Full episode transcript (beware of typos!) below:
Nick Jikomes
Berra Yazar-Klosinski. Thank you for joining me.
Berra Yazar-Klosinski 2:25
Thanks for having me.
Nick Jikomes 2:26
Yeah, super excited to have you and talk about maps and some of the stuff that you guys are doing and related topics. Can we just start off with some very basic background for people? So who are you? What is maps? For those that don't already know? And what do you actually do for them?
Berra Yazar-Klosinski 2:42
Yeah. So I'm currently the chief scientific officer. And I handle anything related to science at maps. And map stands for the Multidisciplinary Association for Psychedelic Studies. And so maps is understandably a much easier acronym. It's a mouthful. So Maps is a nonprofit, tax exempt charity. That is a research and education organization. And it's been around since 1985. So we recently celebrated our 35th anniversary together. And Maps has two wholly owned subsidiaries that include maps public benefit corporation, and maps Europe, BV in Europe. And so the subsidiaries are tasked with running the research about of psychedelics of various kinds. And the overall goal is to demonstrate any risks as well as benefits of controlled substances that are actually beneficial for treating chronic psychiatric disorders?
Nick Jikomes 4:02
And what is your scientific background? And why was that relevant to becoming the Chief Science Officer at maps?
Berra Yazar-Klosinski 4:10
I have a My undergrad was in biological sciences. And I have a minor in drama. And I have a PhD in Molecular Cell and Developmental Biology from University of California at Santa Cruz. So I actually started working at maps, right when I was finishing up my PhD dissertation, and I essentially brought what I learned from grad school in terms of how to conduct research projects and and infuse that into Maps. So I was one of the original people who ran all of the clinical trials for maps of for treatment of post traumatic stress disorder. With various control substances, including MDMA, and LSD, and observational studies with Ibogaine, and also with cannabis,
Nick Jikomes 5:12
I want to start off by just having you basically tell everyone, the basic high level results of your recent recently announced phase three trials with MDMA. And before we get into too much detail about like, all of the detail for those trials and how they were conducted, and getting into the nitty gritty, I then want to back up and kind of unpack PTSD and MDMA for people that aren't familiar with this illness and with that drug and how it works. So again, just starting, what was the recent result that you guys published?
Berra Yazar-Klosinski 5:47
Yeah. So the reason result came out in May 2021. And we published in the well known scientific journal Nature Medicine, on the results of our phase three clinical trial of MDMA assisted therapy for treating post traumatic stress disorder or PTSD. So the really top line result was that the study was highly significant. And the it was so significant it was, it would be described as statistically very persuasive from an efficacy standpoint. And also the safety data was really good too. And we didn't uncover any, any new, serious safety signals. It was also the largest study that's ever been conducted of MDMA assisted therapy. So 90 patients were treated in the study. And the fact that we're able to do this in a multi site, clinical trial, spanning across the United States, Canada and Israel, and collected data at 15 different clinical trial sites and oversaw the conduct of the study from the public benefit corporation side was really, really good. And MDMA has breakthrough therapy designation, from FDA for treatment of PTSD. So we benefited a lot from added attention and interaction with the US Food and Drug Administration.
Nick Jikomes 7:21
What is breakthrough designation, designation.
Berra Yazar-Klosinski 7:24
Um, so this is one of the special programs that FDA has that enables sponsors to get additional support in terms of developing their clinical trial protocols from the agency. And we obtained it on the basis of comparing our phase two clinical trial data to the data that was used for approval of Paxil and Zoloft for treatment of PTSD. And so from the side by side, from the historical comparison to our data, we had a much larger effect size and hence warranted additional attention.
Nick Jikomes 8:07
I definitely want to get into comparison between your results and sort of the the standard treatments that have been used historically for PTSD. Can you briefly just talk about the patients in the trial, they all had PTSD? Were they all veterans that they all share some other characteristics? Or was it a mixed bag?
Berra Yazar-Klosinski 8:25
It was a mixed bag, because we really wanted our results to be as generalizable as possible to the real world. So PTSD, patients often have a lot of other psychiatric diagnoses and medical diagnoses along with having PTSD because it's not just a mental health issue, it's also kind of a issue that affects the body because of chronic exposure to stress. And, you know, as we're coming out of, you know, a global health pandemic, many people can relate that chronic stress is not good. And so, PTSD patients in the study had very high levels of depression along with PTSD. And they also had a history of alcohol or substance use. And some of them also had active mild alcohol or substance use, you know, coming into the study, and they also, on average, had experienced severe adverse childhood experiences measured with the ACE score. And so, this was a measure that was actually developed by Kaiser Permanente to monitor kind of the meta the medical impact of having adverse childhood experiences. So we included that in order to help characterize our baseline demographics, Overall, the the patients were majority white, Caucasian, and 67%. Female.
Nick Jikomes 10:11
I see. And then so roughly speaking, is that match up with the general population that has PTSD?
Berra Yazar-Klosinski 10:18
Yeah, in general, female sex of birth is, you know, associated with having a PTSD diagnosis. And, you know, typically people hear a lot about veterans with PTSD. But the majority of the population that has a PTSD diagnosis is actually females who are who are survivors of sexual assault.
Nick Jikomes 10:46
If that was actually going to be my my next question is any some of the major cohorts of people that tend to have PTSD? So that's, that's the biggest one it sounds like?
Berra Yazar-Klosinski 10:53
Yeah, I mean, we only had 13 veterans in our study. And this is, you know, of course, it's only a small subset of the overall population, but reflective overall. And we also measured socio economic factors related to the patients that who were in our study or participants for in our study. And they had on average, had most of them had had some college classes, so, but not completed college degrees, their average age was like 41. So and then, we also looked at the, like how long they had had PTSD symptoms, and our study, and about 25% had had PTSD for 20 years or more. And so the maximum was actually somebody who had had PTSD for 63 years. So this is definitely a pretty highly traumatized population. And in order to be eligible for being randomized to MDMA or placebo, they also had to have severe PTSD, or at least severe PTSD. And how
Nick Jikomes 12:09
would, you know, most people, I think, have at least a vague notion of what PTSD is, or very basic idea? How would a psychiatrist define what PTSD is? And what is diagnoseable as PTSD? And what are, what are the most common constellation of symptoms that people with PTSD actually live with?
Berra Yazar-Klosinski 12:31
Yeah, that's a really good question. So, PTSD, is defined, based off of 20 different symptoms. So there's, uh, in general, there's a lot of hyper arousal. So people are very jumpy, and, you know, feel like, they're always on high alert, always in fight or flight mode. And, you know, the diagnostic criteria for PTSD are clustered into different different symptom clusters. A really important one is actually functional impairment. So people or, you know, their day to day lives are impacted by having PTSD symptoms. They have, you know, with the, with the recent research that's coming out, it's primarily a disorder of, of memory. And so and also comes along with having nightmares, flashbacks, you know, highly prevalent anxiety as a result of those things. Poor sleep. And so all these criteria end up getting bundled together to come up with the PTSD diagnosis. And so if somebody walks into, you know, a clinicians office, they don't always get accurately diagnosed actually, because there's, there's some variability, like some people with PTSD will have more of a certain kind of symptom cluster than others. There's also a new subtype of PTSD that's been defined more recently, with the diagnostic and statistical manual version five, which is DSM five. And this is called the dissociative subtype. So, you know, normally, most PTSD patients will will be in fight or flight mode and hyper reactive. But actually, with a dissociative subtype, they're often in the reverse category. So they're numb and hypo aroused, and essentially, feeling dissociated from their environment and feeling like things aren't real, that are happening and that they're almost like shrouded in a blanket and not Be able to connect with their environment and their community?
Nick Jikomes 15:04
And how do we? How do we think about how much of a social burden This is? How many people have it? How expensive is this to treat? how debilitating is it for people that have it?
Berra Yazar-Klosinski 15:18
It's really debilitating. So it's a little bit challenging actually to calculate exactly what the social burden is, primarily because having PTSD also comes along with, you know, having medical diagnoses that kind of outshine having the PTSD diagnosis in terms of claims, medical claims for the insurance system, for example. So it definitely takes some some legwork to try to pull out all the cases where, you know, PTSD, diagnosis is involved in the claims for treatment, because often people prioritize having their medical diagnosis treated over their mental health diagnosis treated. So that's a little complication, in terms of speaking to the overall healthcare, system burden. But in in, in the case of PTSD, most people you know, after they get a diagnosis, they end up going on antidepressant medications that are first line treatments. So I had mentioned Paxil, and Zoloft. So they'll go on the first line treatments and try that for, you know, approximately 120 130 days or so. And then quickly, they end up moving into trying other off label treatments, which are second line, and even third line. And so, you know, within that point of getting a diagnosis, half of them, and trying evidence based treatments, and then quickly move into off label treatments, because the approved treatments are not working for the majority of the people. So it's really important to have other options.
