Psychiatry & Psychotherapy Podcast - Psilocybin Therapy - Part 2: Clinical Trials, Secondary Effects, Brain Imaging, and the Future of Psilocybin Therapy

Episode Date: January 5, 2021

With the background from part 1 in mind, in part 2, we review the modern era of research exploring the treatment of various psychopathology. The results for these studies begin to elucidate the various effects individuals experience with psilocybin. The benefits are potentially impressive, however, there are significant limitations that are noteworthy. Psilocybin therapy is just coming out of its nascence and it is useful to have a critical view of the research coming out to avoid pitfalls in the future.  By listening to this episode, you can earn 2.5 Psychiatry CME Credits. Link to blog. Link to YouTube video.

Hello and welcome to the Psychiatry and Psychotherapy Podcast. I'm here to talk about getting rid of burnout, increasing job satisfaction, and feeling like an expert in what you do. One thing that created a lot of burnout and angst for me was trying to get continued medical education right at the last minute. So why not join the CME membership and do CMEE while listening to this podcast. Go to Psychiatrypodcast.com, sign up, sign in, take the test, and the certification is email to you in seconds. All right, welcome back to the podcast. Today I'm joined for what will be psilocybin therapy, part two. This will stand alone, so I hope you enjoy this one. If you haven't heard the first one, the first one, we really talked about the introduction, the history of it, mechanism, some of the early studies. This episode, we're really going to jump into the bulk of the main studies on this.

So, Nadav Kline, MD, an Ohio State University third year, going into Paleo of care is joining me. Welcome to the podcast. Nadav, good to see you. Thank you so much. It's great to be back. Part two. Part two. Yeah, this is exciting. The most exciting part of this is to educate people on stuff that patients are already having questions about. And to see where the science is, you know, we have no conflicts of interest. I have no skin in the game, so to speak, in terms of investments. I'm just trying to look at this as a clinician, looking at the evidence. Nadav Klein is a little bit more enthusiastic about it, I would say, as someone who's an early adopter, potentially. Yeah, so let's jump right into it.

Yeah, so, I mean, today we're going to talk about a lot of different studies, and there's a lot of data here, and I did my best to try and make it simple and give it across as understandably as possible. Yeah. I think you did a good job. And really, we want the data. At this point, we don't want a charismatic preacher talking to us about the virtues of psilocybin therapy. That's not where the field is. The field is probably like me a little bit more skeptical.

So I want to look at the studies. And yeah, so let's jump into this first one, pilot study of psilocybin treatment for anxiety and patients with advanced staged cancer. This was in 2011 by Grobe at all. So tell me a little bit about this study. Yeah, so this was a small trial with 12 cancer patients with various diagnoses of some form of anxiety or adjustment disorder. And they were either given, it was a double-blinded trial, so both the participants and the therapists were blinded. And they were given either niacin, which is a medication that will give people, flushing and have them feel warm, comparing it to a small to moderate dose of psilocybin,

which is 0.2 milligrams per kilogram of pure psilocybin, which is 14 milligrams per 70 kilograms. And so different trials will be using different measurements. So I'll try and keep it telling you exactly whether it's a small, medium, or a large dose in each of the trials. So pretty small study, and they found what? So pretty small study. They found that there was, for anxiety, it reached significance at one month after the study, one month and three months after the study, but it wasn't immediate.

And they used a self-administered anxiety scale and a self-administered depression scale. And while this study wasn't particularly focused on depression, they saw that there was a 30% drop in depression on this, the Beck Depression inventory, which is a patient rated scale. And it wasn't significant until the sixth month follow-up when they noticed that there was a difference. Overall, they found that there was no adverse events. and among the subjects, their consensus was that they would have liked a follow-up experience to reinforce and extend the therapeutic benefits that they felt that they had during the session. Okay. So a pretty small study, which makes it really hard to tell the difference between treatments.

