MedEvidence! Truth Behind the Data

Schizophrenia, Psychadelics, and Seeing the Future

• Dr. Michael Koren, Dr. Paul Miller • Episode 368

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Dr. Paul Miller joins Dr. Michael Koren to discuss ongoing research in the field of psychology. Dr. Miller expounds on the complex interplay between genetic predisposition, trauma, and the way the brain misprocesses memory, and the potential negative psychological outcomes. Dr. Miller then discusses treatments and the changing treatment landscape, including techniques that mimic rapid eye movement (REM) sleep to help process memories in a less traumatic way, and newer medications under investigation that may help people who have traditionally had trouble with current therapies.

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Have a question for Dr. Koren? Email him at askDrKoren@MedEvidence.com

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Music: Storyblocks - Corporate Inspired

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Announcer:

Welcome to MedEvidence, where we help you navigate the truth behind medical research with unbiased, evidence-proven facts, hosted by cardiologist and top medical researcher, Dr. Michael Koren.

Dr. Michael Koren:

Hello, I'm Dr. Michael Koren, the executive editor of MedEvidence! And I'm really looking forward to this interview. I've just met this uh fabulous gentleman, Professor Paul William Miller, and he and I have been chatting already off-air, and now we're gonna chat on air and talk about his amazing work in psychedelic research. And Dr. Miller is a physician, a clinical scientist, and also a hell of a guy. So he and I have been having a fun conversation, and he's gonna educate me on his recent work with EMDR. And that's something I never even heard about until this week. So, Paul, welcome to MedEvidence and tell us a little bit about yourself. Tell our audience about how you got to this point where you're doing really cutting-edge work in psychedelics.

Dr. Paul Miller:

Thanks, Michael. It's really nice to have the opportunity to speak with a colleague and someone interested in the area. So I as you've said in your introduction, I'm a consultant psychiatrist and I'm a specialist in working age or general adult psychiatry, but also in the psychiatry of late life. So I transitioned over that. I had started on a surgical track and then transferred across, becoming much more interested actually in the impact of trauma on the mind. And I had a wonderful-

Dr. Michael Koren:

-that's quite a transition!

Dr. Paul Miller:

yeah it is, from surgery to psychiatry. It surprised my board whenever I met with them and told uh this group of orthopedic surgeons that I was moving into psychiatry. They didn't really quite know where to go with that.

Dr. Michael Koren:

I can imagine.

Dr. Paul Miller:

Yeah, but it's uh it's been a change that I've never regretted. I think I make a better psychiatrist than a surgeon, but it it brought with it having seen the impact of trauma. And I think that throughout I was born at the time when what we now call The Troubles had started. So, really, all through uh my early life. This this is in Northern Ireland, and so the population in Northern Ireland is only 1.6 million people, and so in those days when there were large attacks and and loss of life on a very regular basis, that was something that just rippled out throughout society. And I think my mother was a psychiatric nurse, so I think I've always had a bit of interest, and then again, just sort of my practice leading me to a place where there were certain mentors who drew me into the interest in the psychological impact of trauma, and then had the opportunity where one of my mentors said, Look, this fun eye movement training coming over from America, and uh, why don't you come and do that? And that was uh eye movement desensitization and reprocessing or EMDR, which was created by the late Dr. Francine Shapiro. So it was an interesting piece because my journey had been from the medical, surgical, especially then into psychiatry. And again, there was it felt like psychiatry was much more of a an art than a science at times. I had the opportunity to be part of the Irish Schizophrenia triad study, which was really led by Professor Kenneth Candler, who was doing the work on this the genetics of schizophrenia, and uh the genetics of that team collected went on to identify the first gene of risk for schizophrenia. But I was very interested to see then sort of where where were we going to go in terms of would that actually ever be realized and and uh identifying the genes of risk have still not yielded a treatment for that. So I came across the work of a Canadian psychiatrist who's worked and practiced in Texas for a long time, and uh Colin Ross, and Colin was espousing in terms of even with regards to something that we tended to view as biological, like schizophrenia, that it was amenable in some parts to treatment psychologically speaking. And uh, so part of that linked into then the legacy of the troubles and trauma. And so those different strands of research sort of all came together for me.

Dr. Michael Koren:

Yeah, so so let me yeah, let me uh help our audience understand a few things. So you talked about schizophrenia, which is a horrible diagnosis. So uh explain to everybody what schizophrenia is as a diagnosis and what the prognosis is, particularly if it's not treated, so people understand that we're talking about really a very concerning and extraordinarily difficult illness to treat and to change the natural history of. So go ahead, break to break that down a little bit for the audience.