Nick Jikomes 17:13
So it's hard to calculate any specific level of social social burden. But this is something that's very severe for most people that have it, you're living with it for years or even decades. So it's very burdensome. How many actual people have this is hundreds of in the USA is hundreds of 1000s. if not millions,
Berra Yazar-Klosinski 17:33
millions? It you know, and this is pre COVID numbers. So and, you know, I think that the prevalence estimates I had seen were about 8.6 million before COVID. And, you know, usually, like many people are exposed to trauma, and a subset of them end up developing PTSD. And, you know, and then that number was 8.6 million. But now since trauma exposures so much, even more prevalence and chronic stress exposure is even more prevalent because of the pandemic, it's likely that those numbers are going to go up. And in our study, the average duration of PTSD symptoms was 14.1 years.
Nick Jikomes 18:19
Wow. So millions of people have it, have it for many years. Some people have it for many, many years. Can we talk before we get into like brain stuff, and more of the hardcore biology behind this? You mentioned that PTSD, and I've heard this before is thought of, in many cases as a disorder of memory. I've heard it described as the inability to unlearn or forget trauma, say or something that happened to you such that, you know, when you have PTSD, you basically have some terrible thing that happened to you that you're exposed to. And the typical person would effectively unlearn the emotional salience of that thing. So you don't you don't forget what happened. But you don't keep attaching the same level of emotional salience that you did in the moment when you experienced that the first time, people with PTSD sort of just continue carrying that with them. And so there's, there's something going on that has to do with memory, and forgetting and attaching or D attaching the emotional salience of something traumatic from the actual content of the memory. So what do we know? Can you just unpack that a little bit more for people? Is it really should we think about PTSD as a memory issue?
Berra Yazar-Klosinski 19:36
Yeah. So when you go to sleep at night, that's when your your memories from the day are kind of consolidated and put into your long term storage. And so we think that memory and memory consolidation might be involved in the development of PTSD. So if your memory are not consolidated and put into long term storage, then they're still around and still available to be experienced. So that's one theory. And we've done some studies that, you know, we've funded some studies in rats at UC Denver that aims to, you know, recapitulate, you know, in a rat PTSD model, what that might entail. And so, and there's also been independent studies conducted in mice. And so it seems that the studies between rats and mice generate a different results. And a very important caveat is that you can't get wrote in psychotherapy. So. So there's definitely some limitations in terms of translational studies that have aimed to address this. But both the studies did find that MDMA was somehow influencing memory consolidation or reconsolidation is the models,
Nick Jikomes 20:59
is it fair to say, even if we're caricaturing a little bit, that maybe the basic idea here with this viewpoint is we're making memories all the time, some of our memories get consolidated into long term memory. So if something happens to us, we remember it for a little while, then we forget it, something else happens. We remember it for a little while, and then it's consolidated into long term memory. So we carry it with us for a long period of time, in the process, the brain healthy brain uses to make something go from short term to long term memory. Is it accurate to say that that comes with a stripping away of some of the emotionality so that you're sort of just remembering the content, but you're not moved by it in the same
Berra Yazar-Klosinski 21:42
way? Yeah, I would say that's true. And so I really like the way you describe the emotional salience aspect of it. Um, and so the, the other part of this is that, you know, sleep quality is, is so poor, in PTSD patients and, and I think there's, you know, a number of treatments that have really tried to just improve upon sleep quality in order to see if it can have an effect on PTSD. And I think those have been marginally, marginally successful. So they're, you know, there's been a couple treatments that ended up stalling in their development pipelines, because the results just weren't as dramatic as they needed to be in order to really create a change. There's another theory that I think is interesting, that involves, kind of form hormonal regulation of, of stress. And so there's this thing called the hypothalamic pituitary axis. And this is how your body kind of regulates, like homeostasis and how you're feeling in general. And so there's some really interesting studies that have looked at how the HPA Axis regulates stress through cortisol. And so in the context of PTSD, when somebody experiences stress, then cortisol is expressed, and it shuts down the fight or flight response through, you know, converting you from being in the sympathetic nervous system to the parasympathetic nervous system, primarily signaling. And so this is the difference between fight or flight versus like, vegetative contentment and digestion. And so, in the context of PTSD, the cortisol doesn't seem to function in the same way and is an actually is too low. So then there isn't this negative feedback loop that tells the body Hey, it's time to switch off your fight or flight mode. And you can, you can relax now, right? So then there are, you know, there's there's definitely some merit to looking at treatments that might be able to temporarily increase cortisol.
Nick Jikomes 24:13
I see. So So paradoxically, at first, if I'm hearing you're right, people with PTSD tend to have low cortisol levels, they have this low level of stress hormone, you might intuitively think that they have high levels, right, what you're saying is because their levels don't increase the way a normal person's do it sort of not flipping an off switch that normally gets flipped. Yeah. Interesting. Okay, so PTSD, it's a stress disorder. People with PTSD basically have chronic stress to put it in very simple terms. And stress doesn't turn off because their home hormone systems are out of whack. Perhaps that's related to this memory issue. Yeah. You've mentioned that the first line of defense is basically SSRIs. Can you explain why they're the first line of defense? How will they work and what is SSRIs are and what they do.
Berra Yazar-Klosinski 25:01
Yeah. So, you know, these studies were were conducted by a pharmaceutical companies, you know, more than 20 years ago. And at the time, that there's some interesting history, they were actually having a hard time convincing clinicians and regulators that post traumatic stress disorder was a thing. And so there was a luckily the VA was aware of PTSD being a problem. And so had developed a clinical interview, called the caps the clinician administered PTSD scale, in order to measure changes in the symptoms. And so I think that that likely contributed to to why people think of PTSD as primarily a veteran's disorder is because the VA actually developed the way to measure it, and really made a case for it, when they, you know, created this measure, and so the pharmaceutical companies that were originally like they had gotten Paxil and Zoloft approved as antidepressants. So they already had a bunch of data on the safety and toxicology of the drugs. And so then PTSD was added on by doing several phase three clinical trials to their label. And so, I think, you know, a big limitation there was, um, you know, kind of distinguishing between depression versus PTSD, especially because there is so much overlap and comorbidity like, you know, 80, depending on the study, like 85% of people who have PTSD also have depression. And our study, it was even higher, like 90% of our sample also had depression. So it's like, PTSD just doesn't exist in isolation. It's extremely difficult to get a homogenous PTSD population. And it's also not generalizable. They also suffer from chronic pain, which isn't even mentioned until now. So it's really a systemic and community disorder. Anyway, so with the Paxil, and Zoloft, they, they use the same measure that we actually use today to measure changes in PTSD symptom levels. And at the time, the data looked pretty good. So they, they were measuring their outcomes on a one week basis, which is a bit different than what we do, we measured on a one month basis. And then they had, you know, a series of repeated measures throughout their studies, and these were 12 week clinical trials. And they did have, you know, decent p values, which is your probability of incorrectly concluding that something works, how good
Nick Jikomes 27:57
were How big are the I don't I don't think this is a good podcast, we're talking about p values and effect sizes, but how big are the actual effects that were measured as significant?
Berra Yazar-Klosinski 28:08
Yeah, they were small, to medium and effects. And so there's, you know, there's, it's always challenging to compare across different kinds of clinical trial designs. But just the magnitude of the effect is pretty agnostic to the design and the measure that you use when you talk about something called effect size. So based off of that it was a small to medium effect and with MDMA assisted therapy, in comparison to placebo with therapy, the difference is a large effect.
Nick Jikomes 28:48
So for a long time, the first line of defense has been SSRIs. They were sort of CO opted from their original intended use for depression, and anxiety to be used for PTSD. And in some sense that that seems perfectly sensible, right? They these things help with depression, anxiety, there's overlap there. Can you talk a little bit about how SSRIs work and then after that, we'll move into how MDMA works by comparison.
Berra Yazar-Klosinski 29:15
So um, it's actually funny that SSRIs were originally named as selective serotonin reuptake inhibitors. And this was a result of a marketing exercise. So at the time that they were developed, they, there was this prevailing opinion that you didn't want to have drugs with multiple targets. And those drugs were conventionally called Dirty drugs, because they weren't they weren't targeted. They didn't address a Hypo hypothesized you know, imbalance in brain chemistry. And, and hence, they you know, they couldn't be applied with like this almost surgical precision. And so then the, the marketing teams at these companies came up with the idea of calling them selective serotonin reuptake inhibitors, implying that they only target the inhibition of serotonin reuptake through this transporter, which essentially is a pump that pumps serotonin, which is a neurotransmitter that has lots of different functions in the brain involved with, well, a sense of well being, you know, digesting your food. So there's a lot of serotonin receptors in the gut. Anyway, serotonin is great. And so but you and serotonin can also not be good if you because it can, like flood the system, and then everything just kind of goes on the fritz. So SSRIs they prevent the pump from emptying out this gap in between brain cells, which is called the synaptic cleft. And so by blocking that they're keeping the serotonin in that cleft, and enabling the signaling in the brain between these neurons to continue longer than what they normally would be signaling. And that was, you know, supposedly helpful with PTSD. And of course, like these days, I think, where we have a lot better tools to measure what's going on in the brain. You know, there's EEG and brain imaging, and like functional magnetic resonance imaging, that looks at different activity levels in the brain. But overall, these studies are not necessarily diagnostic, like you can't just look at somebody's brain image and say, Oh, I think they have depression, or Oh, I think they have PTSD. But what you can say is that certain areas of the brain are not talking to other areas of the brain. And you can, if you can correlate that with some sort of behavioral output, then you can start to, to make some guesses as to as to why that might be.