So I think we won't sort of linger on this too long. Let's jump to the next study. This was psilocybin produces substantial, and sustained decrease in depression and anxiety in patients with life threatening cancer, a randomized double-blind trial, Griffins et al, 2016. Yeah, so this is by Griffithson, the Johns Hopkins Group. And this was one of two sister studies, one at Hopkins and one at NYU, which we'll be talking about. So this was had 51 participants with two sessions, also blinded, where the one group had a low dose of one to three milligrams per 70 kilograms or a moderate to high dose, which, where the participants received 22 to 30 milligrams per kilogram.

So the big take home of the study was that for a clinical response, which is considered a 50% reduction of symptoms at six months was 78% of people with depression and 83% of people with anxiety experience that clinical response. And for complete remission at six months, 65% of people with depression experienced full remission and 57% of people with anxiety experienced full remission of their symptoms. So we're talking, you know, huge numbers here with, you know, 80% have clinical response and around 60% have complete remission of their symptoms. Right. But, you know, we can't, we can't say if that's just because of spontaneous remission because there's no placebo control arm, right?

Exactly. And so that's why we're going to get into the nitty, gritty details of this. So everyone got better, but we don't, from the problem with a study like this is we don't really know if they got better because they spontaneously had remission or they got better because the treatment or how much the treatment had an influence on that versus how much spontaneously they would get better if they had no treatment. Yeah. So just as a reminder, again, there were two sessions. And so the control group, which had a very small dose, like a micro dose of psilocybin,

after that, 16% of people had full remission after that session. That was the thing that struck me the most by this study, actually, is if you look at the difference between the two groups, the group that got the low dose first and the group that got the high dose first, for some of the measures, there isn't much difference between them. Well, so for 11 out of 17 of the measures, there was a difference, and for 6 out of 17 measures, there was no difference after the first session. Yeah, okay. So it leaned overall towards the larger dose is what you're saying. Definitely. So you're talking after the first session, the half of people who got the high dose, 60% of those people went into remission immediately while only 16% of the low

dose. So some people are going into remission. For which measure in particular are we talking about? So the Ham-D is what we're looking at right now. So the primary measures, the primary outcomes for this were a clinician-rated depression scale and a clinician-rated anxiety scale. And then all of the other scales are all patient-rated. So for the depression, clinician-rated depression scale, which we consider a more objective scale, is we're talking about, on average, the people started with an average score of 22 to 23 on the grid hamdie and anything above 20 is considered moderate to severe depression and they ended on average with a score of you know between six and seven and anything less than seven is considered

complete remission or not having any depression and the effect size overall for the grid ham d is almost three at six months. So at that, they're comparing it at six months compared to baseline. And it's a really difficult thing to compare. And I'm sure Dr. Peter, you have a lot of reasons. Like, we can't really say that that's the effect size, because three is, that's three standard evasion. So that's a huge difference. But you're, you're not taking into account all kinds of things like regression to, like people will stop being depressed often after a period of time. Right. Yeah. So the effect size is significant. A three is like three standard deviations.

Like if we were getting medications with that compared to placebo, we would be like, it would be a totally different world for psychiatry. But the thing is, is that this is six months in both arms. So at this point, both arms have gotten the same treatment six months out. And both arms are doing about the same. So they've gotten one dose of the high dose, one. dose of the low dose. And so, you know, six months, they're both doing really good. What I was impressed about, like, okay, so like at the Hamdi, since we're talking about the Hamdi, for the low dose, it dropped from a 22 to a 14 after one session. That's a huge drop in and of itself. I was very impressed with that drop. I mean, the other one was dropping from a 22 to a, like a seven, basically, which is a very nice drop as well. But a 22 to a 24th,

that's a very nice change in depression score. Yeah, and I think there's something to be said about the therapists who are doing these studies are very good therapists. And on top of that, the people who are participating in the study, they have moderate to severe depression, but most of them are not on any medications, and they have all kinds, their depression rating is moderate to severe, but they've got all, kinds of diagnoses. Not all of them have major depressive disorder. Yeah. Yeah. So I think in summary, this type of study, what it says to me is we should look at this further. We should have a