Dr. Paul Miller:

So when uh basically, if we look at the history of the diagnosis of schizophrenia, Kraplin first described it effectively in his big hospital, he had a group of people who would be admitted. And some of that group came in, got better, and left. And they were really the neuroses, but there was this group of individuals who came in and just got worse and worse and worse. And he termed that dementia precocks or like an early dementia. Ultimately, that illness, you've got to remember that in mental health terms, we diagnose illnesses as really syndromes. So they're collections of lists of symptoms. So the genetic work with Ken Candler was really looking at at the stage I was involved with the diagnostic statistical manual version three. And it was really the tightest definition of what Ken Kandler believed was schizophrenia and per outcome, schizoaffactive disorder were believed to be the same thing. And so really purifying down the impact upon the mind, how the mind processes and how the mind processing stuff relates to then the emotional life of that person. People are often aware of the positive symptoms, which are like delusions and hallucinatory experiences, hearing voices being probably the one most people think of initially. But then we have the negative symptoms, and those negative symptoms really leading to withdrawal, social isolation, and impaired functioning, really, as an individual in the interpersonal space. So, as an illness, it's it can be very wide-ranging, but there was a very negative prognostic picture to it. People weren't really expected to do that well. And I was intrigued by Colin Ross's work that began to say, well, maybe this is more amenable to treatment. And whenever we actually look at some of the research which has gone into the background of when that illness was diagnosed, the history of it shows that there were actually a majority of models looked at schizophrenia or an illness that was similarly named at the time as being something which was coming out of the environment. In other words, it was a response to what had happened to you. So if we look at work done here in Northern Ireland, what it showed was if you have three traumas before the age of 18, your risk of pathology level psychosis, which could include schizophrenia, is increased by 13 times compared to the general public. Whereas if you look at adding two more traumas, so five traumas before the age of 18, your risk of a pathology level psychosis is 172 times. So it's a massive increase. And this dose response relationship between psychotic presentations and what has happened to individuals has been found right across the globe. And work by organizations like the Hearing Voices Network again has shown that there is this dose response, and that's quite an important signal to be finding, not only a correlation, but something that, as we increase the risk of exposure to that. And that meant for me, I had to pay attention to this thing called trauma. And so while I was doing a research MD looking at tardive dyskinesia and more the biology of the medicines we were using, and looking at what exactly schizophrenia was, what I then was able to do was to take an individual who met all those criteria to be included in the Kendler study, but then treat them with a psychological method. And that psychological method was the EMDR. Again, borrowing from the history of how we get to schizophrenia is quite interesting because it comes from, first of all, split-off of an illness that was never going to get better. And that risk carries forward into how people look at the illness now. We talk of a severe enduring mental illness. It doesn't convey a lot of hope if I was giving you that diagnosis. And Kraplin used to say, well, when asked the question, well, what happens if somebody gets better from dementia precox? And Kendler's response was well, or sorry, Kraplin's response, sorry, Kraplin's response was, well, they didn't have dementia precox because nobody gets better from dementia precox. So there's a circularity in his argument,

Dr. Michael Koren:

In the reasoning, yeah.

Dr. Paul Miller:

But with a very negative view.

Dr. Michael Koren:

Well, yeah, let me let me ask you a few questions about that, because I think our listeners and viewers will will want to understand this better. So I'm under the impression, and historically, the training that we get in medical school in general is that there is a genetic component to schizophrenia. Is that still felt to be the case, I assume?

Dr. Paul Miller:

Yeah, I mean, I think most psychiatrists would agree that there is a there's a psychological component or sorry, a a genetic component to it. And there are genes of risk. The model, I think, now, however, would tend to tell us that there is an oligogenic model. In other words, we have lots and lots of genes of small effect acting in concert. And so whilst that's true, I think it is also still true that there is a fairly sizable impact with regards to what's happening from the environment that the person is in. And then through, for example, epigenetics, that the external environment is affecting how your genetic code is actually.

Dr. Michael Koren:

So there's a there's a yeah, there's a genetic predisposition to to this. But let me let me ask you this question. So if you have the genetic predisposition and you're never exposed to a triggering factor, will you get sick? Uh, do people that have the genetic condition but never get exposed to trauma get sick? Let me ask you that.

Dr. Paul Miller:

Okay, that that so that's a great question, Michael. And I think that the a way to answer that is for your listeners to understand it. When we think of a genetic condition, we we can think of if there's genetic risk, is it necessary and is it sufficient? So if we look at an illustration Huntington's, having the gene is required, so it is necessary. And if you have the gene, you can have the illness, so it's also sufficient. But that's important that we understand that's not the case for the genetic risk of mental illness. And so it confers a potential risk. So, as you've alluded to in your question, there is a potential that an individual may carry a risk to a pathology-level psychosis at a higher level. Um, however, if they're never exposed to a triggering factor, that person may not go on. So the genetics in themselves, as we understand them currently, do not appear to be sufficient. And we're not even sure of what genetics are also necessary. And it's likely that there are a lot of different sort of final common pathways that get expressed as the syndrome we now call schizophrenia.