Nick Jikomes 32:12
So SSRIs typically a first line of defense for PTSD for depression. People are generally familiar with them, they know that they're out there. Many people have even tried them for some period of time, they are preventing the reuptake of serotonin, so they're effectively increasing the level of serotonin tone in the brain. You mentioned something that I didn't know about, and I want to hear more about which is the selective part. So you said that they were named this way for marketing purposes. But you imply that they're not actually selected for serotonin reuptake inhibition. What else do they do?
Berra Yazar-Klosinski 32:52
Um, so I've heard depending on which SSRI you're talking about, some of them have affinity for, for norepinephrine, reuptake transporters. Some of them have affinity for dopamine reuptake transporters. And so I think when other companies that were competitors of the original pharmaceutical sponsor companies picked up on this, it actually led to the development of all sorts of different kinds of reuptake inhibitors. So now we not only have SSRIs, we also have SSRIs, which is serotonin, norepinephrine reuptake inhibitors. And we also have SDRs, like serotonin, dopamine reuptake inhibitors. So there's MDMA actually blocks all three of the monoamine reuptake inhibitors, which includes serotonin, norepinephrine, and dopamine. So technically, if we're looking to put it into a class, we could say, MDMA is a SN dri.
Nick Jikomes 34:02
So it's increasing the tone of serotonin, norepinephrine and dopamine.
Berra Yazar-Klosinski 34:07
Yeah, but we think that the in humans the dopamine effect is less.
Nick Jikomes 34:12
Okay, so normally, like one of my next questions was going to be about MDMA and neurotransmitters. I think a lot of people out there just sort of associate MDMA purely with serotonin like it's dumping serotonin, but that's not quite accurate. It's it's increasing serotonin levels, but it's also increasing these other neurotransmitters.
Berra Yazar-Klosinski 34:31
Yeah, that's right. And it's just that the amount that it increases, it is the most for serotonin. And then the next amount that it increases is norepinephrine. And then the next is dopamine. And then there's a couple other targets of SSRIs. Like some of them interact with the histamine pathway, and a couple other things. So yeah, there's Just there's a lot of receptors and all sorts of proteins in the brain that like, totally fine are functioning in various ways. And, and I think that it gets complicated from there. So it doesn't really make for a good marketing pitch or even nice name, naming the drug.
Nick Jikomes 35:14
So, so to summarize, we make sure I got this selective serotonin reuptake inhibitor, that name basically came from probably people sitting in a marketing room somewhere saying like, okay, it's Doctor think it's bad when a drug has many targets think it's good when they're highly selective? What name can we give this? It's a terrible name, there's many different, there's many different SSRIs, they all increase serotonin levels by preventing reuptake. But they all or mostly all prevent other neurotransmitters from doing the same thing. And the specifics of how each neurotransmitter is increased depends on the particular SSRIs you're talking about.
Berra Yazar-Klosinski 35:55
That's right. And it also influences like, their safety profile in terms of drug interactions. So yeah, so I mentioned this first line versus second line or third line treatment. So like, half the people with a PTSD diagnosis are getting some form of medication. And so when doctors are, you know, see a person with PTSD, though, they usually start with what's already approved by FDA, but the other SSRIs haven't gone through this kind of approval process. And so then off label usage is very common. So the doctors will, you know, try anything, really to try to help their patient, understandably. But what we're seeing is that half the patients are getting no medication. And so then what are they doing? A pretty big hallmark of PTSD is actually avoiding that you even have have PTSD in the first place. And so, and also avoiding triggers. So for example, if something happened in, let's say, I have PTSD, and so I had a traumatic event, and that involves the door being shut, and then somebody came in with bad stuff happen, then in my case, anytime a door shuts, that would be a trigger for me. So I may choose to go live in the forest simply to avoid doors, and then not be triggered by them. So similarly, like I have a sense that like half the people who are getting no medication for their PTSD are either not aware that they have PTSD, even though they have a diagnosis, they've suppressed or are in denial of that. And some of them are likely getting psychotherapy. And so, with psychotherapy, it's it's a pretty rich area of study, and has been studied a lot by the VA and other researchers, who are PTSD researchers. And so from all those studies, there has been kind of a subset of psycho therapies that have been designated evidence based. And so that means that the psychotherapy has been studied in a clinical trial, and there's been measurable change among the PTSD patients, and the amount of psychotherapy is, typically, depending on the kind of psychotherapy, it's around 18 hours total, around this 12 week, timeframe. And there's evidence out there that suggests, like 90 minute sessions are better than 60 minute sessions. And these are pretty manualized. So there's like scripts and homework. And the therapists are, you know, walking you through those, and it's pretty highly regimented. And often, it involves talking about what happened when you had your traumatic event. So this can actually be overwhelming for people. And so then what ends up happening is that people are getting psychotherapy, but they're not able to stick with it to the point of like, adhering to the way that it was validated with manual. And so then, you know, from discussion with other therapists or other therapists to treat patients with PTSD in their private practice, usually what happens is that people are, you know, feeling a little better after going through some form of psychotherapy, but and then when they feel better, they don't, they're like, Hey, Doc, I feel better. I don't have to come back. And then when they their symptoms get worse, they come back. And so then people are in psychotherapy on and off for years at a time.
Nick Jikomes 39:38
I see. So the, the way that therapy is done is is very important. And it sounds like basically, you know, the patient, the patient can think that they're cured when when they're actually not. Yeah. So, sticking on MDMA for a little while. So we've mentioned that it can inhibit the uptake of certain toner and other neurotransmitters? What kind of drug? Is this? What class of drugs? Is it? And can you talk a little bit about? Let's actually back into that from the subjective effects? So how would you sort of just describe the classic subjective effects of MDMA? And then how would you sort of start to relate those to what what it's actually doing in the brain?
Berra Yazar-Klosinski 40:18
Yeah. So um, with MDMA, you know, for because of all the neurotransmitter effects that we were just talking about, it is essentially like turning on all the faucets in the brain. And so these neurotransmitters are being released from these little vesicles, or pouches that hold the neurotransmitters in your brain cells. And the end, then MDMA is binding to those vesicles to create that effect. And kind of empty out the little pouches for neurotransmitters, MDMA also primarily binds to the serotonin reuptake inhibitor. And also we talked about norepinephrine and dopamine reuptake inhibitors, but primarily serotonin. And then when it binds to it, it locks it in an open conformation. So now we have this like open kind of floodgate in the in the brain cell. And so then not only are the vesicles pumping out their neurotransmitters, but it's also flooding down the floodgate going into the cleft in between the neurons, and then hitting receptors on the next neuron downstream. And then it actually triggers a whole signaling cascade. So and then also an MDMA binds to serotonin receptors, that pairs up with receptors for oxytocin. And also vasopressin. So these are neuro hormones that influence your sense of well being social bonding. And also, like vasopressin controls your sense of thirst. And so then, now these neuro hormones are flooding further downstream. And that and then, you know, creating continuing to create this signaling cascade. And there's, there's interesting stuff about oxytocin, and that it's a hormone that is also released when giving birth, and nursing. And, and also helps to kind of rewire the brain of, for example, a new mother, because now instead of just being an independent agent, the new mother has to focus on their on their baby.
Nick Jikomes 42:49
This is actually an important point I, I've actually completely overlooked this until this moment. So normally, when people talk about this stuff, they think MDMA makes you feel good and makes you sociable. And they say, Aha, there's also oxytocin. Oxytocin is, you know, the bonding hormone, if you want to caricature it, it's released at childbirth, it's important for Mother Child bonding, and just general social bonding. And it makes for this nice story. But the piece I've always overlooked is that an important part of motherhood, like when a mother has a child is that her brain literally becomes rewired. So that her behavior patterns change. And oxytocin is important for increasing tell me if this is fair, it's been a while since I've looked at the literature, but oxytocin actually modulates the amount of plasticity that can happen. So it's sort of like this permissive signal that allows that change to happen in the context of a mother and an infant. But now I'm connecting the dots to MDMA, and what you guys are doing, and can you connect the dots for people? So what's the importance of like a plasticity hormone like this?