study like this where they're comparing it to standard of care. Like let's do this compared to CBT for 10 sessions, right? Or 12 sessions, right? Or let's do this compared to Prozac, you know? Something like that. We're having an active control for what we would do. in the real world or, you know, at least in the research world, what is the standard of care? Because that kind of effect size comparatively is a lot more valuable to me. But the, but showing that, you know, there's a quick drop and it's better in the high dose than the low dose for most of the measures. That's pretty cool. That's pretty cool.

That's something. It just, it just isn't, you know, like honestly, like my, the IOP that I run, you know, and we'll get to some of the this later as well. but the effect size is three for reducing both physical symptoms and depression symptoms for that you know for what we know is like the standard but there's no control against that right so um it's yeah so it's it's a good study it's a well done study i like the study and uh let's let's jump to the next and we'll have more information on this on our blog about it a little bit on the study Okay, go for it. I thought a lot of deal on this study.

Yeah. Okay, what else do you want to talk about about it? So for the Ham A, which is the other, the anxiety scale, they go from a moderate anxiety, which is a score of 26 to a 7 and 8, which is almost complete remission. And again, this was like 80% have clinical response from the baseline to six months, and with 50 to 60% are in complete remission. And for this, they have an effect size of 1.2. Again, that's a comparison between the baseline.

line and six months. Yep. The Hamay on the low dose dropped from 25 to 16, where on the high dose after the first, it dropped from 25 to 8. So there was a drop in both, but a little bit more in the high dose. It's pretty cool. Yeah. So they go through, they have a lot of other things that they're measuring, and a lot of them are self, the patient administered depression and anxiety scales. But one of the things that I

wanted to highlight was the difference that they're measuring people's death acceptance and optimism and meaningful existence and overall quality of life. And in those scales as well, there is a difference between the high dose and the low dose group after the first session. And then the other thing is that there are six measures, which we have here, which showed no difference between the high dose and the low dose group after the first four weeks, because that's the only amount of time that they were able to measure that. What were those? Those were, if you look a little bit lower down, there's another.

another table. This is a table five in the in the article? Yeah. Okay. So in those there was, they measured death transcendence scale. They had a purpose and life scale. And they had a coherence scale, which coherence means having a consistent understanding of self-others in life.

All of those, they couldn't tell the difference between the high dose of, and a low dose. But again, like all of them between the baseline and the six months, all of those are showing effect sizes that are significant. With like death transcendence, you have a medium effect size with a purpose in life scale. You have a large effect size of 0.85. And, you know, those things in particular are things that in psychiatry, like, I mean, therapy is, I'm talking mostly about medication, but we don't have medication. that address these kinds of things? Well, I mean, we have to look at a study if they've actually measured it when they took the medication

because some of these things like purpose in life will trend up if they're not as depressed, right? Because if you're not as depressed, you have more meaning, you have more purpose. But yeah, in general, I would say it's not something we measure or look at very often when we put someone on Prozac. Therapy, on the other hand, you know, there's a lot of, they do look at a lot of all these things with therapy and they increase with therapy. And I wonder, because the low and the high dose did so similar, is it the therapy? experience and the meeting with the researchers and the talking about this stuff, you know, which is, which is really good stuff, you know, in general, right?

How much of an impact does that have compared to the actual substance that they're taking? And would you say that because the low dose was so low that that physiologically probably didn't do so much, so it's probably more of the therapy? or would you say that that might actually have an effect itself? So that leads us nicely into the limitations of the study. But yeah, so it's, you know, a lot of people will talk about how microdosing psilocybin has a beneficial effect. And the reason why they reduced it from a three milligram dose to a one milligram dose was

because the person who was the first one or two people who they gave it to, they had some perceptual changes and they wanted to reduce that likelihood. So it's possible that it is. The other limitations of the study, as I said, like a broad set of diagnoses, some people have adjustment disorder, dysthymic disorder, general anxiety disorder, major depressive disorder, or a mixture of all of those together. So this isn't any specific diagnosis. Additionally, like 55, 45% of participants had used psychedelics in the past, which meant 55 had it, 55% had in. Because they're telling people what they're doing to recruit them for this study, right? So the people who are interested in this type of study are the people who are kind of excited about taking a psychedelic, right?