Dr. Michael Koren:

Okay. So getting into the to the the traumas that you alluded to, give us examples of these things. Are these extraordinary traumas or traumas that most people would potentially get exposed to in the course of normal human interactions? A bad a bad grade on a test and a bad reaction to that. Give it give us a little bit of a sense for what those traumas may look like.

Dr. Paul Miller:

So again, we really saw with the introduction of the diagnosis of post-traumatic stress disorder, we really saw brought into the diagnostic manuals' concept of trauma. And if we look at the DSM, we have what's typically referred to as the gatekeeper criteria. And so criteria now are substantial traumas which relate to threat to life of oneself or perceived threat to life in others. DSM 5 is now also included, for example, first responders working with evidence of childhood sexual abuse and that prolonged exposure to that type of evidence is now also recognised as being something which is potentially very traumatic. The interesting thing that we've got to bear in mind is that some people recognize that there's there are different degrees or different characterizations of trauma. Some people will talk about a big T trauma as being the classical trauma that we see within DSM V Criterion A, but then they talk about small T traumas, which are not necessarily including threat to life and such like. And I think a colleague of mine, Katie Uche, she defines trauma as any threat for which the mind is not adequately prepared. And so within the EMDR model, EMDR basically talks about how we have this inborn system for processing information. And so if that system gets overloaded by the nature of the event that's happening, and if there is no existing networks that help the person to make sense of that, then it's much more likely that that could be a trauma which then has downstream impacts in terms of function and in terms of then, in some cases, leading to a mental illness. But we've got to also bear in mind Margaret Mead, the anthropologist, when she was asked the question, what's the earliest sign of human society? said that it was a healed femoral fracture. And the the questioner said, Well, how does that make sense? And he said, Well, the fact that this is a healed femoral fracture means that it took six weeks minimum for that fracture to unite, and probably another six weeks for the person to be able to be up and about. So, in a hunter-gatherer culture, if you had a femoral fracture, it was inconsistent with life unless you had a community around you. And so we begin to look at, for example, if I think of a patient who had severe bullying in childhood, we might not think of that as a criterion A trauma. However, when an EMDR we look at the dysfunctional memory network, it's a bit like my water bottle, Michael, that what goes into the time capsule of my water bottle is all the thoughts, feelings, emotions, and action systems of the age and stage at which the trauma occurred. So if that's an eight-year-old, then in here is the eight-year-old setting. And so when that's not processed and integrated, the difficulty is it sits like that little time capsule. So when you open it again, you've got an eight-year-old sort of pattern or or piece of software that then's going to cause problems because it's not going to fit in with maybe the adult software that's running in the person's mind. And it is going to be just re-experienced. If we use the analogy of our intro or our inbox and our email, it doesn't have a different place to sit, even though it's an eight-year-old memory, it's still sitting on our inbox where our current memories and stuff are coming in. And so we see from some functional neuroimaging work, for example, by Ruth Lanius, shows in a road traffic collision between a husband and wife how there are different ways that the brain is reacting. And sometimes we're seeing that when that normal system of processing information and memory making gets derailed, then it's not remembered, it's relived. So rather than I remember being in the room with a lion, it becomes I am in the room with a lion. And this is very important because patients who are six hours after a trauma, serious road traffic with loss of life, we can be compassionate, families can be compassionate, communities can be compassionate. But as we spool that out to six weeks, what about six years? People begin crossing the street rather than engaging in conversation with this individual. Physiologically, it's exactly the same state that the person was in at the time, and it is a reliving event. And so I think that helps us to be more compassionate, and it also helps in the interventions that we have to be designed in a trauma-sensitive way that acknowledges that.

Dr. Michael Koren:

So let's talk about the EMDR eye movement, desensitivization, and reprocessing, if I'm pronouncing that correctly. So explain a little bit more about that. And I'm going to use the initials rather than try to say the whole thing since it's

Dr. Paul Miller:

No, that's fine. That's fine.

Dr. Michael Koren:

It's a little bit tricky to say, but eye movement, desensitivization, and reprocessing. It's just so everybody could hear that. Did I get that?

