where they grew up, which in other words, that information has become kind of Samantha sized, but it might be kind of devoid of certain details, like,

you know, really, really certain detailed information like where, specifically in the city, your house was, or, you know, specific details of the house like colors and whatnot. So I mean, it's certainly not a perfect distinction. But both of these memory types of memories can also be distinguished from other types of memories, such as fear conditioning, or kind of reward learning, which seem to be kind of more automatic. So for example, certain things might automatically trigger you and make your skin crawl. And that's not that's due to a memory that's there. But it's not necessarily strictly due to the episodic memory. But again, all these things sort of interact. And it's not a perfect splitting up of the systems. But episodic memory is typically what we think of as the human sort of reliving of information from the past.

Nick Jikomes 8:03

Yeah, it's always a little tricky to, to disentangle how much of these things, how much of this is semantic. When we talk about different forms of memory, how much of how much of it is just sort of a linguistic convenience for us, versus, you know, really being able to tie different forms of memory to distinct underlying biological mechanisms?

Manoj Doss 8:24

Right. Yeah, I mean, I think and I think that's kind of what the good thing about episodic memories, and I'm going to double back on the statement in a second, when we probably talked about some of my work. But one idea with episodic memory is that you it is somewhat reliant on the hippocampus. And so, you know, without without the hippocampus, you're not going to be able to encode new episodic memories, and even retrieving memories. Although people will say, you know, you get some amount of retrograde amnesia. So in other words, information before your hippocampus was taken out, maybe from the first two years before, maybe some of that will be gone. But you do have these episodic memories of the past. And more recently, people have argued that actually, well, those memories that these music, these hippocampal music patients have, are not quite episodic, they don't really, they tend to be more similar fantasize, they can be kind of ambiguous, vague, and, you know, not as specific as somebody who might have a hippocampus and can kind of recreate some of that information of the past and use that information to give you more kind of details. And I think what's also important is that all memory is kind of at least episodic memory is kind of a reconstructive process. And by having something like a hippocampus and filling in gaps that should be there we might also be aligning ourselves or allowing our memories to become distorted to and there's some evidence actually that patients have amnesia might not have as distorted memories of the past the things that they can remember that are semanticized. So yeah, I mean, when it comes to things like you know, fear conditioning, I think it's, you can show that for example, the amygdala seems to be pretty important for that without an amygdala can be difficult to fear conditions somebody Yeah, with with something like procedural learning. So this would be like learning to ride a bike, you can, in fact, people have done the studies with with hippocampal patients, and I think they'll do mirror drawing. So if you can, if all you can see is is the mirror and your hand drawing what's in the mirror, it can be quite difficult to learn to do that skill, you have to do everything kind of backwards and map on what's going to the mirror to your hand. And what's interesting is, I think amnesic, patients can learn that task over you know, a few sessions, just like your average person, I don't even I don't even know if their rate of learning is that much slower. But more than likely, my guess is by the 10th session that, you know, they're gonna be like, Man, I'm pretty good at this, we're doing it for the first time, even though because they can't remember the episode during which they were performing this task, during which they're getting practice the multiple episodes. So there's, you know, kind of, I think that when it comes to the brain, I mean, this is one situation, which I think the brain does a decent job at kind of parsing up what we know about the mind. I've argued a lot that maybe I haven't argued a lot, maybe more recently, I've argued that, for example, fMRI hasn't really taught us that much as much as we think we know about the mind. And a lot of the things that we've gotten from fMRI aren't even necessary that we could have done all these things without it just using, you know, sophisticated behavioral paradigms. But the brain knowledge here really does kind of constrain some of the what we know. And I think it's, yeah, I mean, I think this is this is a situation where it's not perfect again, all these systems interact, and there's ideas of statistical learning and the hippocampus can perform statistical learning. And that's not exactly an episodic memory by any means. So not perfect, but I think it's not a bad distinction for now.

Nick Jikomes 11:41

Yeah, so So before we dig into memory stuff, and the effects of drugs, let's unpack a few more things for people. So one thing that I think is really important to go over up front here are the sort of different phases of memory. So people often distinguish between encoding, consolidation and retrieval. So can you unpack and describe what those are for people?

Manoj Doss 12:03

Yeah, I'm so glad you brought that up. Because that's become a huge part of my work from even back at my, my PhD work. So yeah, so encoding is essentially the formation of memory traces, although, you know, it's still kind of, you know, you might still be forming them when you retrieve them as well. But it's the idea that you're you're taking information in and coding them in some ways, such that the brain can subsequently represent them. You can say it's the learning phase even. But the word learning is sort of, especially used more by non episodic memory researchers. And so you know, encoding is kind of, I think the the word that for any type of memory, you could say that you're, you're encoding something consolidation. So there's two meanings of the word consolidation. And I'm more using it in terms of the sale of cellular term, the cellular version of it, rather than the system's version. So cellular consolidation is essentially the phase after which synapses can be strengthened or weakened. And then there's, there's a, maybe an hour to six hours, something along those lines, during which they need to be stabilized. And so that's what some people refer to as seller consolidation, or synaptic consolidation. And a lot of times, you can administer a drug immediately after encoding, and you can mess with this consolidation process. So that's probably going to be more related to settler consolidation. There is this idea of systems consolidation. And systems consolidation is more of this idea that you're transferring memories from a temporary store to a more permanent store. So for example, the hippocampus encodes memories. And I was talking about this idea of memories becoming Samanta sized, over time, how they can be less episodic and more kind of fact, like, and then if you take your hippocampus out, you'll still have it. That's the idea of transferring memories from the hippocampus to the cortex. Now, there's been recent disagreement as to whether or not systems consolidation even exists. Part of the debate is whether or not those memories are qualitatively the same without the hippocampus. So the idea is that essentially, you have the hippocampus that points out, it points to various regions of the cortex, sort of like an index. And the memories are really coming from, I guess, you might say, the cortex with the experiences memories of the cortex, but the hippocampus kind of binds everything together. And after you activate these memories enough, over time, they can become independent of the hippocampus. And so some will say, well, they're independent of campus, but they're still basically the same. And so others have now argue that no, that's not true. And that really one reason that memories can essentially slip away or you know, it's not that they don't get consolidated is rather there's an interference has to do with the context, contextual interference. So this is like going way deeper into the wormhole that I probably was initially wanting to go into. But yeah, I don't know about semantic memory and anything that I talked about here about enhancing for

sample memory from post encoding drugs is really talking about cellular consolidation and not whether or not these memories are becoming more Samantha sized and whether or not they're transferring from the hippocampus to the cortex or not. And then lastly, there's retrieval. So retrieval is when you're retrieving memories, or when you're remembering something. And so the, you know, one of the big points here, when you're talking about drugs and different phases is this is a problem that's existed throughout like psychopharmacology research, since, you know, for a while now, and it's really unfortunate that such what seems like a such a simple idea has become overlooked. And people have missed really interesting effects. So you can administer a drug, and then give somebody in an encoding phase. And so you show them bunch of stimuli, like pictures, for example, show you a picture of a bottle, I show you a picture of a card as a picture of, you know, a piece of paper, etc. And then later on, you can have some waiting period, you know, or you can test their memory immediately afterwards. But if you test the memory immediately afterwards, you know, you gave them a drug, and it's impacting the encoding phase, and you test their memory immediately afterwards, you're now going to be likely to impact the retrieval phase when their memories are going to be tested, you're also potentially affecting the consolidation phase. And it's hard not to impact the consolidation phase, because most drug effects persist beyond this encoding phase, right. And so what you can do at least to dissociate, effects and consolidation is you can give people you can show what happens when you give a drug immediately before encoding. And then you can show what happens when you give a drug immediately post encoding. And then again, if you test their memory, really afterwards, you're gonna run the risk of impacting the retrieval phase. So usually, what you should do is probably have like a 24 hour 48 hour delay, or even some people will do five days or one week. And then you're very unlikely to be impacting the retrieval phase, because all the drug effects have washed out.

And then finally, you have your retrieval phase. And so you can have an encoding phase, if you give a drug Amelie post encoding, you're going to impact probably the consolidation phase, and then you test your memory, you're probably going to pack both consolidation and retrieval phase. So instead, yeah, encode 48 hours later test their memory. But before you test their memory, right before give them a drug, and that is now going to impact strictly the retrieval phase. So I think there's been a lot of, I mean, I think I can I can use the best example would be probably with cannabis, TA for some of those examples, let's just kind of summarize where people so encoding, consolidation, and retrieval and encoding is basically you're learning something new, the information is being taken in by by your mind, the brain is doing something to encode that information. And it may or may not be consolidated, you may or may not remember it later. So you know, if you try to teach me something, whatever that may be, I'll sit here and pay attention to it. I'll, I'll learn it with the intention to learn it to try and remember it. I will then say go home and sleep on it overnight. The next day, I may or may not remember everything I learned some of it, I may remember some of it, I may not that general process, which is usually happening in the hours after you learn it is called consolidation and involves the strengthening or and or weakening of synapses, basically. And that will at least in part, determine whether or not what you originally encoded, stays in memory, ie it's been consolidated. Yeah, it's been I mean, it's, I think it's more the stabilization of the strengthening and weakening of synapses. But yeah, exactly. And it's also the case that you can also just not encode things and not remember them for that reason. But we do try to have people perform certain tasks during the encoding phase to make sure that they were the stimuli were attended to.

And you know, this is this is actually a criticism from people who don't like experimental psychology, they'll say, you give people a drug, and it's garbage in, garbage out. And it's like, you know, they're just generally they report they it's funny, because some of these people will say, with psychedelics, there's generalized disengagement. That's probably true of all drugs, like this is what I refer to as psychedelic myopia. I think that all drugs will probably make people somewhat disengaged, but we do try to have them perform certain tasks during coding and make sure that they weren't coded. And then as you said, that it's the issue of how well do they consolidate later, and a lot of times there's an interaction between encoding and consolidation, but then, yeah, keep going. And then the last phase would be retrievable.

Nick Jikomes 19:13

Right? Yeah. Yeah. So So in a lot of the work that you've done, and others have done that we'll talk about, right, there's this. There's this challenge of okay, if you want to understand how a particular kind of drug affects memory, you've got to be careful about if you're giving the drug, you know, early or later in the learning process. Are you giving it during encoding are you giving during consolidation? Are you giving it during retrieval on a subsequent day, say, and part of the challenge there is that the drugs are, you know, if you give someone a drug, whether it's a sedative, or stimulant or whatever that we'll talk about, they will tend to be in your system for hours at a time. So you have to be very careful about when you administer that drug, whether it's at the beginning during encoding, whether it's during the consolidation phase, and that's basically what you're starting to say. Right?

Manoj Doss 19:58

Exactly. Yeah, I mean, as soon as you think it's impossible to decouple encoding from consolidation, for example, even if your drug wears off halfway through the encoding phase, it was still on board during the first half of the stimuli that you showed somebody, unless you like, I think, like optogenetics, probably in animals will be the one way to differentiate things where you can literally just turn it on, turn on a set of neurons, for example, you know, in the moment that something has been coded, and then immediately silence it. But that's, you know, that's not something we can do in humans. But as I said, you know, I think you can do, you can see what happens when you strictly impact something like consolidation, to show that, hey, look, the effect is far different from what we get when we administer something during encoding. And then you can say, Okay, here's what happens encoding, here's this completely different effect that we get a consolidation, these are dissociable.

Nick Jikomes 20:51

I see. So we'll, we'll speak a lot about episodic memory in particular. And just as a reminder, I think you said episodic memory is basically the the it's tied to the ability to do basically mental time travel to remember where you were when you were, so there's a sort of spatial and temporal quality to it that you can you put yourself in some time in the past when you learn something, or project yourself into the future and things like this.