Berra Yazar-Klosinski 43:54
Yeah. So um, yeah, I think a really important point is that, in general, mental health diagnoses, like how much of that is really because of a chemical imbalance, versus maybe, like, more kind of cognitive rigidity. And I think that people develop these like, thinking patterns as they're growing, you know, so in adolescence, usually, one's brain is pretty malleable, you're open to external influences. This is why people spend so much time raising their children in their in their lives, and put so much attention on it is because the, the brain when it's when it's developing is highly plastic. And so then there's actually these critical periods in brain developments that close after adolescence. And so and they they're actually like not even like open until you become adolescent. And then when you're an adolescent, kind of a social reward learning, critical period opens up. And then people are influenced by their environment, like, maybe they go off to college, and they are further influenced. And then then that period closes, and then people start to kind of become adults. And then as they get older and older, their the way that they think about the world becomes more rigid. And so, and there's a number of things about, you know, brain cells aging, that influence this, like, you're not making as many new brain cells, your brain cells are more, they have a thicker coating on them. So they're less likely to make new connections. And so then that plasticity just kind of like Peters off as you get older and older. With MDMA, there's a nature publication by a great friend of mine, who's in my Turkish psychedelic club. And her name is Gil Dillon, and she's at Johns Hopkins University. And so she was able to demonstrate in mice that MDMA was capable of reopening a critical period around social reward for learning. And so now, instead of having that like cognitively inflexible, rigid, entrenched thought patterns that are also probably keeping you depressed, and suffering from various mental health diagnoses, the brain is once again, opened up for plasticity, as if you were an adolescent. And then once again, open to intervention. And the rewiring is then not just limited to the context of the MDMA experience, but also remains open for a while after,
Nick Jikomes 47:03
because it's this why it's so important that this is MDMA, assisted psychotherapy, MDMA is creating this permissive signal, it's altering neurotransmitter and neuro hormone levels in the brain such that temporarily the brain is in a heightened state of plasticity. But if you don't actually direct that plus that is plasticity, somewhere, nothing will really come up.
Berra Yazar-Klosinski 47:26
Right? That's exactly right. And so and this is really the key distinction between MDMA that's used in kind of a more recreational context, versus a therapeutic context. So um, and then just that experience of like, of the MDMA session itself. In general, like it is an altered state, it's not causing hallucinations, but people are turning inward, and having kind of an experience and like, with eye shades on and listening to music, that help them to revisit what happened to them dramatically. But without the fear associated with it. And what we know from brain imaging studies that we've done, and PTSD patients is that normally, the part of the brain that would be signaling associated with the fear signal, when the memories are are being revisited, actually, is signaling less. And then this correlates with the reduction in PTSD symptoms that these folks are able to achieve. So that means that we actually not only just have a picture of the brain, but we're also able to see a change in the way that the brain is signaling that correlates with the treatment outcomes that we're measuring. And that's really exciting.
Nick Jikomes 49:02
I see. So it sounds like in terms of how the drug is administered in the context of these clinical trials, it's extremely different in terms of the context, it's taken recreationally and so instead of going out and moving around and being social, the person is actually lying quietly, presumably encouraged to reflect on whatever is the object of the psychotherapy, and, you know, the object of the trauma. And it almost sounded like you were saying this is similar in some ways to the setup of the psilocybin studies where you're lying down in a comfortable room you have eyeshades on can you talk a little bit more about the actual setup for the MDMA? Yeah. Administration. Yeah. So
Berra Yazar-Klosinski 49:42
we put a lot of effort into making the treatment rooms comfortable. It's not like a sterile hospital environment. We know that MDMA is, you know, it would probably make any hospital room great, but But there's actually certain things you can do to make the environment more permissive for better oxytocin signaling. And when I gave birth, I noticed that the birthing rooms were doing similar things. So they have low lighting, can't little candle lights here in there, to music, sound of water. And then and like flowers, you know, these are all things that like one would say, oh, you know, if I was in a good hospital, I would actually probably have a lot of these nice things, but usually they reserved them for the birthing rooms. And so then the burden with that, it actually Prime's the brain and the system to be better at the oxytocin signaling part. So we kind of take that approach, we have really good artwork, that's not triggering. One time we had a black cat and a room, and that was not good. So we had to take it out. And then and then there's light music and low lighting and comfortable beds. And then there's two care providers, at least one is fully licensed for delivering psychotherapy, according to the regulations that pertain to where they live and practice. And then there's also a doctor that kind of oversees the administration of the MDMA. And we have, in our sessions, we've tested a divided dosing paradigm. So there's an initial dose that's given after people do a pregnancy test and a urine drug test. They got the initial dose of MDMA, with a glass of water, and then about an hour and a half or two hours later, they're given a half booster dose. So this divided dosing regimen, we think, actually promotes signaling of the first dose gets you onto the serotonin, mostly serotonin and norepinephrine. And then the second dose, that's a half booster dose kind of serves to get a little bit more dopamine signaling going. This is a hypothesis. I have not tested this directly. But this is our model.
Nick Jikomes 52:12
Here's the dosing it appears to be effective, you don't yet know exactly why it is.
Berra Yazar-Klosinski 52:17
Yeah. But we have a number of like, you know, indirect things that we're piecing together.
Nick Jikomes 52:22
Yeah. What, what kind of doses are you guys actually using in these studies.
Berra Yazar-Klosinski 52:27
Um, so we tested a variety of doses in our phase two clinical trials. These were small pilot studies. And so we we tried, you know, a variety of low doses of MDMA as a control. So we tested inactive placebo, a sugar pill. We also tested 25 milligrams of MDMA, with this half booster on top 30 milligrams of MDMA, with this half strong top and 40 milligrams of MDMA with the half booster on top. And then for the active group, for the therapeutically active doses. These were initially studied all the way back and, you know, the 70s. And so we revalidated the therapeutically active dose range of MDMA in our Phase Two studies and found that 75 milligram to 125 milligram MDMA is therapeutically active with a halfway strong shot. So
Nick Jikomes 53:28
Gotcha. So 75 to 125%. Yeah. And then half of that again, a little bit later. That's right. Can you compare that? So what someone might commonly take what are people taking in a recreational setting more than that, less than that?
Berra Yazar-Klosinski 53:44
I think it's about that. Yeah, it's comparable. And then the half booster is also pretty common in recreational settings. But when the when the booster dose is not half, it actually can even push that dopamine, dopamine signaling even higher. And then also in recreational context, some people tend to read dose again a third time. And at that point, all the serotonin and norepinephrine is gone. And they're pretty much just on dopamine. So then it's really just actualized and kind of like the stimulant types of effects more than anything else.
Nick Jikomes 54:21
I see. So you're administering MDMA in this space way. You have this very comfortable setup. People are lying down, they're being encouraged to reflect on what they've presumably been talking about in psychotherapy for probably weeks leading up to the first dose. Can you talk a bit more about like the full, the full treatment paradigm? How many weeks of psychotherapy are we talking about?
Berra Yazar-Klosinski 54:44
Yeah, so um, we have 90 minute talk therapy sessions. There's three of those on approximately weekly basis leading up to the MDMA session, and then the MDMA session takes about six to eight hours and then the next Morning, they have a talk therapy session to talk about what happened, like during their MDMA session. And then two weeks later, there's another talk therapy. And two weeks later, there's another talk therapy. So this is this kind of MDMA, followed by three integrative sessions is repeated three times in the context of our phase three clinical trials. And we've tried it with two sessions as well. So for some people, two sessions is enough. And for some people, it's not. And the thing with severe PTSD is that, you know, the majority of the patients actually had multiple traumatic events. And so kind of the theme during the MDMA experience is often like, processing, you know, one or two traumatic events is highly variable based on the individual but and then it's almost like peeling off layers of an onion. And so if you look at
Nick Jikomes 56:00
our chart all the way down, yeah,
Berra Yazar-Klosinski 56:02
exactly. If you look at our data, three sessions was the best because people were able to really get down and, and peel off multiple layers, the onion,
Nick Jikomes 56:12
I see one thing that was sort of interesting, interesting kind of parallel, perhaps, is, in some of the psilocybin trials that have been done, I recently had a guest named John cost accomplice on who was one of the first participants in a psilocybin trial for alcoholism. And he was lucky enough to be in the non placebo group, which means he got three space to doses of psilocybin therapy sessions in the context of, you know, more psychotherapy. So broadly speaking, similar sort of basic idea to what you guys are doing, except psilocybin instead of MDMA and treating a different thing, in this case, alcohol addiction. And the results were very well for him and more or less, what he said is, they work well for the first dose, but he really feels the second two are necessary to fully make a lasting impact. And curiously, everyone that he talked to who was a study participant, it either worked for them. And in all cases that worked for them, they were, they were the group that got three doses. And for the people where it didn't work as well, or didn't work that much, they all seem to be the ones that only got one dose, and then two doses, a placebo. So at least between these two studies, and some others, we could probably point to this recurrent dosing regime seems to be crucially, it's not, it's really, it's truly not a one and done type of thing.