Dr. Paul Miller:

So it's it's really the name reflects what the model involves. So when Dr. Francine Shapiro created the method at the end of the 80s, I think her first article was was posted. I trained about it a bit later in in 1997. And what Francine was looking at initially was she realized that when thinking about something distressing, as she followed, I think the the tail, the apocryphal tail of squirrels moving about uh in a in a in a grass area, and she realized that that sort of shuttling of the eyes seemed to have some sort of an effect in terms of the memory. And although that was a bit bizarre, she she moved forward with that and as part of a PhD, and so then really generated what became initially EMD, and then realizing that there was another component that needed to added the reprocessing piece. And I guess the simplest way to think about it, Michael, is that EMDR, because it had that sort of weird bit involving eye movements, there were a lot of studies that sort of deconstructed it first of all and looked at you know what bits were there. And we had cognitive behavioral therapy and we had trauma-focused cognitive behavioral therapy growing, and we had really at that stage people beginning to see and ask the question is this just another version of CBT with a bit of decorative eye movements added that aren't really doing anything? And so the important thing that it showed was that uh in EMDR, the normal processing of a memory becomes derailed. And so if you think about it this way, if our brain represents a building, we're coming in at the ground floor with all our raw data, and that's the five senses, and then that gets relayed up in the brain stem. And if we think about we can think of the, in a sense, Paul McLean's tri-brain model. And if we use our hand and wrist to demonstrate, so the the fingers are the sort of newest part of the brain, the neo-mammalian or neocortex. The the base of the thumb and the thumb represents our limbic brain, or the brain described by Pinel's or grand lobe limbique. And this here represents so my thumb represents oral factory bulb, which just sits at the top of the nose. So smell is very evocative of emotion, and we know that. I can think of the smell of baking bread, and it immediately activates memories from my childhood and my grandmother baking. So smell can be hugely evocative of that, but in trauma cases, it could also work in the same way and pull up smell of burning from a road traffic placing is a common one that people are very troubled by. And then we have the the wrist really representing the brain stem. So if if if in our building information should come in the ground floor and go up to the top floor, but at the level of the wrist, it's also moving from the right side of the brain to the left side. Of the brain and then back again, actually. So Ian McGilchrist's work talks about the right hemisphere being where we are presencing the world. It's the live feed, but the language centers primarily that take the lead in language and grasping language and grasping the situation and indeed grasping tools is a left hemisphere activity. So information feed gets should get passed across, broken down, understood, connected with existing learning, and then it goes back, feeds back into presencing. So it affects how we are in the world, and that's what ought to happen. But if we think about the information coming in, has to go through an alarm and alert system and amygdala. And it's like a metal detector at the airport. It's really very simply done and it gets triggered. And sometimes it'll get triggered when it doesn't need to be triggered because it's better to react and be incorrect. So I jump out of the way of a hose pipe in the garden thinking it's a snake. That's better than I see the thing in the grass and I just ignore it and it turns out to be a snake and it bites me. So we're sort of we're we're programmed and created to almost overreact. And the difficulty is that for some individuals, that amygdala becomes so sensitive that it just keeps shutting down traffic and nothing really comes through. So with EMDR, what we're doing.

Dr. Michael Koren:

So just to break down what you just said. So to summarize it, there's there's brain processing that occurs, and the brain processing is affected by memories, and how that brain processing takes memories and brings it to your current reality is something that may go afoul, may go wrong, which is sounds like is part of the disease that we're treating. Is is that a reasonable way to summarize it?

Dr. Paul Miller:

Yeah, that's a that's a fair way to summarize. Adaptive information processing as the model which underpins the EMDR would then say that that that experience, which isn't properly processed because of the alarm alert that's associated with it. Well, the first thing is that it doesn't get beyond this more basic level of perceiving. So giving it an emotional label is very difficult, but also integrating it with new learning. So, for example, you can have a very successful CEO of a Fortune 500 company doing really well, perform really well, but because they are the child of alcoholic parents, if they come across having to deal with an alcoholic colleague or an alcoholic employee, they might go back into activating that time capsule we talked about. So now instead of reacting as a very experienced CEO, they start to come from a place of that network feeding into, which could be the eight-year-old who actually just then hid from their parents. And so the difficulty is you see somebody then maybe in their adult life hiding or avoiding areas that they do have competence but fully do not.

Dr. Michael Koren:

Okay. Okay. So again, so talks to us a little bit more about this desensitivization, uh reprocessing. What does that mean in a practical day-to-day sense? Help us understand that.