Manoj Doss 21:18

Oh, one second, my partner's asking me a question. I know that's. Cool, I'm back. Sorry about that. Okay. Yeah. So yeah, that's exactly what it is. It's mental time travel. It's the reliving of information from the past to be differentiated from something like, yeah, procedural learning where you can learn to ride a bike. And, you know, in fact, a lot of times, I think people have shown that if you try to use episodic memory for certain skills, like, Okay, if I swung last time, a little bit in the wrong direction, if I just go a little bit higher, and you're a pro at this, you can actually make yourself worse. So that comes, you should rely on your procedural memory system to not use your episodic system, at least for professionals and some of these these sorts of areas. So yeah,

Nick Jikomes 22:08

yeah, no, I think that's, that last thing you said is probably intuitive to a lot of people, right, the idea of, you're learning a new skill, or you're using a skill that you already know, the idea of overthinking it.

Manoj Doss 22:20

Right. Yeah. And I think, you know, it is interesting, because I think it's on a Shapiro who's showing that with certain types of motor learning, that you initially when you're learning, then you do use something like the hippocampus, whether or not you're actually explicitly using episodic memory is probably unclear and a task like that. But my guess is when you're initially learning, you're kind of, you're using it a little bit more, but when you get better at it, it might start to interfere. And exactly, it's like you're overthinking it, and there's probably certain stages throughout of learning where sometimes use it sometimes don't, and then you know, eventually becomes this trade off. And then eventually, you probably shouldn't use it much at all. But yeah, you know, here, I'll be talking about episodic memory. And I guess, just to complicate things further, there's going to be two types of two processes, we think about an episodic memory. And one of them is recollection, which I think is more of our standard way of thinking about retrieving information from the past. So where and when information. You know, so I might, for example, see, see you one day at a conference. And I'm gonna think to myself, you know, I've, you know, I can remember that I met you on this podcast, I can you know, that you had the P Callen, T cow in the back in your back room. Remember that you did your PhD in 2016, et cetera, et cetera. And these are all details of record recollections that I can, you know, recapitulate from, you know, when I when I initially encoded them. familiarity, though, is this weird sort of form of memory, you might think it kind of sits between almost semantic memory and episodic memory. It's almost like the recent activation of the semantic memory or perhaps even certain perceptual features. And so it's more just this feeling of knowing without having any kind of corroborating evidence. And typically, these things co occur familiarity and recollection. And I think that sometimes the way I describe familiarity might not necessarily be the same way that other dual process theorists describe familiarity. So, you know, don't don't take my word for exactly what it is, you know, to go do your own research. But Familiarity is the feeling of knowing and so. So, you know, one distinguishing thing that tolling said was that episodic memory involves auto noetic consciousness. So placing yourself in you know, a given situation and this could be even automated unconscious can even be for example, future simulation. So thinking about what you'll do the future and placing yourself in that situation, where a semantic memory is, is doesn't involve this sense of self right and evolves this kind of universal fact. And so familiarities also, if you ask me involved in basically this noetic consciousness, this feeling of knowing that something is there without any kind of corroborating evidence. And you know, what's interesting is that people want to under psychedelics, they talk about, you know, the self being dissolved, but then yet there being this noetic quality, and as we'll discuss, to some degree recollections impaired under psychedelics, familiarity is either spared or even enhanced. And so there is this feeling of knowing that I think comes with familiarity. And it's, and it's interesting, I guess, maybe I should give you the example of how you can be familiar in the absence of recollection. So I gave you that example, if I can remember where, when, et cetera, you know, if I see you at a conference, well, there's also this situation I think we've all had where I can remember, I can see your face and say, You know what, you seem highly familiar, but I can remember where I met you, when I met you what your name is no details come to mind. I think we've all experienced that. And that's like an example of familiarity in the absence of recollection. Another example that I think, you know, and that's, that's, you know, one example everybody always uses. Another example that I've I've sort of gone through is when you watch a movie, I don't always remember the movies I watch very well. And yet, I'll see a movie sometimes if you like, oh, wait a minute, I've seen this before. Actually, this happens with Adventure Time, I watched, I watched the show Adventure Time all the time. And, you know, the episodes are really short, they're not really linear. And so it's kind of hard to always put that together into a single sort of narrative. And then I'll be like, Man, I've seen this episode before yet. I can't predict what's about to happen at the very end. And then there's a complete surprise that happens at the very end, and everybody around me might be surprised. I'll be like, not surprised, you know, by the twist? Because, yes, you know, it felt familiar in the absence of being able to actually recollect what was going to happen at that end.

Nick Jikomes 26:43

Yeah. And I think this is another case where this will be very familiar to a lot of people this distinction whether or not they've formalized it, in their mind, no recollection, compared to familiarity. Like if you asked me who was the first president of the United States, and I say, George Washington, I'm clearly inaccurately recollecting a fact that I've sorted memory. But then you might ask me, who was the second president? And I might say, I don't remember. But then you say something like, was John Adams, the second president? And I immediately go, yes, he definitely was like, I recognize it when you say it that way. Like, I'm familiar with that fact, even though I couldn't recollect it.

Manoj Doss 27:18

Yeah, yeah, I think you know, and I think and that's exactly the kind of situation you were familiar with it. But again, I guess that's sort of interesting, where you're kind of getting at this idea of, well, it's a semantic memory that you didn't have access to, and you didn't have a recent recollection, to maybe bootstrap off of the semantic memory. This is where you're kind of maybe getting interaction between semantic memory and episodic memory. So if I took your hippocampus out, chances are you still would know that Adams was the second president, which gets to sort of the semantic memory, but that the access to that information wasn't easily there. But if you'd had an episode at which you were recalling and recollecting, you could recollect the episode of you can recollect the episode of using the semantic memory of retrieving that semantic memory. Now, you can kind of use recollection to help your cue your semantic memory. And so yeah, I mean, there's kind of, again, this is where I think that distinction, you know, can get a little murky, and what this, you know, familiarity thing is, and sometimes it's also just the the ease of which you process information. So, you know, even just seeing a, for example, if I like walk you through a layout of house, you and you've never been there before, but you're like man, this feels oddly familiar, you might be because this layout of the house is exactly the same as something as you know, your own house, except I have different things. Instead of having a painting in that corner, I have a hole in the wall. Instead of having, you know, a fireplace here, I have a litter box for a cat or something. And it's like the same spatial layout, but there's just kind of different sort of features. And then there could be something familiar, because it's the ease with which you process that information. And so there is this idea that fluency of processing, whether that's perceptual or conceptual feeds into this feeling of familiarity. And one more thing I wanted to mention is that you can get this familiarity the absence of recollection, and you can also get a recollection of the absence of familiarity. And I think the best, you know, example of that is patients with Capgras syndrome. And so, you know, I might see you one day and be like, you know, what I can I can remember that we did this podcast together and that you had P calla T cow in the background, but you don't feel familiar and therefore, you're an imposter. Or you must be the twin, you know, or something like that, right? And that's actually something that people will go through. And so it's kind of this you know, usually these these processes don't decouple because when they do you get some bizarre phenomena, like, for example, something like that is not good. If you don't have the noetic consciousness that goes with the recollection. There's you might think that there's you're in some you know, simulation or that you know, somebody is a an impostor or something along those lines. So And similarly if when you have low recollection, but Familiarity is high, you don't have recollection to constrain why something feels familiar, you can get other sorts of bizarre phenomena like deja vu, or feeling. Here's the interesting when you get feelings of insight in that situation, even when you're not actually having a vertical insight, and this is sort of, you know, one of the things I've mentioned with psychedelics is that if they do impair this recollection, process, enhance familiarity, this might be where this noetic quality comes from. And people are now going to feel like they there's an insight that they're having, even when there's none to be had. And I think that, you know, this is why we have to be a little cautious about interpreting what we think is in sight. And also what's interesting is people can now like Miss attribute feelings of familiarity, to for example, memories that didn't exist. And that can result in a false memory. I think similarly, people can miss attribute feelings of insight, or feelings of familiarity that gives you this feeling of insight onto ideas that probably aren't actually that good, are scrambled ideas of some sort. And this can result in Oh, I had this crazy and today's can't bring it back to reality. And it's like, yeah, believe you. Yeah, no,

Nick Jikomes 31:04

I think deja Deja Vu is a great example of how familiarity and recollection can be decoupled. And one that, you know, many people will have experienced directly. I mean, Deja Vu is familiar familiarity in the absence of recollection, that's, that's actually experientially what what we mean by that. And I think the majority people have had deja vu, at least to some extent, at least at some point. So so we all have firsthand experience with that.

Manoj Doss 31:28

There's also job a foo, which is essentially the opposite. It's recollection in the absence. And I think the example people will always use if you say a word enough times, and you're like, wait a minute, is that actually how that is that actually a word? Or is that how that is said? And I think that can be sometimes you can get this weird brain fart, we're like, wait a minute, the familiarity doesn't map on to this anymore, but the recollection is there and something feels odd about it. And then there's Preska boo, which is essentially the feeling of insight, you're not actually having one. So there's, it's interesting that we've all these French, like sayings have come up for these distinctions between recollection familiarity and presumably independently of these distinctions of recollection and familiarity. But some people have actually gone out and tried to study them in the absence of drugs like Lyn, reader and Nonlin. Reader. Sorry. I keep forgetting your name, but I will remember it eventually. And she

Nick Jikomes 32:21

you know who it is. But you can't recollect it in the

Manoj Doss 32:23

moment. Exactly. Yeah. familiarity. If you gave me the name, I wouldn't know it. But I can't recollect her name off of the papers that I've been reading. Well,

Nick Jikomes 32:32

one more thing that I think we should unpack up front here to you sort of hinted at it, you know, when you when you mentioned things, like false memories is the sort of playability of memories themselves. And so to what extent you know, so if you learn something, and then you remember it, you store it in your memory for the long term, that memory has been consolidated. And then every time that you recall that memory, you're retrieving the memory from, from its storage in your brain. And, you know, my understanding is that every time you do that, there's actually like a reconsolidation. So every time you recall something, there's actually room for that memory to be tweaked a little bit. And in fact, this, this may even happen quite a lot. It is, is that true? And can you talk a little bit about how pliable memories are after they're initially consolidated?

Manoj Doss 33:16

Yeah, definitely. So again, this is going to be very dependent on you're somewhat dependent Anyways, on your definition of consolidation, whether or not something has been, you know, Samantha size to the cortex, or whether you're talking about just, you know, recently encoded information that still hasn't quite stabilized yet at a synaptic level. But I think either way, you get this Yeah, as soon as you retrieve the memory, you're allowing for the possibility of strengthening it, weakening it, or distorting it. And I mean, that was a lot of my work. Were in grad school, actually, I had a whole separate area, I could have written a whole dissertation on that had nothing to do with drugs, about how we can distort people's memories through different routes of processing information. And so you can give people a bunch of perceptually related things, I can show you a, you know, I can show you pictures of a scrambled stimuli of like limes and oranges and grapefruits later on, ask you Did you see a picture of a lemon? And you might say, Yes, I can show you I can just show you the words lime, orange, and grapefruit. And because those words are going to be processed and feel quite familiar. You can now Miss attribute that to, let's say, a mental image of a lemon. And you'll say, Yeah, I saw a picture of a lemon even though you never actually did. And so yeah, I think there's ways in which essentially, you know, after you encode information that they it's, you're now opening them up, they're now susceptible to distortions, and every time you retrieve information, they you know, it can so for example, if I see you at a conference, and then I say, oh, yeah, you were wearing a green shirt during this podcast, you're like, Yeah, I was wearing a green shirt. Maybe if you typically wear green shirts, that's gonna seem something plausible now forever in your memory. Do you remember that we did this podcast with a green shirt turns out, you're wearing a gray shirt, you know, that's an easy way in which you remember, memory could probably be manipulated. But yeah, I think there are, for example, more Samantha sized type some memories, let's say these these ones that might be consolidated at a systems level, whether or not you believe in systems consolidation are not, but they can become almost factual, it'd be very hard to, to kind of disrupt those types of memories. So it's, you know, you can do a lot of brain damage to me, and it's going to be a while before I forget that George Washington was the first president of the country, it's kind of like patients with Alzheimer's, they'll lose the ability to form new memories, they'll lose the ability to remember recently encoded information like the doctor that they've now met several times over. But you know, their mother's face, it takes a minute before that goes away, not to say that that doesn't, but at least the person that's most prominent in their life, they've probably some fantasize their face to some degree, that takes a minute. And then of course, when that happens, it's a really, you know, scary and terrible situation. But, you know, they'll probably lose some other types of factual information rather than the like, really hard coded ones. And I think that those are the types of memories though, ironically, sometimes that we do want to manipulate during treatment with things like psychedelics. Given that, you know, we can, our sense of self can become very hard coded, for example, and I'm a terrible person, because I did these things, and every day is the same and you know, there's nothing worth living for, etc, that can become a very kind of normal way of living, or, you know, with PTSD, you know, people talk about how this traumatic memories really just take on a life of their own, that becomes who you are. And so we do want to disrupt those types of memories. And in rodents, you can show that you can take these memories that are no longer reliant on the amygdala or the hippocampus, and you can do certain things, you reactivate the memory. And now places in the state that's labile, you inject a protein synthesis inhibitor into the amygdala hippocampus, because now they're supposed to become reliant on the hippocampus and amygdala again. And then it's not immediately they don't go away. But the next day, when they reconsolidate, they have some time to destabilize with that protein synthesis inhibitor, you can now delete those fear memories that are you know, that were really hard coded into the cortex. In humans, it's been a lot more difficult to do. And this is, you know, kind of one of the interesting sort of sides to this idea of looking at recollection, familiarity of psychedelics really do enhance the coding in the cortex, you might imagine that learning information through a enhanced route, the cortex, might be better able to disrupt or overwrite some of those hard coded memories, though, some fantasize memories in the cortex. But this is definitely somewhat speculation.