Right. So what impact does that have, you know, if compared to if you have a patient who's, like not excited about taking a psychedelic, freaked out about taking a psychedelic, you know, does that impact them differently? Would not recommend. Okay. And then we also have a chart here that's just like the demographics. It's a mostly white. It's a highly educated cohort. Yeah. 64% in this or around 50% had postgraduate. education. So that's definitely a different group than the normal population. Highly white, like 95% white, although I don't know of any evidence that psilocybin would affect a white

person's brain differently than a, you know, other ethnicity. And then there were, like, people with different stages of cancer. So about a third of people were in remission with the possibility of occurrence, 37% or by, a third had a less than two-year anticipated survival and about a third had greater than two-year anticipated survival. So a real mix of people. Okay. And they checked about like, it was double-blinded, so neither the participants or the therapists knew what they were taking before they took it, but 90%, they only asked the therapists, but 90% of the therapists knew, or could guess correctly what it was that the participants were taking.

That's actually... That's actually pretty huge. Like, I think I would probably score lower on that. Stick me in a room with someone, low-dose or high-dose. I probably would be like 50-50. No. Well, you know, and I think how does that change the... How does that change the placebo, right?

Or the placebo response of the therapist. Now, the therapist has different thoughts going into this. They might be thinking, okay, the person whose high dose is going to have a bigger response. Or, like, how do I treat them? How are they treating that person differently than the person that they know is probably on the low dose? I think having a good placebo is a really challenging part of doing evidence-based medicine with psilocybin. because there aren't many things that can replicate such an experience. There are, I know that one of the groups wanted to, they wanted to do a high-dose benedril

group so that people would be hallucinating, but the IRB wouldn't let them because it can be dangerous. Oh, come on, IRB. But, like, there are other things, and there are things that, like, I've thought about the way that, like, what's a good placebo? Like, could you do, I don't know. Could you do like a stimulant or could you do like cannabis? I know that using two Schedule I substances in a study isn't going to make it easier to do,

but you want to have something that could alter someone's perceptual experience and make it more, you know, not sure how long it's going to be lasting. But these are having a good placebo is not a particularly easy thing to do in these studies. It kind of reminds me of there was a study that they did of Botox for depression. and it came out in this article and, you know, oh, the effect size is wonderful, you know? And then I looked at the fine print

and the fine print was that like 90% of the people who received the normal saline injection knew that it was a normal saline rejection or something like 95%. So people knew what they were receiving, you know? So does that, that totally changes the placebo, right? Or TMS, you know, do people know if the sham TMS is actually, you know,

do they know that it's a, sham TMS. And I will have to say that I think when we're talking when we're looking at the placebo effect here, I think more about just how much of these people would spontaneously get better because when we normally measure placebo like a like a sugar pill compared to Prozac, there is that some of the people who are taking that sugar pill are spontaneously getting better and that's why the placebo works. And some of the people actually believe it's, you know, an act of medication and some of the people are getting better because of that. And some people are getting better because they've had increased contact with other human beings

who care about them, enough to give them a medication and enough to do a research study on them. And, you know, there's some of the therapeutic alliance that goes on. And that can be healing as well. So it's like all of that is wrapped into the placebo. The problem with this kind of study in my mind is like, we don't know six months after the fact how many of these people had improvements just from, you know, being in a relationship. with a therapist, talking about what's meaningful, being asked a lot of questions about their mental health, you know? I would say just like the, just like medication trials

with these, and we'll see this a little bit later on, but the therapeutic alliance is probably as important, if not more important, than the experience itself and allows for the experience to manifest in what the possibilities really are in terms of therapeutic process. Yeah, yeah. Well, I'd like to see that. Okay, anything else from this study you want to talk about? No, we can move on.