Dr. Paul Miller:

So we follow the ouch. And so I would say to you, you have had a road traffic collision. Imagine what's what's the worst part for you. So a lot of clients, because now most cars are fitted with airbags, the airbag, once it deploys, there's often a smell of burning in there. So a person has had a road traffic collision, they maybe feel like they're trapped or they're certainly disorientated after the airbag deployment. And often the initial thought, I smell burning, the car's on fire, I'm going to die. So we would look at that memory network. And it's important to remember that a memory is not a memory of an event. A memory is a memory of the last time that memory network was activated. And so every time that memory network gets activated, it makes it vulnerable to change. So there is the potential for us to then degrade that memory, and that's really what Francine was utilizing. And so if we think about it this way, normally there is a signal coming down from the neocortex down to the level of the amygdala and sort of saying the thalamus saying, look out for this stuff. This is dangerous. That's okay, let it through. And so if we think about that as being a description of a written individual given to airport security, we only want you to look for a white guy who's six foot seven and has a beard and wears glasses. So, what does that do? It improves the flow of people through that security node because there's loads of people you can just let through without having to search. And that's like a normal functioning brain. It knows what to look for and it can filter through a lot of information. So processing is maintained at good speed and efficiency. In trauma, that descending cortical phalamic signal gets degraded. And so there's difficulty in being able to decide between level of risk or better worst actions, and that that problem-solving aspect is it really struggles because that signal is missing. And what we know now from the research is that EMDR, the eye movements is only one form of alternating bilateral stimulation, but that replaces that descending signal. So the Dutch research shows us that it has two things. So if I ask you to think of a troubling memory and I do a set of BLS, we should expect two things to occur. One, a reduction in the vividness and emotionality of the memory network that we're working on, and a greater ability to distance and notice and therefore bring new information. And so we now know that part of that is happening at the level of the brain called the anterior cingulate cortex. And so the ventral part of that system deals with the emotionality, and so we see emotionality coming down, but the dorsal part of that same structure is the cognitive part. So it's like a seesaw. We get the distancing and noticing increasing because we're getting that affective tone coming down. So somebody comes in, can barely talk through the first five minutes of their road traffic collision. Maybe it takes them a whole hour, a whole 90 minutes to do that. By the end of the session, or by the end of the treatment, the person is able to talk through that road traffic collision in a very quick way because they're not reacting to it like it's in the present tense.

Dr. Michael Koren:

So let's just uh I'm gonna interrupt you there for just make sure I understand. So you're you're doing a session, and these explain exactly what the the therapeutic technique is, because I'm not sure that it's not clear to me. So just for everybody else, help me understand that. So yeah.

Dr. Paul Miller:

Yeah. So the first thing to say is EMDR is one of the gold standard treatments for the record recognized for post-traumatic stress disorder. So you're the model itself has eight phases and then three-prong protocol. So the three-prompt protocol means we're dealing with past events, present-day triggers, and then future catastrophizations, and ultimately we want to put an idealized future in there as well. So there's a past, present, future aspect to what we're dealing with, but also then we have eight phases, which are involving assessment of the patient. And then in phases three to seven, we we call those the EMDR reprocessing sessions. So across phases three to seven, we're really only doing [...] things. So we we identify and activate the memory network, and that's phase three work. And what that does, it activates the memory system, puts some energy into it, and then that makes it vulnerable to change. And so then we change it, and so part of that is looking at the story a person tells themselves. I see myself trapped in the car, the worst part is the smell of burning, and I tell myself I'm going to die. Okay. So that's that's activated that memory network. And so then by putting in the BLS, what that does is it helps the brain to think about that problem in a different way, in a different level of thinking. So I use the analogy of a coffee shop. If you and I went into a coffee shop and we wanted to have a private conversation, however, everyone around us was sitting in silence, what would that do? Well, it would impair our willingness to communicate about this private topic. And that's your brain in trauma. It's shut down, it's reluctant to communicate the way that it it ought to communicate the problem solve, and it really everything's a bit stuck. However, if we now picture a coffee shop where in Starbucks it's really noisy, people are talking, well, that is two effects in the communication between us. Firstly, I need to concentrate much more on you because I'm deaf. So I'm going to have to really focus in and concentrate on you. So it improves focus. But also, we're no longer worried that everybody else is sitting in silence listening to us. So it actually facilitates communication, and that's really what we see happening in regards to the activity of the eye movements, that they're putting in that additional. And I wrote a paper about that referring to helpful randomness, because we see that in the biological system already called stochastic resonance. And whenever we look at the signal that goes in, a study by Herccht and colleagues looked at a sham signal where nothing was being done. They looked at bilateral simultaneous signal, and then they looked at bilateral alternating. And in that functional MRI study, they showed that the benefit was from the function from the alternating bilateral signal compared to the simultaneous bilateral compared to sham being the least effect. So we know that the BLS is a very simple thing.

Dr. Michael Koren:

Let me so okay, so you're talking about uh sort of placebo-controlled trial with a sham. What was the actual intervention for that? Uh help me understand.