Nick Jikomes 37:36

Well, I mean, this sort of gets in an anchor point here, for people who are familiar with the podcast and this work generally, the work of MDMA assisted psychotherapy, if you think about it, what you're really doing in those clinical trials is you are having multiple therapy sessions, and then you're introducing the MDMA. In other words, you're getting the person to talk about their trauma, to recollect their trauma and call up those memories. And the idea would be that every time you're retrieving those memories, the synapses in the circuit storing them are in a labile state, which means, you know, they can potentially change and the MDMA would seem to be somehow taking advantage of that. So when you introduce the MDMA, while they're in this state of recollecting their past trauma, the plasticity or the potential of the memory to be changed, allows them to actually decouple the emotional, the traumatic sort of emotional, salient, emotionally salient part of it from the, the recollection of the episode itself. And that does seem to be what they say afterwards, right? When this therapy works, as it often does, people aren't forgetting what happened to them. It just doesn't carry the same kind of emotional weight that it used to. So some, somehow the sort of facts of what happened to them are becoming decoupled from the emotional salience that used to be associated with those facts.

Manoj Doss 38:58

Yeah, and I think that there's there's other aspects to this, like one is that, you know, I was kind of I was saying that in humans, it's been rather difficult to really show, you know, reconsolidation. I mean, it's kind of been there, but a lot more difficulties compared to rodents. But what you can think about is that Well, one reason is that we're there's a couple of reasons. One is that it might be difficult to trigger that reconsolidation process such that the memory becomes labile. But we have this drug that supposedly induces plasticity or meta plasticity or whatever you want to call it. I think, you know, some people, there's been some argument now between David Olson and Google when about what kind of plasticity is important, and you might increase the ability ability to Label Label allies to make the memory more plastic. And so the other thing is that sometimes you really need a really hard retrieval to like make a memory labile. And so it's like so people have shown for example, a week sort of retrieval or triple that doesn't have good prediction error. doesn't end up being very useful and triggering the consolidation process. But at least with something like psychedelics, maybe these two things are directly linked to that plasticity inducing mechanism as well as the, they enhance your mental imagery. And so, I'm not going to say that the retrieval of whatever, whatever you're retrieving is more vertical, it's more true, but at least it could feel more true and really kind of trigger that as well as one more thing that I've thought about is that, you know, I've wondered, you know, you can take a rodent that doesn't, has had a very impoverished sort of, you know, life, it lives in a cage, you know, white sterile environment. And when you play it a cue that is now associated with, you know, a shock, that is the first time it's heard any sort of, you know, sound like that, and it's gonna be very easy to delete that one memory, right. But as humans, we're hyper associative and anything that's, you know, kind of scary. In fact, one of the issues with PTSD is if there's an overgeneralization where maybe the sand from the desert, I've used this example all the time, Sandy from the desert, because you fought a war in Iraq, that's going to now be associated with trauma. But now, you go to the beach, the sand is there, and now you're overgeneralizing, you're going to have like a full blown episode because you know, you're at the beach, you know, and I wonder if you were to take, let's say, a New York subway rat, rather than, you know, one that's been raised in a an impoverished environment, that New York subway rat has heard all kinds of beeps and tones from the New York subway from people's cell phones, whatever. And my I would wonder if you try to delete the memory, the way that people have done this and these reconsolidation paradigms, if that hyper association that the brain is known to do with actually fill in the gaps, and you're not actually going to be able to delete it very well, unless you delete all the associations that comes with that tone, that smell associated with a traumatic shock. And I think one thing that, you know, psychedelics have kind of been shown to do is, at least one study showed this is that you can get enhanced kind of semantic priming or enhanced semantic spread. And so not only are you you know, making certain memories, labile it's perhaps making a lot of other things labile that are related to those. And so if we can not just rewrite the like single trauma, but all the associations with that trauma, I think that could also be useful. And, of course, there's, you know, certain hard coded things you wouldn't ever want, you know, rewritten and I think the example I've used is that you see a chunk of metal, you shouldn't think of it as a chunk of metal, you should know that that's a car that automatic mapping between the percept to the concept should never be broken, or else, you're gonna find yourself walking the street with chunks of metal and then find yourself hit right, where the mapping between what is red and green, you don't ever want those two things to mix up. Or else again, you're going to run a red light, you know, and people do sort of talk about sometimes under after psychedelics, that these really hard coded things do start can become a little plastic and people you know, for example, HPPD, they might get forever color constancy. So that's kind of now a hard coded thing that might become kind of broken down, Samantha size, you know, sort of way in which you know, in the cortex, that probably is hard to break. But if it does get broken, really bad things can happen. And I think this is where we have to be really careful of what we're overriding in the cortex, assuming these drugs really do enhance information processing, psychedelic, specifically, in the cortex.

Nick Jikomes 43:10

So in starting to think about how different kinds of drugs affect memory, you know, at different phases or different kinds of memory. Let's talk a little bit about what like what distinct classes of drugs are like, what is a class of drugs? What makes a what makes something a sedative versus a dissociative at the level of the chemistry in the pharmacology? How do you start to think about that in the abstract?

Manoj Doss 43:34

Yeah, so this is something that I've, you know, it's not totally arbitrary how I've parsed things. You know, other people have have kind of made similar sorts of taxonomies for drugs. But yeah, I've sort of classified drugs that alter the GABA a receptor as sedatives, I know that, you know, other drugs can be sedating THC can be sedating. We know that opioids can be sedating. But just for the sake of simplicity, I've started referring to sedatives. There's anything that modulates the GABA a receptor. So GABA is your main inhibitory neurotransmitter in the brain. And so, for example, when you're having a seizure, they might give you something like something that modulates the GABA a receptor to kind of mellow out the activity. Alcohol has many different effects. But probably its main effect comes from modulation of the GABA a receptor, you also have a GABA B receptor. And there are some drugs that modulate the GABA B receptor such as GH V. ghp also seems to modulate the GH B receptor. And so it seems to have this weird biphasic effect where you get this initial almost MDMA like effect at lower doses and then I think it can really sedating at higher doses when it hits the GABA B receptor. And you do have other drugs like Fen Fen abuse and some other ones that modulate the GABA B receptor and clearly they haven't slept a different effect. I think GABA A's is probably more sedating. But you know, I'll eat my words when somebody shows me some good GABA B data. But other drugs that manage modulate the GABA receptor, you know, and all these drugs do kind of share some effects is so you've got alcohol, you've got benzodiazepines like Xanax alprazolam. Any of us have been traveling etc. Traveling is also sometimes used as a in anesthesia. Then you have Ambien. So zolpidem, this is you know, a, these are drugs use for sleep aids. And so all these drugs, interestingly enough, yeah, you take a lot of them, you become addicted. They're the only drugs that'll kill you if you go off of them immediately because you can get seizures. So you keep inhibiting the system over and over and over, then you get a rebound effect. If you if you go off of them. Opioids, you'll feel like hell after going off of it, but it won't kill you necessarily. Stimulants, you will feel depressed a lack of energy, but it won't kill you. If you go off of them. I think these are the the GABA a drug. And actually with alcohol, when people are withdrawing, they give them benzodiazepines. And then you take benzodiazepines, you know, low doses over time and hopefully try to come off them eventually.

Nick Jikomes 46:08

So so. So at a high level, basically what you're saying is what allows you to care to classify certain drugs as being one type of drug like a sedative is that they have at least directionally the same qualitative effects. And those are due to some sort of shared underlying mechanism that they they modulate receptor in the same general direction, so they might not have identical effects. But if you're, if you're increasing GABA transmission through the GABA a receptor and this is resulting in lethargy and sleepiness and that general kind of psychological effect, then you would say, okay, that drug is a sedative.

Manoj Doss 46:47

Yeah. And you know, there's other interesting things that these drugs unique Lee do that I guess we can get into in a bit. But yeah, I mean, I think these drugs do kind of group together nicely. And as you said, they're not it's obviously not the case that they do the exact same thing. People like their benzos more than they like their alcohol. And it's not just because the hangover that you get with alcohol, but you don't get so much with benzos people Ambien, it clearly has this borderline hallucinogenic effect. And then what I should say is all these drugs modulate the GABA a receptor, those three drugs and they might modulate different types of GABA a receptors that have different subunits, but they all modulate them by binding to kind of similar locations on the GABA a receptor and facilitating your endogenous GABA. So the natural inhibitory transmitter that you have in your brain now acts even better if something like a benzo or alcohol or Ambien is now bound to the receptor. There's also barbiturates and those also modulate the receptor and forgetting what the exact terms between those benzos are but it could be that I think benzos increase the probability of opening sodium channels or something and then I think that barbiturates just kind of hold the sodium channel open but don't you know, don't quote me on that. And then you have drugs like you know, the this is these have yet to enter the psychedelic Renaissance. But I did speak to I don't know if I should say his name for fear of I don't know if he wants his out there in the open but I was at this conference this past weekend in Toronto from research reality, and I spoke to somebody this pharma company and they're potentially going to be looking into a two moose camel Mooska mole is a drug that exists in the Mario Mushroom Alice in Wonderland mushroom, the fly Garrick Amanita muscaria, the red mushroom with white dots on it. That is not the same type of magic mushroom as what's a you know, psilocybin containing mushrooms. It takes Musco and this actually agonizes the GABA a receptor and activates it in the same way your GABA your endogenous GABA might it binds the same location, it doesn't modulate the receptor. And that one is especially thought to cause certain types of hallucinations and associations. And so I've referred to that those types of drugs as being a dissociative sedative. And there's also a box at all that was a drug that was attempted to be marketed for as a sleep aid, but then it it ended up I think maybe because of the hallucinations that people got from it, it wasn't as good as Ambien it didn't make it forward. Although I think maybe somebody arguably better sleep aid and I don't know but um, so those drugs are also somewhat sedating. But you know, they clearly have a another side to them. That's borderline hallucinogenic, as does Ambien for whatever reason, even though it's not an agonist so yeah, qualitative differences, but they do overall have share many features. And their main effects can be attributed to the GABA a receptor but how they activate that GABA a receptor is probably playing a role into the difference in their effects, as well as some of the things they're doing outside of the GABA a receptor like alcohol, which is a pretty pharmacologically promiscuous drug.