Okay. Boy, that was good. So that's, you know, this teaches us a lot about evidence-based medicine as well, though. Because, like, as I'm listening to you saying, what is a good placebo for these people? You know, because if you did, like, CBT, If you just said, okay, you're either in the psilocybin group or you're doing CBT,

then everyone who does the psilocybin knows that they're doing celibin, and everyone who's doing the CBT knows that they're doing CBT. And if they signed it for that study, you're going to have some people who are like, oh, man, I really wanted to be in the psilocybin group. Yeah, and I think one of the reasons why all of the studies that we look at, they're all crossover studies, is because you're going to have a huge amount of people, dropping out if they are not going to get the psilocybin and they're going to know it because they're going to be taking a niacin pill or a really low dose and they're going to be like this is

not what I signed up for yeah I'm now in a room with a therapist for eight hours after freaking niacin I know this is not real especially if 50% of them have have used you know LSD in the past you know it's going to be hard to trick those people they'd be like yeah this is this is the placebo. Dang it. Yeah. Okay, so should we move on? Let's move on. So the next study we have is by Ross et al in 2016. This was the other sister study. They were published side by side was rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer, a randomized control trial. Okay, so this one's differed because it's a niacin control.

Uh-huh. And instead of the low-dose psilocybin. What are the other big differences in this one? Just in how they set up the study. So the time between the doses is a little bit different, and they use slightly different scales for the secondary effects, and then they also have a really long-term follow-up. So they, for this study, there's a second paper that's published that goes all the way out to four and a half years. Okay.

Cool. So for the take home for this, really similar. So seven weeks after dose one, 83% of the participants in the psilocybin group, and they received a 21 milligrams per 70 kilograms, which is a moderate high dose met criteria for response. and 58% of them had an azeolytic response. Okay. Yeah, it seems to be considerably better than the niacin, looking at these graphs. So.

Nyacin had like a not as good improvement. And the effect size, they have some nice, and some nice pictures of the graph of the two different groups, how they did compare to each other, the effect, effect size and you know you have pretty good effect size you have good around like one to 1.5 in most of these differences which is you know that's one standard deviation to one and half standard deviation that's excellent it's really good that's excellent but once again it's not

like I don't think you can compare that effect size the effect size of something like prozac would you agree yeah it's It's difficult because... It's different types of studies. That's what I'm saying. It's a totally different type of study. And that's kind of where... Or exercise.

I would say or exercise. Because there's a lot of exercise studies, if you look at my most recent one that I did, podcasts on exercise where I talk about the effect size can be around one, you know? But then what are you comparing the exercise to? The control arm is usually no exercise or stretching or... Right.

You know, passive exercise. So these are different studies that can't be put... side by side. Okay, but talk to me about this one specifically. So they found rapid benefits. They didn't find any difference in effect of gender, whether they had used hallucinogens before, about their spiritual background, their stage in cancer, all of those, everyone had similar benefits from it. They measured in this study whether or not people found that it was a very significant experience. And 52% of people rated this as the singular, most spiritually significant experience of their life. And 70% rated it as among the top five

most personally meaningful experiences of their entire lives. And 87% are reporting increased life satisfaction and well-being that they directly attribute to the experience. And they were putting this on par with marriages or their children being born. So there is beyond the depression and anxiety scores that we're seeing getting better, there is something else about the experience that's that this is kind of where I want to get you, Dr. Peter, is that like they're bringing meaning into their lives. Like people are finding these meaningful experiences. How do you how do you feel about that though? How do you feel that this, that chemically you are creating an experience, which is as meaningful as their marriage or their baby being born.