Berra Yazar-Klosinski 57:29
It's not a one and done thing. And it's not a magic pill. And people have to be open and motivated in order to, you know, go through all those screening procedures, in order to get into the study, they need to be at the clinic on time. They, this is also often an issue for people with PTSD, because they're just kind of avoiding that they haven't, right, and then they don't want to necessarily experience a trigger. So we've really had to, you know, work with people who are who are motivated to commit to study procedures. And so that's one of the things that is in our criteria that we've posted actually publicly on clinical trials.gov. So if people want to read more about that, they can look up these studies there.
Nick Jikomes 58:16
So, you know, these are very intensive trials, right? You're not just giving someone a pill, you're doing weeks and weeks of therapy, you're very methodically designed this whole setup, right? Giving them a certain number of doses in a certain way, all embedded in this context of psychotherapy for this very particular population. Can you talk let's, let's kind of come back to the trials now, now that we've given people a background on MDMA and on PTSD and and sort of unpack the full structure start to finish here. So let's just start with how long does it take to do a phase three trial like this? And how much does it cost?
Berra Yazar-Klosinski 58:55
Yeah, so I think some, some people would like to see much larger studies, but these trials are so intensive to set up and run that. I feel like it's a massive undertaking, with the number of people that we had to screen and in order to treat 90, and so our original plan was to do 100 person study. And we started in November 2018. And leading up to that point, when we launched the study. We had about two, two years of regulatory interactions with FDA upfront. And so I mentioned that we had breakthrough therapy designation. So a big part of my role is actually writing the documents that make the case based off of research that's published, or that we have in hand to the regulatory agencies, that you know, we think that this treatment is is worthy of study, and that there's a lot of literature, scientific literature that forms the basis of these studies. And so I mentioned Maps has been around for 35 years, and the toxicology program actually started 35 years ago. So I'm actually 36. But anyway, so, you know, we initially got the breakthrough therapy designation, and then we did a special protocol assessment with FDA. And then that is kind of like an insurance plan for your ultimate FDA application for marketing, because it's a lot of input upfront from the agency, on the design of the study, and how you're going to analyze the data coming out of it. And there's been some, like, more recent kind of thoughts around how to handle the statistics of these clinical trials in a manner that is like, not unduly biasing the analysis that we had to incorporate into how we analyze the data. So we, it gets quite complicated in terms of statistics, it's not like a simple t test. And so all of that stuff happened over a period of like, nine months or so. And then we went back and forth with FDA on like, you know, six versions of the statistical analysis plan during that period, and finally resulted in an approved protocol, and SATs plan. And so, on that basis, then we like build the database. And there's a lot of like, extra quality measures that we built in to the database. And we also had all these systems that support running the studies and also support generating a lot of documentation and files that overall help you to understand the integrity of the data, the qualifications of the people, the approvals that you have to get. And so let's talk about approvals for a minute, because it's not just FDA that has to approve. There's also institutional, there's a central, independent review board that looks at the ethics and safety of the human participants. For any clinical trial, so we had because this was a multi site study in three different countries, we had to interact with three different regulatory agencies, three different IRB centrally, and then also each clinical trial site has its own IRB, or they have to defer to the central IRB. So
Nick Jikomes 1:02:43
I'm sure I'm sure every step of this is just so so much fun, right?
Berra Yazar-Klosinski 1:02:48
Oh, yeah. I mean, we had a mix of university sites, and private practice sites, because we want to, we want to be able to measure if there's any difference right between a university site and a private practice site in terms of the ultimately resulting data. Luckily, we didn't see any difference in between sites, in the clinical trial, so that was really good. And I didn't even mention that there's a lot of training that the therapists have to go through, in order to be ready to work on a study like this.
Nick Jikomes 1:03:23
These are all people that have never done this before.
Berra Yazar-Klosinski 1:03:25
Yeah, these were people that had never, the majority of them had never delivered MDMA assisted therapy before. And so they had to go through a pretty rigorous training on specifically on the method, we didn't train them on how to treat PTSD, because, in general, these were either addiction researchers or people who are already like treating people with PTSD or addiction, on average, and then they would go through our training program. And then they did a a small pilot study on a multi site basis, and treated one PTSD patient in that study, and then they were ready to work on this phase three study. So you can you can appreciate that this was a very long multi part process. Um, and then DEA also has to approve each researcher at the individual sites in the US. And then in in Canada, you have to get a special permission, called the section 56 exemption for the clinician to administer a controlled substance.
Nick Jikomes 1:04:35
I'm guessing when you submit all of your paperwork, they're they're not getting an answer back to you the next day.
Berra Yazar-Klosinski 1:04:40
They're not Yeah, I mean, um, the the most questions that we got from university IRB was like 50 questions, and I had to sit and answer all with a lot of support from the team, but it was a it was definitely cool. constantly negotiating, justifying, negotiating, justifying, and then eventually we would get approval at every single spot. And so we also had to deal with, how do you contract with the universities for something like this, you have to get insurance to cover something like this. And it's, um, it was just, it's a huge undertaking. So for all those reasons, it's quite expensive.
Nick Jikomes 1:05:25
Yeah, yeah. And what's I mean, I do think it's important to put a number on this just to give people a clear sense, like to do this, how much money did you guys have to spend? All in on this last phase three trial?
Berra Yazar-Klosinski 1:05:39
I mean, it kind of depends where you start counting, right? Because we want an order of magnitude, order of magnitude. Yeah, I mean, it's definitely on the order of like 15 million. So. And that's not even counting all of your infrastructure costs that you have to develop, because we have to, because we're working on preparing for a new drug application. We have to implement and valid tests, validate all the systems that we used in order to support the studies, and we have to audit the vendors to make sure that they're doing what they say they're doing.
Nick Jikomes 1:06:18
And so this is 10s of millions of dollars.
Berra Yazar-Klosinski 1:06:21
Yeah, then you're probably looking at when you look at total cost, that's more on the order of 30 million.
Nick Jikomes 1:06:27
And then we didn't really talk about this yet. But where are you guys getting your funding from? And can you talk a little bit about why you why Maps has structured itself the way that it has?
Berra Yazar-Klosinski 1:06:39
Yeah. Um, so we have not received any grants from the government. And the majority of the funding is all philanthropic contributions. And the majority of the funding is from private donors. Some are from family foundations. And there was also an influence of cryptocurrencies, when we were really trying to do our big push for, for raising the money in order to do the phase three trial, because we didn't want to start the trial without knowing that we had the funding in hand in order to complete it. And so we had to do a big fundraising drive, and we're very luckily, the recipients of some cryptocurrency donations that we're, we're able to use.
Nick Jikomes 1:07:31
Yeah, can you? You know, I contributed a little bit of Bitcoin when you guys were doing this. Can you talk a little bit more about that? How, how many people did you have giving you cryptocurrency? And how, how substance? How substantive was it? In the end? And what are your What are your thoughts on that? Looking back on how it turned out for you?
Berra Yazar-Klosinski 1:07:51
Yeah, unfortunately, this is the development and fundraising part is not really in my domain. But I can tell you that there was this pineapple fund that got announced on Reddit. That was a really big influence. We, we have a pretty strong social media team. That was run by Bryce Montgomery. And so he's been with maps for 10 years at this point. And I've been there for 12 years. So we've had a lot of overlap. Anyway, he found the pineapples on posting on on Reddit, that somebody was going to donate an anonymous donor was going to donate millions of Bitcoin through this pineapple fund, and was very secretive about their identity.
Nick Jikomes 1:08:38
Like millions of Bitcoins,
Berra Yazar-Klosinski 1:08:40
like I don't know, it was a lot of money. But it equated to millions of dollars,
Nick Jikomes 1:08:45
millions of dollars. Yeah. And then do you guys, how did you guys think about that, given the volatility of Bitcoin? Did you sort of hold on to it for a while not,
Berra Yazar-Klosinski 1:08:57
we did not hold on to it because of the volatility. So we just quickly converted into dollars and use it. In hindsight, if we had been able to hold on to it, it's possible that it would have amounted to even more.
Nick Jikomes 1:09:10
Wow. So that was actually I knew that you guys were doing this because I participated in my my own little way. But I never actually got the story on how how consequential it was, it was
Berra Yazar-Klosinski 1:09:20
very consequential. It enabled us to like, be able to finish contracts with universities that were going to do the work. You know, that's important.
Nick Jikomes 1:09:29
Interesting. So you did these trials. We've talked about how the MDMA was administered and some of the basic structure of the trial and the psychotherapy. Can we we talked about in the beginning that they were very effective, you got really good results. Can you talk in more detail about what that exactly means? So you've got 90 I think you said 90 people going in with severe PTSD. When you say that the trial was effective. What does that mean in terms of how many people came out with and without PTSD?