Nick Jikomes 49:43

Yeah. So So there's many, many sedatives. They all directionally have the same effect. They basically make you sleepy, some of them more than others. Some of them also have some kind of dissociative and or hallucinatory and are some other components of them. So they're not identical, but they're all acting on this one. except or they might also act on other receptors but there are possibly modulating this GABA a inhibitory receptor. So that's why we cluster them all together. So Now compare that to something like dissociative. So why would something like ketamine be classified as a dissociative? And not a sedative?

Manoj Doss 50:15

Right, yeah. So I guess now moving on to dissociatives we can we can basically move through my paper of unique effects in that order, because I think that the drugs tell us we group them that way on purpose because I think they tell kind of this building story. So yeah, the NMDA antagonists are, these are drugs that yeah, they modulate the NMDA receptor. So the NMDA receptor is very much involved in we talked about long term potentiation strengthening of synapses. That's a receptor in the brain that's very much involved in that. And glutamate is kind of one of the endogenous ligands for NMDA as well as NMDA itself, which is a chemical that binds to the NMDA receptor. And when you bind certain drugs to it, that when you block that receptor, you get these pretty crazy, you know, effects like Academy, you know, you get these very dissociative effects. Ketamine is certainly also a promiscuous drug that binds to various other things. I think, you know, the RNA antemer of ketamine, so you've got the left handed and right handed one, the S ketamine has now been, you know, approved for depression. But the AR, for example, I think binds to like sigma receptors, like the sna antemer. S ketamine binds also to opioid receptors, but you can say most of its effects probably come from this NMDA blockade. And one way you can say that is because drugs like dextromethorphan, which also are pharmacologically promiscuous, but it seems to also do very similar things to dissociative things by binding to the NMDA receptor. dextromethorphan is in various over the counter cough syrups, nitrous oxide and NMDA antagonist similar sorts of dissociation. I think that you know, some people will kind of talk about the really crazy nitrous oxide effects you get, but that's because you're just getting such a high dose if you were to K hole. I'm sure that the effects could be somewhat similar. I'm trying to think of another there was another entity Yeah, the other ones like Annex II meta net doc said amine or something and some of these other drugs that kind of come about over the years, but those are your your NMDA antagonists, they bind to the NMD Yeah, they blocked the NMDA receptor. And they also cause you know, somewhat kind of they can be somewhat sedating, especially with their higher doses, but they pretty much all share somewhat hallucinogenic properties. And they're definitely somewhat different from what you get with a GABA a positive allosteric modulators or the you know, any GABA a sort of drug trying to think of whatever they you know, they do produce some, you know, this, this dense amnesic state so with I think the GABA a drugs you get like a blackout with the NMDA drugs, you get a like K hole, but I don't think anybody would say those two things are necessarily the same, right? And so again, you have a shared pharmacology across these drugs, and then certain shared qualitative aspects to them that then I think group makes me call them dissociated. And these other drugs sedatives. So yeah, then there's it dude, should we go over more about the dissociatives? Or should we use?

Nick Jikomes 53:06

No, I mean, I think yeah, I think that's it's certainly become clear to people, right, so sedatives and dissociatives. Basically, the difference is the things that we call sedatives interact with one receptor, the GABA receptor in a particular kind of way, in a certain kind of direction, to give you a certain kind of effect. So, you know, I don't know what a good analogy is here, maybe like a guitar chord or something like there's many different e chords, you can play, they'll all have somewhat different notes, but they share like a common a common structure. And so the sedatives are all acting through this GABA a receptor in some way. And that's distinct from the dissociatives, which are interacting with a different receptor in a different kind of way. And that accounts, at least in part, or in large part for the differences in the qualitative effects they have.

Manoj Doss 53:49

Yeah, and I think that one thing that's worth mentioning, because this will, this, again, will tell you something unique about psychedelics, once we get to that point, is that many of these drugs, they, they really facilitate inhibition. So GABA a, you're driving the GABA a receptor activity at it, they're increasing the ability for GABA to do its job, therefore, you're facilitating inhibition. Glutamate is the main excitatory neurotransmitter in the brain. And now you're blocking glutamate with dissociatives from doing its job. So in some ways, you're inhibiting, you're causing more inhibition. Now, there are some weird downstream effects from NMDA antagonism that can result in more glutamate release and whatnot. But it just had a very, you know, basic level at the initial step, you are talking about blocking a excitatory neurotransmitter from doing its job.

Nick Jikomes 54:45

You're basically explaining why sedatives and dissociatives are kind of, you know, you might consider them close cousins.

Manoj Doss 54:51

Yeah. Why they both impair the encoding of new memories, for example. And so that's, you know, that's one idea. then if we go through this through my unique, you know, effects paper, the really long title because I had to include all the different drug drugs in their drug classes, you know your psychedelics. And so these are also hallucinogenic, right? Like the NMDA antagonists or even some GABA a drugs, but they activate the serotonin to a receptor. So serotonin is interesting compared to some of your other neurotransmitter systems, there's like 14 different receptors. And as far as I know, that's more receptors for a given system that a single neurotransmitter can bind to compared to I think, dopamine, maybe there's five receptors, GABA, there's GABA, A and B, you know, I'm sure some pharmacologist going to come up with come on here and correct me. But you know, there seems to be a lot of receptors for serotonin. And what some will say is that the serotonin to a receptor has low affinity for serotonin itself, not the serotonin doesn't bind it, but maybe serotonin will bind it when there's more serotonin kind of floating around to the system, because now it's higher probability that'll hit that receptor. Although I think there's low affinity and high affinity states of the serotonin receptor to you know, complicate things. But but the point is, is that when you activate that receptor, you then get kind of your classic psychedelic effects. And this is what I refer to as psychedelics are drugs that bind to this specific receptor. Because they do share some what you know, the types of visuals that you might get, they share maybe some of the weird thought loops you might go through, they share the same auditory distortions, the color constancy breaking down, you know, I guess for those who don't know, you see a white wall with shadows on it, you see, it all is white, it's good that you see it as all white because it's all one solid, you know, it's all one solid material. But if you would actually take individual pixels out of that white wall, blow them up onto a white background on a computer screen, you would notice that there's actually probably all kinds of different colors in there, yellows, reds, greens, etc. And it's, you know, under psychedelics that might break down there like color constancy, I'm sure you also see various colors that aren't actually there on psychedelics, but a lot of that the color cortices, maybe that first step of breaking down color perception, and in some ways you are seeing what's actually there. It's just not very useful to be adaptive, it would be good if I thought this wall was made of many different materials, and that's why it's shining different colors. So but yeah, with you know, psychedelics, so you have drugs like LSD, psilocybin DMT, I think I'm doubtful that five Meo DMT actually has relatively low affinity for the serotonin receptor. But you know, it'll Time will tell if you block that receptor, do you remove its effects. And that's at least what a lot of people have shown now with regular DMT. And with psilocybin, and with LSD, if you block those receptors, and you take LSD, you're pretty much removing most of the psychedelic experience. And so even MDMA, so in this paper that, you know, I've got it's a preprint, we group MDMA in with psychedelics. And the reason we do this is there's a couple of MDMA is really a stimulant, or maybe I should say, intact, a gin, stimulant, psychedelic hybrid, and the order with which that you might be considered the intact genic effects are coming from the fact that it's preventing what does that explain a contact again? You know, there's not a great it means, like touched within, it's not a great,

Nick Jikomes 58:21

but it's the empathy, touchy feely component. Yes, yeah,

Manoj Doss 58:24

I avoid the term empathy. Because it's interesting, right? There's this terrible distinction, if you ask me, and I'm not a social psychologist, maybe I shouldn't, you know, critique their field too much. But there's this distinction between cognitive empathy and emotional empathy. And they'll say, Hey, here's a bunch of pictures of faces that are morphed between neutral and sad, neutral and happy, whatever, tell me, you know, it's like 10%, happy 30%, happy, 50%, happy, etc, tell me what emotion is in this face. And a lot of people will become worse on that task under MDMA. So let's say my threshold for detecting a happy face is, you know, let's not say happy because I think they're happy when actually either gets better or stays the same with MDMA, but like fear, let's say my threshold early detect fear would be like 30% of it needs to be 30% fearful. And then you know, the 70%, neutral, you can morph these faces, you know, with different percentages, right? But then when I'm on MDMA, I need a 50% fearful face to detect that it's fearful. Well, if I can't detect what's going on in that face, how do I know what they're feeling? It's a cognitive empathy is its ability of, of detecting, you know, what's in it face? It's usually the answer. Yeah,

Nick Jikomes 59:33

yeah, that's interesting. I mean, I can even see that tying into why it has these pro social. So when people hear the word entactogenic, it's sort of speaking to the pro social side of drugs like MDMA. And right if you can't tell that someone is looking angry or unapproachable, you'll be more likely to approach them. And you know, one of the hallmarks of MDMA is, you know, people are very approachable,

Manoj Doss 59:54

right. Yeah. And so I think that's, I think the pro sociality is is a good one. I think the empathy. I'm like, sometimes I'm like, wait a minute. And so there's this idea of emotional empathy that at nbma creases, you look at somebody, you know, an emotional base, and you're like, oh, I can feel what they're feeling, right? But if you don't actually know what they're going, if you don't know, objectively what their are they, you think, oh, yeah, this person is surprised. I'm surprised. He was like, no, they're fearful, you know, it's like, that doesn't really count as empathy to me, you wouldn't say that somebody is empathic, who feels the emotions of others, but doesn't get the emotion, correct. That would be Yeah. And so I think that yeah, it's unclear to me if it pathogen is not a great, I think term for these drugs. But yeah, I think that the pro sociality and I think that this is something Harriet DeWitt has done a lot of where she has kind of defined what's the distinction on the social effects between MDMA and other types of stimulants like methamphetamine. Right? MDMA is methylene Doxie methamphetamine. And I mean, you know, I think it's still sometimes unclear to me what the distinction is because clearly other stimulants make people social. But I don't know if they do so you know, it's, it's kind of almost like confidence versus arrogance, I feel like is maybe you know, the way that somebody might be social and by me, both drugs make people more talkative. They make people approach people more, certainly less people are getting into fights and MDMA, more people getting into fights under stimulants. So maybe there's an aggression side to it. There's also it makes you wonder. So here's the other side of MDMA. It does affect dopamine and norepinephrine and this is what a stimulant is, is by So serotonin, the way it affects all these chemicals mpma is that it not it binds to the transporter that would normally shuttle synaptic serotonin, dopamine or norepinephrine, there's one for each of those serotonin transporter, dopamine transporter, norepinephrine transporters that cert, dat and net, and so it'll bind to those transporters and not only prevent those transporters doing the job shuttling serotonin back into the presynaptic neuron, but they also take that transporter back up into the presynaptic neuron, and then cause a release of a bunch of serotonin or dopamine or norepinephrine. And so, you know, one difference between for example, methylphenidate and amphetamine is that methylphenidate doesn't do that reversal of the transporters blocks the transporter doesn't release a bunch of extra dopamine and norepinephrine is when it was MDMA does that it's unclear now if those stimulant effects are also needed, which come from the dopamine and noradrenergic effects or norepinephrine effects. And so it's the other side of MDMA. It's definitely a stimulant, and anybody who you know, doesn't want to call it a stimulant is just, you know, playing themselves. It certainly has very strong stimulant effects. And there are drugs that have been developed that more selectively modulate this like synaptic serotonin, this drugs like it's methylene Doxie amino Indane I think a lot of these were developed by David Nicholls. So yeah, and dai there's an E ai, there was a drink called pace that was sold in Canada that contained MBI. Eventually, the Canadian government took it off, and I think for a bit it was being sold. I know David Nutt in the UK at one point wanted to create a drug based on something like this, that was a you know, modulating the serotonin transporter in this fashion, but didn't affect dopamine and norepinephrine to try to create a new drug that people can do on the weekends that might not be as neurotoxic as something like MDMA, and maybe doesn't have the stimulant effects that can keep people up all night, etc. I think he abandoned that project, but you can find all the interviews of him talking about and by old, I mean, like, seven years ago, five years ago, something like that.