Does that blow your mind at all? Like, is that, like, how do you feel about that? Like, is that okay? You know, I'm a, I'm a sucker for therapy. Like, I think therapeutic experiences and powerful experiences, wherever they come in, if they are increasing life satisfaction and well-being, like, let's have more of those. Okay. I want more. of those. Okay. Yeah. But, you know, I get it though, because I had this, so I'm, so I'm, so I'm, so I'm saying goodbye to a lot of patients every day. And I've had a couple of patients tell me that, like, being able to talk to me is, like, more important than being able to talk to their, their kids or their husband, you know, and sometimes it's like, ooh, like, this is a huge loss

that this person is experiencing. And it, it shows, it, it speaks, to the meaningfulness of this type of relationship, which is psychotherapy, like usually weekly or twice a week psychotherapy. And I feel honored to be a part of that. So what you're saying is you would feel honored to be a part of their life and give them a meaningful experience. Definitely. It was like such a treat.

Yeah. So among the secondary things that they also measured, you know, people felt that there was psychological benefit, positive behavioral change, spiritual benefits, better death transcendence, spiritual being, social relationships. The one thing, one of the things that I was kind of, I was hoping for was the death anxiety scale. They didn't find any benefits. And, you know, I, I'm surprised. And that's what you're. I was surprised too. That's what you're interested in with that palliative care, right? That death anxiety? Yeah. Yeah.

Well, yeah, that's interesting. So you couldn't, because I know I've had patients who, you know, are on their deathbed and they've had spiritual, real spiritual experiences. Like their, you know, pastor, their religious leader comes and it does decrease their anxiety considerably, you know, as they prepare for death. so it's like this sort of medication-induced spiritual event did not decrease that death anxiety at least in this study yeah i don't know how like you can get more death transcendence without less death anxiety or like improved psychological health and improved demoralization and less hopelessness and well-being and life satisfaction so a lot of these seem like they should overlap or they should all overlap in some way but

when you kind of, you're a splitter, which is what happens when you give them a bunch of scales, you see differences. Yeah, and we'd have to look at the questions, the specific questions, and sort of reflect on that as well if we really wanted to get into it, get into why those questions maybe didn't shift. Yeah. Okay, should we talk about side effects? Yeah. Okay, so, quote, in terms of, you know, adverse events, attributes.

attributable to psilocybin, the most common adverse event were non-clinically significant elevations in blood pressure and heart rate, 76%, headaches, migraines, 28%, nausea, 14%. The most significant psychiatric adverse events were transient anxiety, 17%, transient psychotic-like symptoms, 7%, which was only one case of transient paranoid ideation, and one case of transient thought disorder. Yeah. So essentially all of these side effects are they're mostly limited to the session itself and they have people there who are trained to deal with it and are addressing it as needed. If I remember correctly, the most significant side effects that be extended beyond the session was like, I don't know, it's like something like 50% of people had headaches the next day that

resolved with and said. It's like, you know, there were. There were. where there just wasn't that much here in terms of adverse events. Yeah. Well, it doesn't decrease libido semi-chronically. So that's a good thing. That's kind of a joke because a lot of outpatient psychiatry is like often you're trying to deal with side effects after they're out of their depression or anxiety. It's like now you're dealing with like, okay, how do we reduce the amount of side effects that they have?

So talking about the other limitations from the study, again, it was double-blinded, but 98 out of 29 staff members were able to predict what 28 out of 29 participants received. Right. So the staff knows, you know, what is really going on, even if they don't know, right? They're not told they're giving niacin or psilocybin, but they can. figure it out because they're, you know, into this stuff. So that, you know, how does that affect the actual experience, right? I think it does affect the actual experience. I think it's impossible to hide our sort of thoughts completely from patients. Definitely. Our expectations,

especially if works, like all the, all the researchers are really excited about this. Yeah. And you know what? that being said, like, that excitement is contagious, but no matter what you're excited about as a physician, your patients will feel that. So if you're excited about, you know, homeopathic remedies, your patients experience that excitement and you know what, that homeopathic remedy will work better than the water that it is, you know? So the next study is a long-term follow-up of this study. And there were 16 living participants at this point, and 15 of them participated. And they're doing this 3.2 or 4.5 years after their psilocybin sessions. That's when they're asking them to rate their depression and anxiety in these secondary characteristics again.