Dr. Paul Miller:

The intervention was the intervention was just looking at the alternating BLS. So eye movements are referred to as as bilateral stimulation or alternating bilateral stimulation, but they can also be delivered as taps or tones. And so that particular study was looking at, if I remember correctly, taps and using simultaneous and then alternating to see if there was a difference.

Dr. Michael Koren:

There, there are taps, a therapist is giving these taps, or a machine is giving. How does that work? Break that down for me a little bit more. What is this actual intervention?

Dr. Paul Miller:

So the intervention session would be me asking to first well for you to tell me what the worst part of the image is. We'd be looking at where you feel that in the body, and then we would be looking at you know this the narrative is going along with that. So I'm going to die in the example that I gave you. And so once you hold the target, I'd invite you to hold the target in your mind, and then I would introduce the bilateral stimulation. Now it's important to state here that I'm not asking you to hold on to the image because it's not an exposure method. So I'm not saying keep the image in your mind. I'm literally saying the famous phrase in the EMDRs, go with that. So it's really about I'll do a set of BLS and it's very fast, as fast as we can. Then I'll say, look, take a deep breath in, take a mindful pause. Okay, what comes up for you now? And so the person will then, the memory will often be my experience of being an EMDR client would be that the image goes very quickly for me and I quickly move the felt sense in the body and the emotions of it. Other people will move through it in a more narrative way, that they'll see the image changing and they'll be moving through the traumatic experience or series of traumatic experiences.

Dr. Michael Koren:

But again, the the actual intervention when you say the tapping and then the sham, how's that applied? I I I'm still not clear on that. I'm sorry.

Dr. Paul Miller:

Yeah, no, that's okay. So so what once you bring up the trauma network, so you bring the memory to mind, you bring then the emotion to mind, so you feel fear, and then you're connecting to where you feel it in the body. So that's we've activated the memory network, and once we've done that, I would just simply say follow my fingers. And so you would then be watching the therapist's hand sweep backwards and forwards, shuttling your eyes, and that that's what helps to create the change. So, whatever Bob Stickgold, who looked at the work, his his wife is Debbie Korn, who's an EMDR therapist, and so he was thinking as a sleep researcher, well, is that shuttling of the eyes similar to rapid eye movement sleep? And so part of his proposal was in REM sleep, we see that there's a much uh wider connecting within the brain. So the brain, although it's creating the challenge because of its exposure to the environment, that you could actually have the brain think at a different level of thinking as it does in REM sleep. Now, another sleep we start to.

Dr. Michael Koren:

Yeah, I I think I I think I get it. So that was very helpful. So basically, when you bring up the traumatic memory, you want to do something with the eyes that creates another neurological input that may re help the brain process it differently than it had been processing it previously.

Dr. Paul Miller:

Yes. And and so the current research looks at that uh Dutch work, they really favor the texting working memory model. Uh and so the the way to think of it is if we take all of our trauma memory out and we have it sitting in front of us, if we don't do anything else to distract us from that, we should be able to put most of it back into the time capsule again. And so that's what happens many times for individuals who've been traumatized. There isn't a change, and and the same material just gets put back into the container after it's been triggered. But if we tax working memory,

Dr. Michael Koren:

You put you pull up, you pull up the traumatic memory and then you do something with your eyes to try to change that the way it's put back into wherever it came from in a in a different format, if you will.

Dr. Paul Miller:

Yeah. And so some of it, if we think of a traumatic memory, traumatic memories are more there's a reliving aspect to them. So if I was to ask you to turn around and describe the books on your bookshelf, well, it would be an observational task. You just read out the titles as you go along. And that's like in a sense, the observation of a traumatic memory is that the person doesn't really need to think about because it's right there in in front of them. Whereas once we process it, it's like me asking you to tell me about the books on the shelf behind you without turning around. It becomes a uh it becomes a something which is about recollection then. And and so, in a sense, the the traumatic event is something which has a time stamp now. So we can say, well, that was then, this is now. And so that dual awareness of one foot in the traumatic past and one foot in the present is something that we then are are going to be seeing as pretty much in line with most psychotherapies, actually.

Dr. Michael Koren:

Yeah, interesting. So fascinating stuff, absolutely fascinating. So I I think I have a better understanding of of what you're doing and and thank you for that great work. So, as a person that's really interested in clinical research and clinical trials, I want you to talk about a little bit of your experience with the IMPACT 1 trial. I know that you've been involved with that, and so explain to people what that is and what you are looking at in terms of an intervention for some of these psychological illnesses.