And so yeah, anyway, so MDMA. But the last thing that MDMA does is MDMA is actually two drugs, like the way we're talking about ketamine, you have a left handed version, and a right handed version and all the same chemicals. They're just organized in a fashion, just like my hands have, my left and right hand have all the same material, let's pretend they do anyways, except they're organized in a fashion that directly mirror each other. And you can do that with chemicals. And so the R enantiomer recto of MDMA actually binds to the serotonin to a receptor. And people have shown if you block the serotonin tour, so if you're like you do with something like psychedelic drugs like LSD, psilocybin, classic psychedelics, or more full psychedelics, maybe we should call them, you do remove some of the effects of MDMA. And if you take a drug like MDA, so that's methylene, Doxy, amphetamine, not methamphetamine, you get some more of the a bit more of the psychedelic effects, it's probably still much more on the MDMA side than the LSD side or psilocybin side, but it certainly has a little bit more of that psychedelic flavor. I've heard even if you take like, you know, 200 milligrams, you're not, you know, 200 milligrams of MDMA might be I don't think I recommend anybody do that. I think you can. You could, in theory, so people could die for us a lot. Yeah, I think that there was actually somebody who died from a pure 250 metal festival in the UK, I remember reading so but in theory, if you take a high dose of MDA, MDMA, you know, you might still want to be socially even though you're going to be kind of stone to a chair I've heard an MDA can get kind of weird, where like, it becomes almost like psychedelics where I'm socially awkward. I'd rather be laying in a bed you know, with one or two friends or something right? And so, you know, then you have drugs like to CV, which I think it does actually bind to the serotonin transporter and you get some of this entactogenic effects, but it also binds to the serotonin receptor and it's certainly more of the LSD psilocybin type drug than it is MDA, MDMA. And so I think all these a lot of these drugs do have these kind of, in between qualities. And, you know, I think MDMA is just a hybrid that certainly is more entactogenic stimulant than it is psychedelic, but it has some psychedelic effects that I think we can't totally ignore. But I mean, time will tell once we give a drug that if we can give a serotonin to a antagonist during an MDMA session to show that, hey, it has all the you know, good effects that we need, then we can say, hey, those are the most therapeutic effects. We don't need the psychedelic effect, but at least a lot of animal research is showing that you do need the serotonin to a effects to to get at least some of the animal models of treatment of fear memories and whatnot. And then okay, This now brings me to stimulants which I can briefly go over because that stimulates basic because I've already sort of explained them. They mess with the dopamine and norepinephrine transporter. And so these are drugs that you know, like amphetamine, methamphetamine, but methylphenidate, as I mentioned, and cocaine actually don't reverse the transporters action. They don't release dopamine, norepinephrine, they just block it. But it's interesting because if you just block these transporters, you don't quite get the same type of stimulant effect. A lot of times there's drugs like Reeboks, a teen which is a serotonin and norepinephrine reuptake inhibitor also, if you just block the serotonin transporter with something like Prozac, you know, or satella, fram, you don't get MDMA, like effects. And same thing here. So it's interesting, I don't know what you methylphenidate, clearly still in cocaine still clearly have something they share with amphetamine and methamphetamine. But it must not have to do with just releasing, you know, it's not releasing serotonin and dopamine that's strictly it, but those things do apparently add to the stimulant effect. And I realized that caffeine could also be a stimulant here, I mean, just these dopaminergic neuron adrenergic effects is what I refer to as a stimulant. They keep people up, they can enhance focus, although there's probably an inverted U, et cetera. I don't think we have to talk too much more about stimulants. Unless Yeah,

Nick Jikomes 1:07:13

so So to summarize, so far, basically, we've talked about sedatives, dissociatives stimulants, psychedelics. sedatives are drugs that make you sleepy and they do this at least in part by cranking up inhibition through this GABA a receptor dissociatives have this very interesting dissociative, weird type of effect that people report and they block a different receptor called the NMDA receptor. stimulants are the ones that that most of us are familiar with, to some extent they, they stimulate you, they activate you and make you more awake, basically. And they're acting primarily through dopamine and norepinephrine based mechanisms. And then you said that the psychedelics have their effects. The true psychedelics are the strong psychedelics by activating the serotonin to a receptor. So each class of drugs is characterized by interacting with a different set or a different type of receptor to give rise to different effects. One that we haven't talked about yet are cannabinoids. So how do I how do they differ?

Manoj Doss 1:08:11

Okay, so yeah, so then you have your endocannabinoid system. This is kind of interesting, because I think they found the receptors before they found the endogenous, you know, neurotransmitter essentially. And so there's this idea that oh, my god, were we just meant to all smoke weed, you know, like, what's this receptor doing in there? There's not a chemical in there. I don't think any scientist was actually thinking that but I'm sure the public I'm sure it's the scientists were like, there's definitely an endogenous chemical that binds to these receptors. We just haven't found it yet. And so I think that the receptors like see this either CB one and CB two, one or both of those receptors, cannabinoid receptor, one cannabinoid receptor two were I think it was they were found in like the 60s or something. And then it was not until the 90s, that they found one of the endogenous ligands which they named anandamide. So Ananda means bliss and Sanskrit and so this was kind of a you know, they they named it because of you know, THC, but really, obviously, this thing came first in terms of evolutionarily binding to things it's not like people are using THC and then we develop these receptors or whatever it is, or that we developed anandamide. We created endogenous version because of use of evolutionary use of, you know, cannabis or anything like that. So it was, yeah, it was just developed later and so they named it anandamide. And so, yeah, you have endogenous anandamide that binds to these receptors. What's interesting about most of these cannabinoid receptors will, CB one, I think is more densely distributed in the brain. Whereas I think CB two is more around the body like your gut and whatnot. And, you know, again, I'm not a like, neurobiologist, I would be happy if you know some pharmacologist corrected me on that. But your CB one receptors generally tend to be presynaptic. So you have one neuron that's projected. In order to another neuron, and every receptor we pretty much talked about, generally speaking, is on the second neuron that is having another neuron, you know, impose on to it. And so CB one receptors tend to be more presynaptic. So they're in that first neuron that's shooting out to the second one. And they're essentially so you know, dopamine and norepinephrine can generally be activating. As, you know, I think a lot of things the first two drugs, we talked about NMDA antagonism, you're sort of inhibiting your you're inhibiting the ability for the main excitatory neurotransmitter to do its job. GABA is inhibiting is enhancing the inhibition of the brain. This is CB one receptors are also inhibitory. I think they prevent the presynaptic neuron from firing on to that next neuron. So again, generally inhibitory I did find out recently, there's one set of excitatory CD one receptors in this region, the internal cortex, and then I heard from another, you know, set of people that that might be bullshit. And so anyways,

Nick Jikomes 1:11:04

it gets a little bit tricky. So yeah, so the cannabinoid receptor results in inhibition of a neuron. But there's a lot of CB one receptors on inhibitory neurons. So if you inhibit an inhibitory neuron, it leads to excitation to negative

Manoj Doss 1:11:17

equal positive. Exactly. So you know, and here's the thing, so I didn't talk about serotonin and what so dopamine, norepinephrine generally are excitatory. But there are, for example, D de to their auto receptors, essentially, in certain areas where if you activate those receptors, you can actually decrease dopaminergic tone, and you can decrease, you know, maybe it caused more inhibition. But you know, just broadly speaking, I think dopamine and norepinephrine, I think are more kind of excitatory. And, you know, GABA and NMDA tags of war inhibitory and then cannabinoid receptors are generally inhibitory in many ways. But serotonin is a weird one, you have things like five HT one a so you have 14 receptors, you have one a receptor, and that's actually I think, inhibitory of the serotonin to a receptor, which is generally excitatory. But again, there are serotonin to a receptors on inhibitory neurons in also an internal cortex, probably an interesting structure. It's the entrance to the hippocampus, by the way. So it's a it's some people refer to it as a wall of inhibition, lots of inhibitory circuitry, that prevents all information from getting into the hippocampus, or else you get catastrophic interference, and you wouldn't be able to remember anything. But yeah, the general the general consensus is that you get probably more excitation from activating the serotonin to a receptor, which is excitatory. And located mostly on as some people say, anyways, you know, on layer five pyramidal neurons throughout the cortex, which those are projectors that tend to be excitatory. So, you know, so I guess, you know, this now kind of brings me to what's interesting about some of these drugs is in terms of if we talk about these drugs and their effects on you, let's just start with memory encoding. You have all these drugs that inhibit the system, surprise, surprise, they, they, they make your encoding worse. And again, I don't wanna say retrieval, I'm not going to talk about consolidation. I'm talking about the formation of memories. So I give you a drug, I show you a bunch of stimuli. I'm now going to test your memory two days later. So you know, all the acute effects are gone. Let's pretend the consolidation stuff doesn't exist for now. And so forming those memories, entities drugs. Another way that you can test consolidation is you can test people immediately you can test them later and if the effect is larger later, you can say that okay, it was probably affecting somewhat the consolidation as well. But anyway, that's a whole other. So yeah, you have drugs that you inhibit, so GABA, a positive allosteric modulators. They an NMDA antagonist and cannabinoids, they impair your ability to form recollection and familiarity based memories. So if I test your memory the next day, you know, you're not able to recollect as well, things you're not gonna build to make the associations and where and when information. If I just show you Hey, did you see this? Did you drink this beer last night? This is not a beer. By the way. This is some weird probiotic drink my partner got. But um, if you know, I show you this, did you drink this last night? You'll be like, I don't know. It doesn't feel familiar, you know. And so all these drugs generally impact both those types of memories. And what's interesting, at least one of the things you know, we found was generally speaking, impairing familiarity was more difficult at higher doses, you get impairments of familiarity of some of these drugs. And I think that makes sense. You know, a lot of times Yeah, you can't recollect things someone's like, hey, but to remember you did you like got up on the bar, and you did some stupid things last night, you danced up there, and it's like, oh, yeah, I did do that. You know, you might recognize that and there's also situations in which you just saturate there, all the receptors throughout your brain, probably you're blacking out and you're now like, I have no recollection that is unusual familiar to me nothing. Right.

And so, I think that, you know, one thing that this tells us about Familiarity is that it's a distinct repeated sort of process that it takes, you know, perceptual semantic information. It's the activation across all these things. And that's what's kind of a backup process almost, that is probably developed. For when recollection fields, your hippocampus is susceptible to all kinds of problems of Korsakoff syndrome. If you drink too much, you know that your hippocampus gets massively messed up. Herpes encephalitis. So I think even I mean, somebody can correct me if I'm wrong, but I think even type one herpes, the one that 80% of people or whatever have the cold sores on your lips, I think it's like some rare proportion of people that can infect your brain, your hippocampus goes away. You know, obviously, epilepsy and then you have to take out your hippocampus, you know, parts of your head became a lot of times the medial temporal lobe, but hippocampus gets hit pretty hard. So you have this backup process familiarity that seems to be generally pretty good at giving you at least some ability to recognize things. So if I take out your hippocampus, and I asked you, I show you a list of words, I'm gonna ask you, Hey, recall as many words as you can, you might say to me, what list of words and then instead, I'll be like, here's a list of words that I'm going to show you that you've previously seen and stuff that you haven't previously seen. Tell me which ones you've seen, and you might be like, okay, and you're like that feels familiar, you'll still be able to perform above chance because you can use familiarity, this backup process. So, again, all of these drugs, so cannabinoids, NMDA antagonists, so you know, yeah, THC dissociatives, like ketamine, and GABA, a positive allosteric modulators like benzos, alcohol and zolpidem. They all drive sort of inhibition, and they impair recollection at higher doses and pair familiarity. But the one last thing I want to say about that is in our review, we had one zolpidem manipulation, so Ambien. And it was a weird sort of study. And there might be reasons for this that are just explained by the differences in the study design. Interestingly enough for that study, I think familiarity was this is the only manipulation in which familiarity was hit harder than recollection. And so you know, it's like this would be something very interesting to study the future. Like, wait a minute, is this an actual difference between this type of sedative some of these other sedatives does it really produce? Does it really you know, produce almost like what you might think of as Yeah, like Capgras syndrome, where, you know, you can recollect what you what you finally can recollect might still not feel familiar, even though you might go to bring information mind you might be like, and that still doesn't feel familiar, though. Basically, auto noetic consciousness is higher than noetic consciousness when usually it's the other way around.