Berra Yazar-Klosinski 1:10:00
Yeah, so there's two ways of of measuring how well a drug works. So one is efficacy, which is on the group level. And the other is effectiveness, which is on the individual level. So the, and you can, depending on what you pre specify in terms of how you're going to do your analysis is like what you have to do at the end. And so we we pre specified that, we thought there would be a significant group level average difference, after three sessions, and the endpoint was measured 18 weeks after randomization, and the randomization happened, like after people went through a couple of sessions of talk therapy, so it's a little bit of an enriched design. So we didn't want to just measure the results off of people who were also responding to talk therapy, like the drug had to be the significant determinant of what we're measuring in terms of the change. So. So it amounts to about two months after the third session. So we're not measuring afterglow, soon after the MDMA or placebo session we're measuring two months after. And then the participants who were in the phase three study, then terminate from the study, they go back to their daily lives, and then they're currently coming back for a long term follow up. And just because the trial took from like November 2018, to like August 2020, to finish, then people are gonna end up coming back for their long term follow up assessment over a range of months after, so it's like 12 to 24 months or so. And we're measuring people both in the placebo group and in the MDMA group to see how they did. And then the placebo group were eligible for a crossover study with MDMA, where they know they're going to get MDMA. And that's also about to launch next week.
Nick Jikomes 1:12:09
So yeah, can you give people a sense of the magnitude of results that you've seen so far?
Berra Yazar-Klosinski 1:12:14
Yeah. So on average? I don't know. Can we use p values?
Nick Jikomes 1:12:21
I mean, yeah, but I think we should definitely not limit ourselves to that. Sure.
Berra Yazar-Klosinski 1:12:25
I'd say both ways. Yeah. So the, the p value that we got was less than point 0001. So this amounts to like a one in 10,000 chance of incorrectly concluding that your trial is successful. And then on an individual effectiveness level, we had 88% of the individual participants responded to treatment and the MDMA group
Nick Jikomes 1:12:52
actually responded to treatment. Does that mean they got better? To some extent? What exactly does that are? To some
Berra Yazar-Klosinski 1:12:57
extent, okay, yeah, so it's like a 10 point change. And then the, and then 67% of the MDMA participants, actually didn't meet diagnostic criteria for PTSD anymore at the end of the study. So that means for two thirds of the people in the MDMA group, they, they didn't have enough of the symptoms to qualify for PTSD diagnosis.
Nick Jikomes 1:13:25
And, you know, just to be conservative, we probably wouldn't conclude that their PTSD is fully cured, and that it can't come back or anything. But they effectively no longer have PTSD at that point.
Berra Yazar-Klosinski 1:13:37
Yeah. And just because of the way that the measure is designed, like, they may have one or two symptoms, but in order to satisfy the diagnostic criteria, they have to have at least one symptom in each cluster.
Nick Jikomes 1:13:52
And how, how does how does this compare to effectiveness of their traditional first line treatments? So if you were to give a large group of people, the traditional first line treatments with psychotherapy, that must be have some level of effectiveness? How does it compare?
Berra Yazar-Klosinski 1:14:08
Yeah, it's a great question. Um, and I think that there's like a difference in terms of what you would see in a clinical trial versus what you see in the real world. Yeah, because then, based off of real world data, with SSRIs that are approved for PTSD, 40 to 60% of people don't even have a little bit of a symptom change. Whereas, and so it's a little bit hard to compare, because we're basing our data off of clinical trials, and then talking about how SSRS are doing out in the real world. So what we're saying is, you don't have real world data yet from us.
Nick Jikomes 1:14:45
So presumably, the real world data, it's just noisier it's messy, or people aren't gonna always use the proper protocol. So the effectiveness should go down somewhat, but the levels that you're seeing are actually so high, that even my understanding is Even if it goes down somewhat, it's still much better than most traditional treatments would be.
Berra Yazar-Klosinski 1:15:06
Yeah. And we have, after going through the three session package, five of the MDMA group didn't respond in a manner that would like meet criteria for a treatment responder. So and that's out of 46 people dosed with MDMA. So we think the non response rate is probably around 10 12%. And then, but it's still really good. You know, I think that I think that is really the the important part is that, if nothing else, like let's say, in the real world, the effectiveness goes down. If nothing else, people are interested in trying MDMA assisted therapy, and it's going to get them in the door. And I mentioned, half of the people with PTSD aren't doing much in terms of treatment. So at least it gets them in the door, and then they're able to try it as a as a as a treatment in the toolbox.
Nick Jikomes 1:16:04
I want to ask a little bit more about the past, before we talk about the future. Can you talk a little bit about so like you guys are obviously you're doing these trials. Now you've like just completed phase three, you've been working on this for a number of years now. When did MDMA come onto the scene? Both in terms of researchers being aware of it? And then how did it sort of seep into popular culture? Can you sort of connect the dots between the origin of MDMA? Its its leakage into popular recreational culture, and then the origins of maps?
Berra Yazar-Klosinski 1:16:41
Yeah. So MDMA was, from what we know was first synthesized in 1912. by Merck, they were kind of doing like your standard, medicinal chemistry, like trying different chemical structures and seeing and seeing what they what they got. And so then, at the time, it wasn't tested in humans, it was just kind of part of a library of compounds that were just generated that way. And then from from what we know, Alexander Sheldon, synthesized MDMA, I think, in the 60s, and then before then, the army actually started testing. You know, MDA, which is a chemically related compound to MDMA is actually an active metabolite of MDMA. So the army was doing these tests in the 50s, characterizing the, the lethal dose for 50% of the animals, so only 50 of like LSD, and MDMA, and MDA, and all sorts of different animals. And their original goal was to was to potentially use psychedelics as like, a kind of chemical warfare, or biological warfare. And so that's when you start hearing about like, MK Ultra, and the CIA and all these things. So this actually, like historically, has created a lot of political baggage that prevents the, the Department of Defense from being open to studying psychedelics today. Because just, it didn't go well. Put it that way. And so subsequently, like after that, you know, Alexander Shogun was, he had a DEA license, and he was synthesizing research chemicals under his DEA license. And I believe there was another chemist also involved. I just can't recall his name, but he was working together with Shogun, and he was the first one to try MDMA. And so all that had was happening in, you know, the Berkeley California area. For people that
Nick Jikomes 1:19:07
don't know, can you just briefly talk a little bit about Alexander Shogun and why he's interesting.
Berra Yazar-Klosinski 1:19:13
Yeah, he's, um, he's like, everybody likes to be called the grandfather of psychedelics. I think he's, he counts as a true grandmother psychedelics. I won't ever be the grandfather's. Anyway, so yeah, he's a, he's a Russian origin. Chemist. He was very talented chemist and so he and his wife actually took it upon themselves to try out a lot of these research chemicals that he was synthesizing. And unfortunately, he's passed away several years ago. But he really you know, you published a the Synthetic routes on how to make these research chemicals and kind of generated a lot of prior art that prevented psychedelics and the man manufacturer of them from being patented. So, to me, this is really the most important contribution that these are, you know, these chemicals are are i should i say this, they're, they're similar chemically to compounds that are already present and a lot of natural sources like plants and fungi. And so they're, and our bodies are kind of naturally evolved to, to respond to, you know, plant based psychoactive materials throughout evolution. And so a lot of indigenous people were using plants and fungi, to alter their consciousness and as like rites of passage and ceremonial usages. And it really important to acknowledge that this, you know, plant and fungi really, first, the use was first developed by indigenous and first peoples and native people. And so these methods of ceremonial and ritualistic use were around for, you know, 1000s and 1000s of years, and then actually informed the current therapeutic methods that are you in use today with MDMA and psilocybin. So there's a lot of like, breathing exercises, diaphragmatic, breathing exercises, these were subsequently developed by Stanislav Grof, into Holotropic breathwork. So just by breathing, one can alter one's consciousness, because of the existing brain, neurotransmitters and chemicals that are induced in your body and your brain just by breathing in a different way. And it really does, again, remind me of a verse because just by breathing, you know, it's enabling life. And so then, Shogun really felt strongly that these chemicals should belong to the people, and should never be a subject of a monopoly of a corporation. And so he published tickle, and pickle. That, that put it into the public domain in terms of how to how to create these chemicals. And he did get in some trouble, I think, with the EA when he did that. Understandably so, and I think Subsequently, he did end up giving up his DEA license for manufacturing. But yeah, I mean, do you have anything to add to the Shogun story?