Dr. Paul Miller:

Yeah, great. Thank you. IMPACTS 1 was a study operated by Transcend Therapeutics, and they've been looking at their compound TSN D201 or methylone. So most individuals would have heard of methylone, but you'll have heard of its sort of related analogue, MDMA, or ecstasy, or Adam as it was originally known. And so it's the these two medicines can be broadly thought of as empathogen. But one of the things that the early work around methylone has shown is that it it results in this increased potentiality for growth, or what we refer to as plasticity in the brain. So they've come up with the term for it as a rapidly acting neuroplastigen. In other words, it shows that increased or enhanced potential for growth. And really, connections in the brain and in regards to the neural systems, if we give it connection and organization, is the more adapted state. And when we look at the impact of psychological trauma, we're generally looking at a more disorganized, almost de-attached state or fragmented state. And so with the IMPACT 1 study, it was an open label study. So people knew that they were being dosed. I think if I remember correctly, there were 14 people recruited to that, and our site recruited six of those. It was very interesting because the people had to have uh a moderate to severe diagnosis of post-traumatic stress disorder. So many of these individuals had actually PTSD for you know quite a long time and had been through, they had to have had two field treatments. So these are individuals who'd sort of done everything that they felt that they could do and then were going to be trying this medicine. The difference compared to most psychiatric drugs is that most psychiatric drugs are something that I give you and you take every day. Whereas with the with the methone within the sound therapeutic study, it was much more like the MDMA work that uh Rick Doblin and MAPS have been championing. And so what you see is really more of a procedure. So the individual would come in, there would be a dosing day, and then they would receive a number of those dosing days with follow-up. And what we saw from those dosing days was substantial change uh and for the benefit of the individuals who who came along. So it helped them to be able to look at things in a slightly different way. And again, at this stage, really, because the focus is on FDA licensing of the medicine, there's no heavy sort of psychotherapeutic endeavor around it. Although there is a, you know, there is work to build that therapeutic alliance into the context of it. But I think that ultimately you we're going to need sort of uh the people to to get the best out of it if we look at what's already there in terms of, for example, ketamine work. We know that the ketamine can be effective, but these medicines aren't a one and done and often that you have the maximum benefit, you need to do some sort of therapeutic endeavor.

Dr. Michael Koren:

Right. So just not knowledgeable in this area, but when you do a PTSD study, what's the endpoint that you're looking at? Are you looking at uh incapacitating episodes that are sequella of the PTSD? Or help me understand that a little bit better.

Dr. Paul Miller:

Yeah, they were looking at the CAPS 5 as a measure of the impact of the trauma. So these individuals often are presenting with intrusive thoughts, reliving of the traumatic memory networks, but also then the sort of social withdrawal and such like that comes from that. So these individuals often end up living very highly curated lives with much higher sort of threat perception and maybe additional security features to try and keep themselves safe. So again, the measures were looking primarily at meaningful functional change in the individuals around that, that they retain their caseness for diagnosed with PTSD. It showed substantial improvement with that.

Dr. Michael Koren:

Okay. Interesting. Interesting. Well, that's great work. And obviously, as a clinical trial person, we're very supportive of it. And hopefully this work will continue to occur and we'll we'll get better and better trials. I guess it's tricky to do placebo controlled trials in this space, but at the end of the day,

Dr. Paul Miller:

Yeah, that's a that's a great point, Michael. I think in terms of the Uh well, first of all, I think that when we look at the area in general around psychedelics, I think that Transcend and their version of methylone is different in a sense that it's not like the classical psychedelics, like magic mushrooms or LSD, in a sense that it's not something that's inducing a hallucinated state or what many people would think of as a psychedelic experience. Quite the opposite, actually, it's a very gentle thing, and and people because we're dealing with people who have severe fear and stuff, we you know, that I think is an important piece to consider. And that's why, in a sense, it's not talked about as a as a psychedelic medicine, because it's really it's it's different from the classical psychedelics and particularly also where where they work in regards to the brain.

Dr. Michael Koren:

Right. Yeah, just just just for practical sense to say it, it look again, use LSD. I haven't had any personal experience with it, but I've been around people that have had had it. And you know, that's not something that you can create a placebo for, if you will. So you yeah, the patients are pr will pretty much know whether or not they've gotten the active substance rather than in a typical case for your blood pressure or for uh your cholesterol. Obviously, you might not know if you're on the active drug or the placebo. So so there are challenges there to do research in your traditional model. And uh, I'm wondering if you have some thoughts on how to overcome those challenges.