Nick Jikomes 1:17:21

So, I mean, it sounds like basically, at a high level, you're basically just saying sedatives dissociated and psychedelics drugs that can, can evidence I'm sorry, sedatives, dissociatives. And cannabinoids tend to disrupt memory encoding. So if you give one of these drugs to someone, while they're learning something, they will perform worse when you ask them to remember what they did later.

Manoj Doss 1:17:44

Yes, and they impair both this recollection, hippocampal dependent form of memory. And maybe I didn't quite specify this, but like semantic memory, which is kind of a distributed cortical representation, familiarity seems to rely on the activation of, you know, the cortex, both kind of perceptual and semantic nodes throughout the brain is kind of like the fluency with which you process that information. And so actually, what's an interesting aspect of familiarity Is that better retrieval of a familiarity based memory actually involves less activation. So it's almost like it takes less processing, and therefore that you get familiarity. So if I show you an image that shows you that image, again, less activation, and something like Perry Rhino cortex, or visual cortices would actually associate with the higher feeling and familiarity. Whereas recollection involves kind of like the reactivation of all the different, you know, involves the hippocampus, as well as the reactivation of many different cortices to try to recapitulate that information and relive what you kind of perceived.

Nick Jikomes 1:18:48

What about. So it's probably pretty intuitive to people that, you know, if you, if you take ketamine, or you drink alcohol or trying to learn something, you're probably not going to remember what you learned quite as well. What about the opposite kind of drug that people would imagine one that enhances memory encoding, the candidate here that you would naturally think of are stimulants, something like, you know, Adderall, or whatever that people often take? And they often take it thinking that it's going to help them learn and remember things. So what do we actually know there? Yeah, so

Manoj Doss 1:19:17

um, yeah. Okay. So this was this is interesting. So you get you take, you know, these drugs that tend to activate the system, you know, dopamine and norepinephrine. Again, you know, there are, there are reasons that the noradrenergic system can actually be less active. And, you know, this is kind of a simplification. But generally speaking, we think of these drugs as activating. And it turns out that it's not as easy to enhance memory encoding, as people might think it is people think that they're studying better. I think it's probably more that they're one they do maintain folks, to some degree it seems to be they also might help you re study things over and over again, because you're more perhaps interested in your work. But you know, it really suits me If you have a deficit, then they work better. So if you have ADHD or if you're tired, I think that's when they work best. But yeah, they tend to enhance memory encoding. So you encode information, you know, I present you budget stimuli, I test your memory now, two days later, and a lot of times you'll get this enhancement. What's interesting is that we didn't really show this enhancement in this massive reanalysis and review in healthy adults. And there could be a couple of reasons for that, I think that there's probably a pretty sharp inverted you that people who are already good probably don't need a very high dose to enhance their memory, and even then maybe a low dose might still not do much or might even be counterproductive. And so I think that there's probably that like anybody who says, oh, Adderall doesn't help me. My guess is there's a dose at which that they probably could boost on it. But I don't know. I mean, I'm not telling anybody to take Adderall. You know, I don't want to say that, but, but one thing we did show is that it enhances your meta memory. This is the one thing I haven't talked about yet. This is how well you understand your own memory. So, for example, I might encode something. And later on, I might say, I've definitely seen this before, I'm unsure if I've seen it before. These drugs seem to enhance your ability to say, I've definitely seen it before. But you actually have seen it before, where I definitely haven't seen this before, when you haven't seen it before or for that matter. If you're like, I don't know, if I've seen this, maybe I'll say No, I didn't see this. And then your confidence is is low. And it's rare that you have seen that before, but your competence is low. That's also good meta memory, because even though you got that wrong, you kind of knew not to be very confident. And so this is what these this is something that we showed was that this was I think, to my knowledge, maybe the first time that we showed that an aspect of metacognition was enhanced, how well you understand your own cognition with these drugs. And so yeah, I mean, that was, you know, something that again, I think that they enhanced, they can enhance different cognitive processes, including memory encoding, but it's maybe not as great as we would hope that it would be. But they at least enhance perhaps your meta memory, which gives you kind of this gauge. And this is maybe is why actually, for example, people are studying while they're on, you know, Adderall, and then they try to maybe test themselves, they're like, you know, I don't think I know that information very well, who knows, if I'll remember it later, I should study it again, you know, and so it kind of gives you this better gauge of knowing. So even if it doesn't enhance your actual cognition enhances your ability to understand your own cognition, at least in terms of memory, whether that's true of other aspects of cognition, like perceptual decision making, or whatever is yet to be shown. But that was a pretty consistent effect that we found. And you know, just to skip up here a little bit, we show that, in fact, it also enhances your meta memory when you're when it's on board during memory retrieval. So if you're retrieving a memory, and you're like, Have I seen this or not yet? I think so. You know, and it turns out, you're wrong, but you had low confidence, that's again, a good aspect of even though you're wrong, you were low, confident, you kind of knew not to be too confident in an incorrect decision. So

Nick Jikomes 1:22:56

people tend to become better at gauging the confidence level or accuracy of their own memories.

Manoj Doss 1:23:02

The correspondence between competence and accuracy essentially, is yeah, what how we measure metacognition here and this specifically meta memory in this study. So but yeah, you know, it will be the point, though, is that if you give the drug though, onboard during encoding, it definitely did not impair memory. The enhancements were kind of, you know, trending sometimes, and other people have shown enhancements in certain areas, whether it's recollection and familiarity is still kind of unclear to me. Definitely, some people have shown recollection based tasks. So like free recall of words, that's probably recollection, hippocampal dependent recognition, not always shown. So anyways, yeah, you get some enhancement. But now if you take a drug like psychedelics, this is, I think, where things get a little interesting. So you administer a psychedelic, you show people just stimuli, you test their memory two days later. As I mentioned, psychedelics bind to the serotonin receptor, those tend to be mostly distributed on excitatory neurons. So you should get activation facilitation. And yet you get impairments in memory. So this is one place in which they're unique, where it's like, wait a minute, all these drugs that, you know, facilitate inhibition, in some ways, whether they're, you know, cutting off excitation, or they're actually facilitating your inhibitory system. They impair memory encoding. And here's like, it's Alex, where they enhance, you know, excitatory neurotransmission, in some ways, and yet, they're impairing memory encoding. So what's going on here? And I think if you just stopped at, you know, using a verbal free recall task, you know, which is here's a bunch of words, how many can you recall later, you wouldn't get down to the bottom of this. And I think that's why we need better cognitive psychologists in this field that can really dig deeper into these questions of behavior so that we don't have you know, non experimental psychologists saying, Oh, it's all just generalized disengagement, which is, you know, the biggest cop out explanation I've ever seen from somebody who doesn't understand cognitive psychology. And so there's a couple of things here. One is that if you look at there was a study done by Fred Barrett who I work with. He showed that dextromethorphan and psilocybin, he had a very high dose reduction with orfalea, I think it was 400 milligrams, which keep in mind, you maybe take maximum 30 milligrams if you're going to take somebody to stop your cough, so quite a bit. And then he had three doses of psilocybin a kind of on the low moderate side, a moderately high side, and then a very high dose. So 1020 and 30 milligrams. This is all per 70 kilograms. But let's forget that this is approximately 1020 30. And then approximately 400 milligrams, and so of dextromethorphan. And so in this study, what he showed was that if you look at just verbal free recall, so again, here's a list of words, how many can you recall, like 10 minutes later, or something like that. And it actually in his case, I think he did it five hours later. So when most of the drug effects are gone, but you can see that some are still there. We're now trying to do the study where we actually have people test their memory one day later to make sure that there's no drug effects during retrieval. That dextromethorphan, it ended up impairing very strongly episodic memory, surprise, surprise, you blocked the NMDA receptor if we think that LTP is kind of the scaffolding by which these episodic memories are formed. And then you disrupt that scaffolding with the NMDA receptor, which is very much involved in LTP, boom, you massively hit, you know, episodic memory.

But what was interesting was that there was a working memory task. I'm glad that none of probably none of my working memory, friends are going to listen to this because they would get mad at me, if I said that the end back was working memory, I agree with them, I'm just going to simplify things to say that the end back is working memory. It's really this task that involves multiple processes, as do most but it's not, it's not a great working memory task is the point. But it's an aspect of working memory or executive functioning. And you didn't get an impairment at all, I think it wasn't significant. Like I'm sure if they'd run more subjects, whatever, they would have gotten it, but it wasn't significant. But and so the back is essentially this task in which let's say I do a two back specifically, you have to say with every stimulus that you see is the same as to behind you. So I show you l and m, you're gonna say no to the LBJ thing before it, you say no to the n, you're gonna say no to the M. And then I say n lnM. N and you're gonna say yes, you know, because behind that to back, there was now an n. So this involves working memory, which means keeping things in mind, like kind of like a phone number, I give you a phone number 5553212, you know, and you're like, Okay, 5553215, you're holding that in mind at that time. If you can recall it the next day, now you're relying on episodic memory. If you've been recalling that information for a really long time, and I take your hippocampus out, you can still remember it, that's probably semantic memory now. So what they showed was that yeah, essentially that the that this NMDA tag is at a high dose dextromethorphan did not massively impaired episodic memory encoding, it did not really impair working memory, at least significantly. And there's actually a lot of studies I've noticed since then, that also didn't show such working memory impairments from ketamine and other NMDA antagonists. Again, higher doses, more subjects, I'm sure that they would. But here's the interesting thing you now give psilocybin and the impact and episodic memory on free recall was there, but it wasn't quite strong. So just recalling words off the top of your head five hours after your psilocybin session after you'd seen all these words under these three different doses. However, those three different and I think the lowest dose might not even impacted free recall, if I remember correctly. But if you look at working memory, this n back task, even the lowest dose impacted, working memory significantly, indefinitely, your moderately high dose at a really high dose did so again, generalized

Nick Jikomes 1:28:40

disengagement impaired working memory,

Manoj Doss 1:28:43

yeah, you get and again, I'm simplifying what working memory executive function, whatever the back is thought to tap into. It's not episodic memory, though. Yeah, you get this this impairment from, from psychedelics that you don't get with dissociative that are quite as strong. Whereas it's the other way around with episodic memory where you don't get a strong impact in episodic memory coding from psychedelics, but you do with the dissociatives. This is a perfect example of why you can't say that it's generalized disengagement under psychedelics. psychedelics are special that you can't test. You know, you can't do behavioral tasks and conquer paradigm. People just disengage. It's like, wait a minute, if people just disengaged and shouldn't just across all tasks, you get larger impairments from psychedelics than you do with something like dextromethorphan. Clearly not because you get this dissociation. But now here's where things get even more interesting. So you can do a recognition memory task. So now I can show you a bunch of things you've seen and things you haven't seen. And I asked you to say Did you see this yes or no? And you say yes, no, you know, things that you've seen and not seen. And then I ask you to rate your confidence. Now using this confidence, I can now model things like recollection and familiarity. There's other ways of modeling recollection, familiarity, but this is one way of doing it. You get an impairment of recollection, but there's no impact on familiarity, even as you escalate that dose to that map. possibly high dose 30 milligrams where people are barely functional, no impact unfamiliarity, unlike what you see with the Gabbay positive allosteric modulators, 15 milligrams of THC, which is, you know, moderate, but not like super high and with NMDA antagonists, which as you move those up the dose yet you'll definitely see impairments of familiarity. In fact, what we saw here with psilocybin was potential enhancements, as an at the highest dose that that p values started to get the lowest the moderate dose, it wasn't quite there, the the lowest dose, it wasn't there at all. But the point is no impact on familiarity, if anything, numerical enhancements, my MDMA study, same thing. MDMA, we showed that recollection impaired and the actual the original study, I did not focus on what happened familiarity. I didn't believe it. It wasn't until I saw these psilocybin data where I was like, wait a minute, I've seen this before. And I was like, Holy shit, like we might actually be getting an enhanced with familiarity. There's now shown that numerical enhancement of familiarity again with MDMA, I think with one situation, depending on the stimuli with emotional stimuli, it was trending or significant with neutral stimuli wasn't there? It was, it was this weird sort of thing where emotional stimuli essentially give you I think, better signal sometimes. But yeah, again, impairment of recollection, maybe even enhancement familiarity. The point is no other drug when you start upping the dose starts to enhance molarity. If anything, you get more impairments of familiarity. So you can see a potential enhancement. And here's where it makes sense. Maybe, you know, this is again, me just massive speculation. Familiarity is based out of the cortex, the fluency of activation through perceptual and semantic networks. That's where you have these layer five pyramidal neurons that have serotonin sway receptors, that can now drive this facilitation. However, the internal cortex, the entrance to the hippocampus, is now where there's these inhibitory serotonin receptors, this wall of inhibition is potentially now being facilitated. And so now you're not allowing information with hippocampus, which is going to impair your recollection, but perhaps enhancer familiarity, which is going to enhance things like noetic, that's noetic quality, that one gets this feelings of insight, deja vu, whatever, whatever. And so it was kind of this neat story, you know, we're waiting to see a replicated, we're doing one of the studies that will hopefully show some kind of replication. We're also working with some people at Maastricht to try to see, with a couple different psychedelics, what we end up seeing in terms of recollection and familiarity. So it's interesting, I think the point, though, is that even if you have familiarity, in the absence of recollection, you still can't control that familiarity with recollection. And it can even if you don't enhance familiarity, having too much familiarity, the absence of recollection can also result in some of these bizarre phenomena. That's kind of my working model for this.