Nick Jikomes 1:22:52
Um, I don't think I have too much more to add, if you look closely, you can see his two famous books on my bookshelf. But yeah, he was he was a very interesting and very important person in this entire area of psychedelic medicine, as you said, he was this organic chemist who, if you just go read about the details of his life was in a position where he could, in an official capacity, synthesize drugs, and then he did a lot of testing on himself and his close friends. He documented all of that in terms of both the synthesis and how to create these things and the effects subjectively they had on himself literally, in these two great books called pecan tea call. They're very accessible. The first half, at least the second half is literally in organic chemistry manual. But they're very wonderful stories that are very, very readable, very relatable in many ways about the experiences that he and his wife and his cohort of interesting friends had when they were testing all of these things. He died just a few years ago, actually met his wife at the last maps conference. Yeah, a few years ago. And she's she's very old now. But she was she was there. And she was cognizant, she gave a wonderful talk. But if you're interested in the history of psychedelic medicine, if you're interested in the chemistry of psychedelics, for interested in their subjective effects and where they come from, it's very difficult to imagine how you would fully appreciate all of those things without looking at these two books. P Caliente call.
Berra Yazar-Klosinski 1:24:23
Yeah. So then, MDMA was, you know, kind of highlighted as a result of that personal experimentation, by Shogun and his colleagues and friends. And he introduced Leo zaf, to MDMA. And Leo's life was a therapist in the bay area at the time. So there, there were, you know, hundreds of people who actually experienced MDMA in a therapeutic context when it was still an largely unknown chemical and That really helped to augment their therapy process. And so there was couples therapy that was tested, they tried it for creating alcohol use disorder and alcoholism, substance use disorders, depression, eating disorders, PTSD, anxiety, all sorts of stuff. And so and then those data were, were published by George Greer and requid. Tolbert was, were a couple that, that ended up, you know, doing the research effort to kind of like, synthesize and write about a lot of those anecdotal reports, these were not controlled clinical trials. And so then, you know, the word kind of got out, MDMA got out of the bag. And then in Dallas, Texas, at the start club, there was a marketing exercise that led to MDMA being renamed ecstasy. Initially, they were calling it Adam. And MDA was called Eve. Because they're so similar and chemical structure and some of the effects. And then everybody decided Adams, not a great marketing name. So they decided to go with ecstasy in terms of, you know, characterizing it and making it sound more exciting. However, we have heard from a lot of our study participants who have PTSD, that they say, I don't know why they call this ecstasy, because it's actually we think of MDMA as a kind of a nonspecific amplifier of whatever the feelings and experiences are there. And this was actually recapitulated in some recent publications that really aimed at looking at this in larger datasets with pharmacology data combined. So really, it's like if somebody is experiencing mental health challenges, those challenges come to the forefront, when they're under the influence, if somebody is largely happy. And in a party environment, they tend to more often report being feeling more social, more outgoing.
Nick Jikomes 1:27:14
So it's, it's perhaps better to think about it as this emotional, cognitive amplifier, yeah, exaggerates whatever's there. And the history in the branding of this drug as ecstasy in the party drug is sort of a side effect of the fact that people were often taking it in that kind of context. And they simply weren't choosing to take it in a different context. That's right. So let's talk a little bit now about the next steps in the future. So you've completed the phase three trial that just came out recently that you've told us about, what are the next steps and what has to happen now before this can become an FDA FDA approved medication? And what exactly does that mean? What will doctors be able to do?
Berra Yazar-Klosinski 1:27:57
We're currently doing a a second phase three trial. And so we're about 35%, enrolled. And so one of the things I didn't mention with the first trial is that COVID happen, right when we finished enrollment. So luckily, we had completed the numbers that we had intended to enroll to meet the requirements of the protocol. And luckily, there wasn't an impact on the data of the of the COVID pandemic. So now, we've had to like really kind of delayed the start of our second study, to have a pandemic in the middle of it all. Because people were concerned about coming in to the clinical trial sites, understandably so. And we had to put in place a lot of risk mitigation efforts, we're having risk mitigation meetings every single week, documenting those going back and forth with FDA in terms of getting permission for some flexibility in terms of how to conduct the study. So the second trial is in place and running and enrolling with all of that. And so our original projections have been impacted, in terms of when we think we can get FDA approval. You know, the COVID pandemic really threw us for a loop. We were not expecting that in our scenario planning. Let me tell you, so. And so now we're thinking that we'll probably be able to finish up our full application to FDA, which will include our toxicology data from MDMA, and the active metabolite MDA, as well as the data from the all the clinical trials that we've done, as well as pharmacology data that we're going to be summarizing based off of the literature that's already published. We have to do a food effects study. So we're going to be comparing fasted versus fed, kind of pharmacology and metabolism Have MDMA. And so we're writing that protocol now. So there's a number of studies that like, we're really still in the thick of it in terms of generating the core datasets. And then we have to write the label, which is something that I'm working on, which is the little package insert that comes with the drug in the box. And we're designing the packaging, and and we completed manufacturing, our validation batches of MDMA. So we have quite a bit of MDMA, over 10 kilos,
Nick Jikomes 1:30:34
I forgot to ask you, where does your MDMA actually come from? It's manufactured
Berra Yazar-Klosinski 1:30:37
under contract in the UK, by contract manufacturing lab, and they have to, of course, have lots of licenses and permissions. And then we import it into the United States for for use in the clinical trials. And then it gets shipped out from the United States to the various locations in the world. And we're also enrolling for a European study right now. That's treated a couple patients. So yeah, there's, there's just a lot going on. And we hope that this will be in clinics at the end of 2023
Nick Jikomes 1:31:14
and of 2023. And assuming that happens, what exactly is it going to mean for it to be in clinics will any licensed physician who is a psychiatrist or psychotherapist be able to choose to use this if they feel it's appropriate for a patient?
Berra Yazar-Klosinski 1:31:30
Yeah, I mean, um, it seems like nothing we're doing is ever straightforward. So um, there's, there's a lot of intricacies around. Like how we envision envision this going out. So um, so FDA doesn't regulate psychotherapy. In fact, they don't even know about the outcomes that are possible with psychotherapy, because they're focused on the drugs. And so because this is essentially a new kind of therapy, they're called FDA is calling it an integrated multimodal therapy. So MDMA, the effects of MDMA, on its own are kind of attitude with the effects of the psychotherapy. And this is not so novel in the sense that like ketamine is currently being tested in combination with psychotherapy as well. And that we think that this actually improves the durability of the effects. So, so there's that aspect, like we're having to explain psychotherapy to FDA, and then the, we have to develop a risk evaluation and mitigation strategy that will require that clinicians who are able to work with patients who are on MDMA have to go through training. And so we have, we have the world's largest MDMA therapy training program currently in progress. There's 300, clinicians are being trained in the current cohort. And about a third of them are people of color. And so there's a lot of diversity and inclusivity and equity work that we're currently engaged in and raising money for, for patient access programs, etc. And so, the way we envision this is that there would be a prescribing physician doesn't have to be a psychiatrist, and they would do an initial assessment of like cardiovascular risk, to rule out underlying cardiac disease. And there's a couple different specific subtypes that are likely going to be going to have a precautionary note in the label about that. Um, and then also, you know, we envision this as a as a treatment that's administered by a team. So the team has to consist of like a physician, they would hold a DEA schedule, 235 license, and then they have to go through our training in order to get the drug. And then they have to agree to work with appropriately trained and licensed providers. And then FDA really wants us to make sure that the providers are are kind of, it's not just one person. That's their ideal. So we're just in the middle of like, working out the specifics with FDA. And we'll be working closely with them on that.
Nick Jikomes 1:34:31
And what is the current scheduling of MDMA in the in the US is drug scheduling system?
Berra Yazar-Klosinski 1:34:39
Yeah. So MDMA is currently a schedule one controlled substance. And like I said, it doesn't work for everyone. So it's really not a good idea to go off and try this on your own. And we think these effects are really just possible in the context of therapy because of all the neurobiology we were talking about. So that being said, After FDA approves MDMA for having medical evidence of efficacy and safety, then it triggers a rescheduling mandate for DEA, the Drug Enforcement Agency. And so that has to happen in 90 days. And so then we'll know if MDMA is going to end up in schedule two or three. We think that based on the data that we have scheduled, three is more appropriate. And then that influences the how you can do the commercial distribution, etc. Because there's different standards for schedule two versus three. Gotcha. So
Nick Jikomes 1:35:39
currently, it's schedule one, which is the most restrictive, once you guys accomplish some of the the next steps, it will determine that it will definitely be rescheduled, but we don't know where it'll actually land, other than it's not not gonna be scheduled anymore. Right. One of the things I probably should have asked about earlier, is, you know, when you're trying to justify these studies, to the FDA, and to all of these agencies, when you are, you know, presenting the case for this, you presumably are talking a lot about safety and toxicology. And you mentioned that a lot of toxicology studies had been done. I know that there's a pretty rich and somewhat contentious history of the research done in terms of the potential toxic effects and potential side effects of MDMA, both in experimental animals and in humans. Can you talk a little bit about MDMA safety and toxicity profile? And what we, what we know there?