Dr. Paul Miller:

Yeah, yeah, great question. So I think the first thing is with Transcend, we've now had IMPACT 1 but also IMPACT 2 and EXTENSION study has just gone to data lock. So we moved from an open label IMPACT 1 into then a randomized, double-blinded, randomized controlled study. And again, that then when that finished, so we had 17 people on that study that we enrolled in our site, and then 12 of those went into an open label extension where they knew they were then receiving the active medication. And so I think now we're moving forward with a phase three, which should be sometime next year. And I think that's you know, that's right and proper. FDA FDA have granted breakthrough status to methylone. And I think it's yeah, it's going to be something which is a really valuable part of what we have to offer, I think. But the challenge that you're talking about is one of the things that the FDA commented around the MAPS and MDMA work, which was functional unblinding. And that is the challenge, I think, in the the area of the wider psychedelic research, psilocybin, psilocin, magic mushrooms. There's even research looking at DMT and ayahuasca and such like as well. And you know, you're pretty clear who's receiving the active drug and those things, as you say, using the LSD example. So I think there is a real challenge. I think the double-blind placebo-controlled trial is seen as the gold standard. I think we need to think of new models in regards to looking at the psychedelic space. For something like methylone, uh, there's not as much of a difficulty with regards to the functional blinding because people aren't having the same types of experience. But you are dealing with an altered state as well. And so some people believe we're and we need to see the data to see were they right or or not. Some people certainly have strong feelings about it, but again, strong feelings can be found to be completely inaccurate, and they they may or may not have received active agent. So there's a bit of data crunching to be done in regards to that. I think the functional unblinding is less a problem for methylone, but I think the wider sector looking at magic mushroom research. We have a couple of magic mushroom studies coming next year, and I think that that's more of a challenge, I think to really have full blinding. It's hard.

Dr. Michael Koren:

Yeah, so it's interesting. And I'm just brainstorming here and with not that much knowledge of the particular area that you study on a day-to-day basis. But maybe if you compare one type of product that affects your sensorium with another, uh cannabinoid, for example, against the hallucinogen, and see if that has effects in terms of PTSD or the outcomes that you're looking at. That might be one way to blind things a little bit more. So the patients who are participating have sort of a chance a change in their sensorium, and it may be more difficult to say what product they're getting, which is, as you point out, a key part of our analytical process when we run clinical trials, is that we try to make these observations in a blinded state so that the people participating and the observers both don't know what product that the patients are taking, so that we're not biased in our assessments.

Dr. Paul Miller:

Yeah, that that and and again, studies have looked at that by using things like niacin, which will cause some degree of flushing. So people will feel something and they think, oh yeah, I must have taken something. So there's there definitely is thought being put into that. I think other studies have also looked at using the same agent, but using different doses felt to be either subperceptual or sub-treatment, but may still induce some of the sensorium change. It's a very interesting area, I think, for for academic minds to put themselves to because it I think it's a question we're going to have to more meaningfully engage with, because really a lot of the classical psychedelics really there is it is impossible, I think, nearly the blind for that.

Dr. Michael Koren:

Yeah, absolutely. Well, Paul, this has been an absolutely fascinating conversation. Thank you for educating me on this area. Good luck with your future research. And any final words for our MedEvidence viewers and listeners?

Dr. Paul Miller:

Yeah, I think stay stay listening to this area, I think, in regards to mental health. I think the things there's two things happening in parallel. I think that the current models that we have for diagnosing mental illness, I think increasingly as the neurobiology knowledge increases, we're going to start to find that they're maybe quite limited. And I think we'll begin to change. And there are already models such as the power threat meaning framework, the Colin Ross's trauma model in and of itself, where we really go back to the work of Carl Manager, who was really an abolitionist in regards to diagnoses because he was saying that it is so important to understand individuals. And I think although we can look at these medicines in broad groups, I think the research coming back down to the individual and what we can do, that's where we're going to begin to see the change. And I think for us as a clinician who's worked in the area of trauma for 30 years, seeing somebody come in and with a course of four doses of a medication be able to do things they haven't done in decades, like go take their children to the beach. You know, simple things. It's not, it's not like huge, big radical things, but small things are not trivial. And I think what we begin to see these changes, it it there's a responsibility on us to do the research and due diligence around it. There hasn't been really a lot of psychopharmacology research really for the last two decades. And I think the return to these psychedelic medicines is important. When we think of LSD, when LSD was banned, it was a political decision made by Nixon's regime. And the reality was that LSD, the most researched psychiatric drug at the time, the next day it was unable to be used. And I think as doctors and as scientists, it's important for us to not be caught in the socio-political, but to look at the socioscience. And I think the science shows that these medicines, if nothing else, deserve our scrutiny. And I think, you know, some will work well, some will not work as well as people think they will, but I think there's a lot of potential here, and I think learning to use them, I think is our responsibility.

Dr. Michael Koren:

Yeah, obviously we don't know if they work or not unless we study them critically in a clinical setting. And certainly I think most of us in the scientific community will be extraordinarily supportive of that type of research. Professor Paul Miller, thank you very much for being part of MedEvidence.

Dr. Paul Miller:

No problem. Thank you very much for having me.

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