71% of their cancer had been in remission, and 29% still had active cancer at the time of the study. So here you're seeing like the depression score, the anxiety score, their benefits are being maintained. And you're talking after one dose of psilocybin integrated within therapy. Yeah. So no control arm, so we don't know how much of this is spontaneous remission. But, you know, if it was the psilocybin, that would be exciting. Like a one-time event reducing the anxiety. You look at the ham, H-A-D depression. Yeah, the effect size is continued. It's the hospital anxiety depression scale. So it's a different. It's not the ham.

It's not the ham. It's the hads. Yeah. Okay. Back depression. The effect size is one to 1.4 in a lot of these, both the anxiety and the depression, which is good. It's a good effect size. Yeah. And then for the secondary characteristics, which they do not give us effect sizes, but they just tell us whether or not they were significant. They were significant differences. There's improvements with demoralization, hopelessness. Here they have death anxiety. I think because they're comparing it from the baseline to the six months and then the four and a half years, spiritual being environmental health you know physical health there is no difference social relationships there isn't a difference and then psychological health there was a difference at 6.5 and 3.2 years but not at

4 and a half years well i appreciate how far they took this out how far they took this study out but you know like just just to give you some ideas is that like i've seen exercise strength training effect sizes 1.5, you know, like as it stretches out, obviously they need to continue it. So that would be probably the difference is like, you know, if you continue to exercise, yeah, you'll still get some strong psychological gains. But that's where, you know, I think we need multiple hammers in our toolkit, right? So I'm glad I'm becoming more aware of this. Yeah. So three participants. were receiving some kind of psychotropic drug treatment after the study, which is compared to eight who were taking some kind of psychotropic drug before the treatment started.

And no participants were receiving medication that was specifically targeting cancer-related psychological distress, which was the reason why they entered the study. Cool. You know, take it as it comes, like depression and anxiety, what's cancer-related distress and what's not. Okay. Okay, so the next study we have, this is psilocybin with psychological support for treatment-resistant depression, which this was an open label feasibility study. So kind of similar to the first study we looked at, small study, 12 patients, just like the other ones they had, four hours of preparation. For this one, they had two psilocybin sessions.

The first one was a low dose of 10 milligrams, and the second one was a, moderate high dose of 25 milligrams. They received it one week apart from each other. And then they had two in-person follow-up sessions, one the day after the psilocybin session, and the second a week after the psilocybin sessions. To me, it looked like for this study that it had less psychotherapy involved

compared to the other studies that we were looking at. Okay. Four hours of preparation. That's something. It's significant. Yeah. Follow up online four times over three months. Yeah.

So the follow up was considered they were doing the screening studies. The outcome measures. So the take home for this was that 67% or eight people had response and there was complete remission in seven of these eight patients when you're looking at the Hamdi and the Beck Depression Index. And seven of them maintained their response. So that was 58% of them would maintain the response for three months. And 42% or five remained in complete remission. This is good.

I mean, these are good effect sizes. You know, we don't really have a control between the and the small number of people. but it's it's it's I mean the study like this is a good initial study showing that we should consider this as an option for future studies right like this kind of studies small study we should do bigger studies to kind of see how it does compared to other cold standard treatments okay let's go on to this next one goldbird 2020 just fresh off the press right so this was a meta-analysis just looking at the four studies that we just looked at. And that's why I put it here,

because it's just like they were looking at all of the studies and they tried to put them together. And what they found was that there were a large effect size on improvements of both anxiety and depression. And for anxiety, they found an effect size of 1.38, which is an awesome effect size and depression 1.47. You know, honestly, since we already looked at the studies, I think actually you can take more from the studies

than looking at this sort of meta thing. This meta thing says, oh look, the effect size is, you know, around 1.4 for anxiety depression, effect size first placebo is around 0.8. But really the benefit of a meta-analysis, they talk about the concerns of the bias. And so they said, you know, these are small number of studies and small samples.