Berra Yazar-Klosinski 1:36:34
Yeah, so um, there's, depending on the intended clinical usage of the drug that you're studying, there's different designs that are appropriate for an actual, you know, registration level toxicology study. And so and then also, these studies have to be conducted on following good laboratory practices. And that means that they're audited, and they come with a lot of documentation to support the quality of the results. So I'm with MDMA. Originally, Rick, had funded and and overseen two toxicology studies where MDMA was administered once a day for 28 days. And those studies helped us to kind of get an initial sense of like, what dose of MDMA causes mortality in animals. And it's unfortunate that animals have to be sacrificed in order to have these studies and it's a required component of your new drug application for further regulatory approvals. However, you know, those studies were, were done so long ago, we actually had to repeat them more recently, in the over the last couple years, and I had to oversee it. So we worked with contract research labs. And they, but we were we successfully negotiated with FDA that, that we would focus on the neurotoxicity question. And so that was the part of the original studies that was inconclusive at the time. And so then, that inconclusive finding fueled all these studies that were like, Well, look, MDMA is possibly neurotoxic. Let's figure out how to study that, oh, my god, we're at these really high doses. So just
Nick Jikomes 1:38:27
just to be clear, in like, a while ago, and like the 80s and 70s. In the 80s. There were some studies on animals and toxicology to look at whether or not MDMA was neurotoxic whether or not it killed brain cells. And you're saying that those studies were inconclusive,
Berra Yazar-Klosinski 1:38:44
they were inconclusive. And at the time, what they did find was that the amount of serotonin decreased after MDMA. So at the time, that was a perfectly acceptable measure of neurotoxicity. But what we know now is that that's actually just about how MDMA works it because all that serotonin gets released, and then MDMA actually inhibits the enzyme that allows you to make more serotonin. So it's like a, it's like a shutoff valve. So if that shutoff valve didn't exist, then you'd actually be at risk more at risk for serotonin syndrome. Because there just be more and more and more serotonin around. Um, so it's actually a good thing. In terms of how MDMA kind of is has self limiting effects.
Nick Jikomes 1:39:38
I see. So they're originally doing the studies giving animals My understanding is a very high dose of MDMA. Yeah, probably much higher than most reasonable people would actually take in a recreational and what they found was not clear evidence of neurotoxicity they found a decrease in the amount of serotonin floating around the brains of these animals after they were given these high doses. Some people probably infer that to mean that cells had died, when in fact, they probably didn't, or the very least you just don't know. Right? You guys fast forward, you guys were doing comparable studies more recently, what was the outcome of
Berra Yazar-Klosinski 1:40:14
those with and with our dosing regimen, we're not getting MDMA every day, and it's not a take home drug. So, um, we made the case that we should we should have, we should test it like a single dose drug where it's given one time, and then the body has time to recover. And then it's given again, and then the body has time to recover. So we, we did the 28 day studies with dosing on a once a week basis, which is more similar to our once a month basis for humans. And so, and we also did expanded neuro histopathology. So we looked at modern measures of neurotoxicity, and all different kinds of stains that FDA had recommended us to do. And from those, you know, we there was also this like, one inconclusive finding from the very old studies where these silver staining and the silver didn't like get into the get into the brain tissue. And it was interpreted as, and only happened in them name animals. So it was interpreted as possibly being lesions, and everybody was like, Oh, my God, like lesions in the brain. That's bad. And so then, we found no evidence of lesions with the better staining methods and the better methodology. And so that was really the linchpin for, like putting the neurotoxicity debate to bed, at least with this dosing regimen that we've set with a once a week.
Nick Jikomes 1:41:49
And can you what were the doses you're using these studies? And what what were the animals actually?
Berra Yazar-Klosinski 1:41:55
Yeah, so we, we did this neurotoxicity study and Sprague Dawley, rats and Beagle dogs. And, and for both of those, like the dogs are more sensitive to MDMA, at higher doses. And we actually unfortunately, had, we went up to the maximum tolerated dose, which means some dogs died. And so then, was around like 12 milligram per kilogram, MDMA or so. And just for reference in humans, where there's it's challenging, to do the scaling between different species, because, yeah, it's nonlinear. And also, the metabolism of MDMA is nonlinear and like, just adding more MDMA doesn't necessarily mean that you're,
Nick Jikomes 1:42:45
there's actually one of my other podcast episodes, for those that are interested in this, this stuff, drug metabolism and scaling of bodies. There's a great book called scale by Geoffrey West, who's a physicist, and in that book, and I had him unpack this anecdote in my podcast. But he tells this very tragic story from a long, long time ago, where some researchers gave an elephant LSD. And so the question arises, how do you determine the correct dose for an elephant, and the naive notion for how you would dose an animal, if it has a certain body sizes, you just multiply, you know, whatever the scaling factor is. So if the animal is twice as big, as a human, you get it twice as much. If it's half as big, you get half as much. And that's actually not the way that those drugs. And so that's kind of what we're talking about here, and he unpacks it and that episode. But what did you guys actually find when you gave these, these, we
Berra Yazar-Klosinski 1:43:38
also found one more really important thing, which is that, at least in rats in the rat study, we found that there was a difference and how much MDMA the animal could tolerate based off of whether they were housed together with another animal, or separately, hello. So we had to really rely on the publications that had previously found this in order to be able to go high enough in the dose in order to have like conclusively put these some of these toxicity concerns to bed. So with rats, you know, we were starting to get mortality at 20 milligram per kilogram, for example. But then when they were housed separately, we were able to go up to 100 milligram per kilogram. The fivefold difference, and it's just from, you know, I mentioned MDMA, the effects of MDMA are highly context dependent. Yeah, I actually think that this is the reason why there's so much controversy in the scientific publications about the toxic effects of MDMA.
Nick Jikomes 1:44:46
Wow, yeah, I mean, that is, I mean, for those that aren't used to this type of data, that's a very high difference, a five fold difference, when you simply change whether or not the animals are in one context versus another in terms of whether or not it's toxic? That's way higher than I would have guessed. Yeah. But anyway,
Berra Yazar-Klosinski 1:45:07
we also did the reproductive toxic toxicity studies and genotoxicity studies, were getting ready to publish the genotoxicity studies. So they didn't find any evidence of, you know, MDMA on genotoxicity, which is great.
Nick Jikomes 1:45:23
To summarize one piece here that I may have missed. So you give these relatively high doses to some animals high enough, you're giving them on purpose doses, where some animals will die for the animals that don't die, you're then looking at evidence of cellular toxicity. And what's the basic takeaway in terms of what you saw in the animals that did not die?
Berra Yazar-Klosinski 1:45:45
Yeah, the basic takeaway was that we found like, some evidence of muscle inflammation in the rat study, that was, um, you know, RFU, if you're, like familiar with, like, marathon runners, but they like, if they, if you exercise too much, it can cause inflammation in the muscle tissue. And then that leads to aches and pains. So we found that, at the height at the relatively human equivalent doses, um, specifically in the, in the soleus muscle, and a couple of other skeletal muscles, but there wasn't anything in terms of, you know, central nervous system toxicity, we didn't find any evidence of that. And in terms of like, peripheral neurotoxicity, that was like, the only thing was that we found evidence of white blood cell infiltration into skeletal muscle tissue, leading to myofiber degeneration, which sounds horrible, but it's actually not that bad. And then we also, you know, there were definitely like, behavioral signs and symptoms of the dose being high, too high at the high doses, and so, but I think with any drug, there's a tolerability limit. I mean, so I think that was not surprising.
Nick Jikomes 1:47:15
And then it was, I guess, the take home was that that what you did find was sufficient to convince all of the relevant regulatory agencies that
Berra Yazar-Klosinski 1:47:24
we don't know yet. We just submitted this, and we do the studies. Oh, I see. So we don't know yet. If they're going to be convinced. Um, but we're going to ask them to do a review of the toxicology data before before we complete the full submission.
Nick Jikomes 1:47:40
Yeah, okay. Well, Barry, you've been generous with your time, and we're unfortunately running short. Before we go. Are there any final thoughts that you want to leave people with? And can you just point people to where they would go if they want to contribute to the studies that maps is running?
Berra Yazar-Klosinski 1:47:55
Yeah. So um, maps, being a nonprofit, has a pretty easy way to donate to, to map studies. So it's maps.org/donate. And then also, we put all of our research publications, open access for free on our website on like maps.org/resources/papers. And you can poke around in there, and there's there's a lot of really good information on the maps website. We also have our treatment manual on the maps website under the MDMA assisted therapy studies. And we also have our, our investigators, we're sure of MDMA. So that is like, all the stuff I was talking about today is like summarized in this like, pretty large document. That's like an encyclopedia on MDMA. And that's all free access, you can just go there and read it.
Nick Jikomes 1:48:51
Great. Well, I'll link to all this stuff in the description underneath the episode when it goes live this Friday. Bear thanks again for your time. This was great. I'm glad that I could finally get in touch with with you and kind of tell this story for people. So thanks. Thanks for coming on again. And I hope to talk to you guys soon in the future.
Berra Yazar-Klosinski 1:49:09
Thank you so much. It's been a pleasure.
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