Nick Jikomes 1:32:38

So so this brings up the, you know, the area of thinking about how psychedelics like psilocybin, for example, acting through these 5g to a receptors, which are found in abundance in these special excitatory neurons in certain parts of the cerebral cortex. This brings us to the idea of what is actually functionally going on in the human brain, when you take something like psilocybin, and how does that start to tie to some of the potential therapeutic effects? So I know that you've worked on this and others have worked on it over the last few years, including some recent studies looking at, you know, functional imaging in the brains of people who take psilocybin versus other drugs? What do we know? What what's the current state of knowledge on what a dose of psilocybin will cause to happen functionally in the human brain?

Manoj Doss 1:33:28

Yeah. I mean, I think this is such a hard question, you know, you can go off of so there's, there's a bunch of different models that I realized that there's one that everybody you know, is kind of bending over backwards to make their data fit. And that's, you know, Rebus, or the default mode network narrative is what I like to call it. And, you know, so I mean, maybe I should start with that one. And so there's this idea that your brain is composed of these hierarchies. And, you know, that's not totally absurd. You have sensory processing that goes through early visual areas, through more complex visual areas, you go from processing edges, just lines, to eventually processing, you know, a face. And then, you know, these certain neurons are very responsive to faces rather than just edges. And so that makes sense. And then you have these regions that are responsive to multiple different senses. They're not just responsive to vision, they're also responsive to audition, etc. And so you have these, this hierarchy in the brain, and that it's the top of the brains hierarchy is the default mode network. And that this is according to this model. And psychedelics, especially hit the default mode network, and then the hierarchy kind of breaks down. And now there's more bottom up information processing it so this might, you know, you might say, well, this makes sense that familiarity, is this bottom up process, this activation of cortical regions? I mean, as I say this, I'm just like, I can't make sense of this. I'm not even gonna try to bend over backwards like some people do. Yeah, that

Nick Jikomes 1:35:00


Manoj Doss 1:35:02

Yeah, yeah. Because exactly. You can say, Okay, well, there's certain perceptual fluency activation. But as I mentioned, it's also very much involved in semantic concept activation, which is a high level. And this is where that this model breaks down actually, is that when they talk about different so so Robert Harris is not an experimental psychologists. He's not a cognitive psychologist, he's you know, he's he's mentioned things on Twitter that kind of talked down on cognition. And he's also a trained in Freudian psychology and he has a master's in like psychoanalysis. And so, you know, Freudian psychology, cognitive psychology don't exactly get along. And so one difference is that cognitive psychology takes empirical observations and manipulations, and typically what we call science, and, you know, tries to look for consistencies Freudian psychology, starts with ideas and tries to look for them in patients. And that's, you know, basically what Freud did was he until he found the patient that proved his idea. He didn't, you know, yeah, he, that's why he started with idea he kept trying to look for in patients that prove his idea. You want to bang your mother, and he kept finding the patients that, you know, wanted to bang their mothers. And so, you know, so that so anyway, I think that there's there's one issue is that if you take proper behavior, these proper cognitive processes, reverse breaks down this idea. So one idea is that your lower level processes are facilitated while your higher level processes are impaired, the lower level process or at least unimpaired or facilitate. And so, you know, well, one could say, well, the perceptual aspects of familiarity, those are enhanced, the perceptual fluency is enhanced with the semantic fluency isn't. Well, semantic priming has been shown to be enhanced by psychedelics. There's also a you know, the example that the law is used in Rebus is that well, you have. So contrast processing versus motion processing contrast comes first in the visual hierarchy, your vision person, is that right? I believe so. Yeah, yeah. And so, you know, I think the one or two does contrast then it takes center contrast

Nick Jikomes 1:37:01

is very, a very basic thing that that most organisms with visual visual apparatus of any kind can can do.

Manoj Doss 1:37:09

Yeah, but so is motion processing. But it does seem to come later, right. And so empty area empty comes later on in the stream versus, you know, contrast. And so what they'll show is that motion processing is impaired by psychedelics. But contrast isn't actually what's a really cool finding is I found one paper with alcohol that finds the flip of that. And now that makes that a lot more interesting. If you think about, you're like, Oh, what if all drugs just do that you're like, wait a minute, alcohol actually impairs contrast more than motion. Okay, now, this makes this interesting. But um, but that's one example where that does work, where it's like the higher level processes now impaired compared to the lower level process. But you can think of pre pulse inhibition. This is a single, let's say, a puff of air to your eye, or a loud sound, let's say. And then if I play a second loud sound, and close sequentially, that first sound is going to inhibit the response to the second sound, because it's, it's almost like a very rudimentary form of learning. It's like, the second sound is like, alright, I already heard that first one, I know that there could be a next one coming up, it's becomes predictive in some ways to inhibit that response. Almost like a form of familiarity, let's say, well, people's inhibitions impaired by psychedelics, especially when the distance between the two pulses is near. And so that's a very low level form of learning. And that's one of the first things Mark Guyer and others have been showing that is like the psychedelics impair this, it's like, Okay, other forms of low level learning that are now being impaired versus enhanced. Like, I don't think fear conditioning is enhanced, but yet extinction learning is, and so they'll use that as the low extinction, learning gets enhanced by psychedelics. So what about fear conditioning? I don't think that's an answer. That's a low level form of learning. And so it just becomes this really weird thing that, you know, I don't know, what's a low level and higher level and a lot of forms of behavior that can really, you know, explain some of these effects. Then they'll say, oh, cognitive flexibility, which cognitive flexibility is probably an extremely high level, like, oh, this gets enhanced, which by the way, it doesn't. It's unfortunate that this has now been written into the literature that it's now been shown in animals and in humans, that acutely psychedelics impair cognitive flexibility is the ability to adaptively switch between cognitive operations in a changing environment. And this is probably a high level process that actually is one reason why the Cubans are successful is that we have high cognitive flexibility we can go from you know, attention that word world, okay, internal attention, you know, let's let's revisit our models outward, internal, you know, all these different ways of sort of thinking that can allow us to solve different problems, and acutely psychedelics that is a high level process that it's like you like to do in Paris, if any of that goes with the model, but oddly enough, they say in their papers this Oh, but psychedelics enhance unconventional, cognitive, unconventional cognitive processes like cognitive flexibility. hydroprocessing. The reason they say that is because antagonism of those receptors in animals has been shown to impair cognitive flexibility seen, for instance, if you agonize the receptors that should enhance them and yet that has not been shown To be true. So this is my take on reverse anyways is why I don't totally buy it. But from a brain level, maybe just let me go real quick and say this, the idea is that you should get larger effects in these areas that it does turn out that these higher level Association qualities that process multiple senses, and not just visual cortex and whatnot, they do have more serotonin receptors generally, it's worth mentioning that compared to the rest of the brain, sensory areas still have a lot of serotonin receptors. But the point that they like to make is that oh, yeah, you're gonna decrease in default mode, network functional connectivity, or get entropy in the default mode network. That is the network that all times gets the lowest the smallest effect. And in fact, in their LSD data, the largest effects that you get on decreases in functional connectivity, or increases in entropy are in sensory networks. And the smallest effects are in the default mode network sometimes. And this has now been shown across you know, I think Natasha Mason ads and psilocybin data, Matias liked he has some LSD data. And across all of these studies, it's like the default network is not the locus of the largest effects and sensory areas do get nearly if not larger effects, which complete opposite of what you'd expect. If the hierarchies broken and sensory arrays are now supposed to be facilitated in some ways.

Nick Jikomes 1:41:19

Let's back up for people for a minute. So can you let's answer see if you can answer three questions or describe what the state of thinking is here. So one, just Just what is the default mode network? And in very simple terms, to what is the effect that psilocybin tends to have? And how well does it replicate in terms of how it's impacting the default mode network? And lastly, is psilocybin and are other psychedelics unique in the way they affect the default mode network? Or do other drugs do something similar?

Manoj Doss 1:41:48

This is great. I'm glad you mentioned that last point. Because, you know, one of the things I've been trying to say throughout this, you know, and this whole paper, the reason why we kind of brought up this discussion is the ideas. Is there something unique about different types of drugs, right? So, okay, so the first question is, what's the difference? The default mode network is actually basically the episodic memory network recollection, maybe more so than anything. If you include the hippocampus, most of your hippocampus, especially, so they formed this symbol referred to as the posterior medial network. But it's evolved in episodic memory. It's not your ego, your sense of self, you know, I think Phineas Gage had a rod that went through, especially I think, dorsolateral prefrontal cortex, it's not part of the default mode network, he's his sense of self was certainly changed. Although you could argue that it went through multiple areas. But you're, it's the default mode network has evolved in various areas that have nothing to do with the opposite of your sense of self, which is the processing of others and what they're thinking theory of mind. That's essentially the, you know, the opposite of that your sense of self. It's evolved a future simulation, it's involved in it, I think the one main I want kind of takeaway is it's involved in kind of internal models of the world, I think might be a better way of describing maybe what the default mode or could be doing. And even then I'm sure somebody could prove me wrong. And give me an example of where that's not true. But it's definitely not your ego. And so that's kind of a weird thing. And it's certainly not the case that you're in is subcortical structures, because that's another thing that kind of is proposed by the entropic brain. The subcortical structures I should mention are not, there are lots of connected to these other networks. As I mentioned, the posterior hippocampus is connected very much. So to your default mode network. It is almost part of that same sort of network. You know, they co evolved with different areas of your cortex. And so there's nothing primitive about your, you know, your thalamus isn't necessarily more primitive than other areas. So okay, so that's what the default network might do. Your second question is, what does psychedelics do to the default mode network? Is that right?

Nick Jikomes 1:43:56

Or yeah, psilocybin reliably affect the default mode network in a particular direction.

Manoj Doss 1:44:01

And that is one thing that does turn out to be true. So now, there's been several datasets resting, not even just resting state datasets, but they do show that psychedelics decrease functional connectivity within the default mode network. And that does turn out to be true that you also get decreases in functional connectivity in other networks pretty reliably other higher level cortical networks, such

Nick Jikomes 1:44:24

as you know, what does that mean to decrease functional connectivity? Ah,

Manoj Doss 1:44:28

so that would be you could think about your network. So your brains communicating, you know, how your different regions of your brain are communicating to each other. They might now you know, they form these networks. That's kind of how you describe a network is, generally there's more communication within this network than outside of it. And you now get less communication within this network. And so essentially, what it really boils down to is just a correlation between the activity of the activity of two regions over time so two regions are co activated high functional connectivity, if they're doing their own thing and not talking, you know, they're not talking to each other when one regions up the other regions down, etc. It's a bad example one regions up to the regions only sort of up, then you're gonna have a not very high functional connectivity. So it has been reliably shown. But here's the thing. If you're gonna call that ego dissolution, as some do, you should then expect other ego dissolving drugs. This now brings us to other drugs. What do they do to the default mode network? Well, our most similar example to psychedelics would probably be the dissociatives, and ketamine. The great thing about ketamine is it's been studied quite a bit. Because it's, you know, legal and you get these big studies, you can get people who aren't invested in the psychedelic effects of ketamine to do these studies, cetera, et cetera. And it's the studies are almost certainly better quality than their Psychedelic Studies. So they have larger samples they'll have between different universities. So you now have multi site. So it's not just specific to one area, and maybe one set of researchers priming people to do something or whatever it is. Ketamine, there's been five studies, I've seen resting state ketamine, to have shown decreases in default mode over connectivity to have shown no effect one is shown increases in default mode network connectivity. So that's already a problem. If you asked me. And, you know, I think one reason which you know, I don't want to go into this too much is the idea of resting state, we have people do whatever they want the scanner, under a drug, you're now especially with, like 20 people, you're getting a random sample of cognitive operations in one sample, a bunch of might pick up their mom, and they're going to now get one pattern of activity that's going to interact with drug effects. Another sample is going to perhaps the paranoid with the research rewards, that's gonna interact drug effects, and other samples going to listen to those scanner sounds really intently, maybe they're gonna get more that's,

Nick Jikomes 1:46:43

that's a really good point. Because correct me if I'm wrong in a lot of these brain imaging studies, right, you're comparing what's going on in the brain in two different conditions. And condition. One is often the so called resting state, the baseline state, they just sort of sit there and do nothing, quote, unquote. But what you're saying is, instead of it's not like, you know, if you've got 10 people in a study, and they're all in their baseline resting state, they're not all in the same state. And one of them's remembering what they did the grocery store yesterday, the other ones thinking about how nervous they are in this claustrophobic image scanner. And you're sort of treating all of those distinct cognitive states as one common baseline almost.

Manoj Doss 1:47:20

Yeah, yeah. And that's the thing, there's no baseline to the brain, you know. And so that's the, the issue. And then here's the, here's the funny thing is you're comparing, while they're on drugs, and they can't fall asleep, because these drugs prevent people from falling asleep. You're now comparing this situation where they're doing whatever they want, things that they actually have the capacity to do when they're sober, too. Let's keep that in mind. You can think about your mother, when you're sober, you can be paranoid what the researcher wants out of you, when you're sober, you can pay attention to the scanner sounds when you're sober. And now you're comparing that to a situation when you're on placebo, when you're actually probably resting. And in fact, 40% of samples will fall asleep, at least according to one study. So what are you really comparing here, you're comparing it aroused state to an unreal state, you're comparing cognitive operations for which people have the capacity when they're sober to a situation when they're actually resting, even if they don't fall asleep. And then you tell people to close their eyes during some of these things. Of course, they're gonna fall asleep when they're sober. So it's just like, this. ill fated comparison if you ask me. But okay, so there's that. Now, what about other drugs, amphetamine and alcohol have both been shown to decrease default mode network connectivity. So the default mode ever tends to come online, when people aren't performing externally directed attention sort of tasks? Well, when the default mode network decreases its activity, that's when you're performing externally directed tasks. Well, guess what you're gonna do when you're under the effects of drugs, amongst all that random amalgamation of cognitive operations, you're probably going to more likely direct your attention outwards, occasionally, here and there, that's going to result in more decreases in default network connectivity. Even if you're drunk, you're probably going to do that more frequently than just you know, introspect and just sit there and think internally. And so

Nick Jikomes 1:49:00

So you're saying so so just make sure I got it, you're saying that a reliable result is that stimulants, for example, decrease the default mode network activity. One study

Manoj Doss 1:49:09

has shown that and there's been one study that shows alcohol that I've found maybe there could be more, but yeah, that's what I have seen thus far.

Nick Jikomes 1:49:17

But no one would ever conclude that, you know, taking a stimulant is causing ego dissolution.

Manoj Doss 1:49:23

Of course not. If anything that's ego strengthening, you know, I think safety with alcohol, people can become egotistical, let's say. And so it's just this, like, what is this even and I think, you know, Robin himself has backed off of some of the default mode network stuff, and it just sucks that he doubled down and Rivas when his LSD data didn't really show that now, people are always talking to development, including scientists who you know, they don't they're not usually great. Actually, even some of the brain scientists are now focusing on the default network. It's just like, god dammit, like, this is an unfortunate side to you know, what we've what we've gone through here. But maybe here look, if you gave me a lesion patient that has, let's say, a hub of the default mode network taken out like the posterior cingulate, or the medial prefrontal cortex, and you give them a psychedelic and most of the effects are gone. But this doesn't happen if you have a lesion in dorsolateral prefrontal cortex, or the dorsal anterior cingulate, I'm gonna eat my words, are you like, you know what, you're right, default, whatever that seems to be most important thing to psychedelic drug effects. But till that happens, I'm Yeah, at the moment, the fMRI data do not speak to this default mode network account. And so, you know, I can go into other types of models and things that could be happening when ideas, you know, just this idea of general plasticity increasing and maybe this plasticity is associated with weird phenomena. I think that you know, you have your thalamus as well, that seems to be a Gates certain types of information, you know, you have kind of top down processes that prevent certain things from getting in, for example, you don't want every single pixel on this wall to be seen as all the colors that are actually reflecting off and you want to see kind of a solid wall, maybe that now gets disrupted. Because if that was processes, sensory information, and so this idea that you can get, it actually involves disinhibition debating whether or not to go into that. Because now we might be going off topic from the memory stuff. But you know,

Nick Jikomes 1:51:16

I don't think we really need to go there. But I don't know. Can you just say a little bit as we wrap up here about, you know, what's going on in your world or the psychedelic research world to do with the effects of psychedelics on memory? Are there any questions you're pursuing right now? Or any interesting pursuits from other folks? Yeah, so

Manoj Doss 1:51:35

I guess there's, well, I don't know about what others are doing. But yeah, we're trying to we want to replicate that effect of do psychedelics enhance the encoding of cortically dependent familiarity based memories, you know, while impairing recollection based memories. I think something else that was interesting that came out, this is something that was shown in animals, is if you encode, if you administer a psychedelic immediately after encoding, you can actually enhance the proxy to a familiarity based memory. This is a novel object recognition. And recently, it was shown, I might have been a reviewer on this paper, that it there was this, you know, interesting finding where they talked about what happens the next day after psychedelics and all you get this enhancement of memory? I was like, wait a minute, actually, no, that's not exactly what you showed, what they had people do is they had a grid, it was maybe like a four by four by four grid, with cards and you know, you flip over one card, and that's the Can you flip over another card, and it's something else, you got to find where the other can is, and you have several trials of learning this to like, you know, learning this to a point where it becomes almost familiarity based and not recollection based, you know, then they administered LSD afterwards. And then the following day, they then had enhancements of that task. That's basically the animal version of novel novel object recognition. In other words, administering a drug post encoding a psychedelic might enhance the consolidation of some of these memories, which is a crazy idea that imaging post encoding is going enhance that's been shown only with GABA a positive allosteric modulators. So this is a very weird thing that this is where again, if you know you might hate the way I grew up sedatives altogether, Ambien, benzos and alcohol if you study on them, you're not going to get anything the next day if your test if you study and take them immediately afterwards, you'll remember more for your tests and had you not taken them at all. Let's forget about hangovers for a second. But yeah, that'll that's like it's known as retrograde facilitation is one of the craziest effects. What are the people talk about psychedelics? sedatives have some really cool effects like retrograde facilitation, waking people up out of comas. That's a crazy thing that happens with benzos and Ambien. Yeah, it's you know, and then of course, you have a GABA agonist that have their own hallucinogenic effects. So

anyway, psychedelics might do that, that's not been shown it. So there's a really simple explanation for getting retrograde facilitation, which probably isn't the whole story. If you take something after you encode, you're going to block new information from coming in that can interfere with the old information. So it's been shown if I learned list a and then I learned list B, List b is going to interfere with my memory for list a had I just sat there and done nothing at all. list a is gonna be remembered better. If I do a stay, and then I can't remember anything that I learned from this be Well, it can't interfere with LIS day, right. So that was a simple explanation. However, there's some really weird things that happen that can't fully explain that one drug like THC, it doesn't work. THC also impairs memory doesn't work, too, you get disproportionate memory for certain types of stimuli like emotional information, sometimes. Three, you get enhancements of sleep based consolidation processes. So there's some of these stabilization processes that exist during sleep. There's only been shown with Ambien, so I don't know if it shows up with alcohol and benzodiazepines. And you don't need sleep for this to work. But at least you can show that you get enhanced sleep spindles, and the coupling of sleep spindles to slow waves. And so those are usually associated with enhancements in episodic memory. So anyways, it's it's like a deluxe, who knows what they're doing, but there's this post encoding cycle. like that could enhance your memory. And in fact, what we're seeing with familiarity, it might just be because psychedelics are lingering into the consolidation phase that it might have nothing to do with the encoding effect. And so that would be something I'm super interested in. I think the last thing with episodic memory that I would want to do is look at their effects, psychedelics effects during memory retrieval. So most drugs, when administered during retrieval will increase false memories. So you will falsely say with high confidence that you saw something that you never actually did, including very crazy stimuli that you would normally think that I would remember that, you know, like a picture of a dying baby, that's literally a stimulus that we've used before. And you'll say, Yeah, I saw a picture of a dying baby. No, you didn't? Wouldn't you thought that you'd remember that students do say with high confidence, right? And so that shows up the THC has been the one to show that the most. So this is kind of gets at the importance of dissociating drug effects between encoding and retrieval and consolidation and whatnot. This study was sitting back in the 70s 1970. I think, that showed if you administer THC, just during retrieval, you will get an increase in how often you're going to false alarm to certain types of stimuli. You'll be like, oh, yeah, I'm more likely to say Yes, I saw the stimuli whenever actually did after that most studies administered THC during memory encoding, and then tested their memory shortly afterwards, whilst while THC was still on board during retrieval, they get impairments and true memory, you're less able to say what you've actually seen, you'll get increases in false memory. And for reasons I can't go into, but it will signal detection theory, if your memory is really bad, you'll get impairments in true memory and increasing false memory, because there's gonna be guessing, right? And if you're just guessing, you're gonna say yes to some things you've seen, but also haven't seen, you know, and then you're gonna say no to things that you have seen, but also haven't seen. And so that false memory effect was basically forgotten about, and people were like, oh, you know, this is just all due to this impairment of true memory. And then we came along later. And then we showed gesturing retrieval. If you give THC you get this increase in false memories, it shows up across multiple tasks, high confidence, false alarms, people will use the high competence button. And we forget, we didn't realize that there was a paper from 1970. And I stupidly didn't sign it. And then somebody sent it to me later and was like, Oh, shit, I'm an idiot. And so anyways, it's important to dissociating drug effects from encoding and retrieval. But it turns out that shows up with a ketamine we saw trending effects with MDMA, I regret doing this modeling and seeing that MDMA might impact true memory, when really I think what was happening was that modeling approach is sensitive to false memories. And if you get to with false memories, you get a decrease in a true memory parameter. It's, you know, again, complicated explained, but again, we see this trending trend towards increased false memories with MDMA, especially for high confidence, false memories. And yeah, you see, even Fetta mean, and then my guess is with something like psychedelics you would as well which suggests, again, we should be cautious with psychedelics, and this idea of repressed memories is mostly garbage. And so psychedelics might instead enhance the ability to retrieve false memories or form false memories and you know, this is something that I'd like to test in the future.

Nick Jikomes 1:57:56

Awesome. Well, Manoj das thank you for your time. Yeah, yeah, I guess it's for two hours. All right. Have a good one.

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