Well, of course, because this is like brand new stuff, So yeah, break down some of the concerns that they had some of the limitations. Specifically, what is performance bias? Do the lack of complete blinding? Like, they had a concern about that. Yeah, so performance bias is when the therapists are treating the participants or the experimenters are treating participants in different groups differently because they know what they're receiving.

And so in this case, even though they're supposed to be blinded, the therapists were able to tell which group and who was receiving psilocybin at what time. Yeah. Okay, let's jump into the effects of psilocybin-assisted therapy on major depressive disorder, a randomized clinical trial, Davis et al-2020, fresh off the press. Yeah, this study, I think, came out three weeks ago. Yeah, I think I sent it to you when I saw it. I was like, oh, we should definitely put that in.

That's brand new. Okay, so tell me about this study. What was unique about this study? What does this study teach us that the other studies hadn't taught us yet? So this study was dealing specifically with major depressive disorder. And this was a study it had an end of 27 and 24 of the people completed treatments and was adults with moderate to severe major depressive disorder who were not on medication and they compared the treatment groups with an eight-week delayed treatment.

So again, this was a crossover study, but they had eight weeks to determine the differences between the different study arms. All participants in this study, they received two psilocybin sessions with the first being 20 milligrams per kilogram, which is like a moderate dose. And the second being 30 milligrams per kilogram, which is a high dose of psilocybin. And they did effect sizes. and the effect sizes for at week five were 2.2, and at week 8, they were 2.6. So this is before the crossover. Yep. So really significant effect sizes.

So it's a good effect size. It's comparing it to people who did not get any therapy, right, because they delayed the treatment for that group. So it's basically a wait list. But, you know, that's still a big effect size. I mean, if you look at most psychotherapy with weight list, the effect size is like one, you know, in a lot of the studies. And so this is an effect size of two, which is pretty significant. Okay.

So Nadav, anything else from this study that it uniquely sort of contributes to the information that is out there? This is just one of the first samples that is uniquely looking at depression by itself. and you're looking at 58% of participants who are in full remission. And again, when you're looking at this, people are rating it extremely highly in personally meaningful experiences,

spiritually significant experiences, psychologically insightful, psychologically challenging as well. So the paper itself talks only about up until week eight. And then I watched a talk by the lead author of the study. And he in this, it's available on YouTube, but he gave a talk and he gave the data that went all the way out for a year. And going out for a year, they also, it continued to have significant decreases in depression. It didn't increase after that two-month mark. So,

58% of people continue to be in remission after 12 months. So one person in the, I'm a part of this like psychiatry network and one person commented that number one, you can't compare this to SSRIs because there's no fair blinding. There's some people who will actively malinger to get this type of treatment similar to ketamine where people drop out post randomization in unblinded trials. So if people, for example, know. that they're not going to get the ketamine, they'll drop out. I think Willinger is a strong word.

People do want to be part of these studies, but I just, you know, if you look at my NeoPI, like, I generally trust that people are, like, they're willing to, like, change things a little bit, but they're not just, like, completely lying. Well, like, the question is, like, would you lie to say you're more. depressed, if you knew that by saying you were depressed would get you into the study. I don't know. I'm saying that there's a person out there who, when we looked at this group as a group of psychiatrists, this is what the person said. So this is not my words. This is what the person said. Fair enough. And I think it's fair to put out the concerns of people in the psychiatry

community, even if we don't agree with it. So I would hate to call anyone a malinger. And I never would because I'm not a forensic psychiatrist, and because writing that down could get you into a lot of legal trouble later on, right? I like to believe that people are telling the truth. This person also commented that if you looked at early studies with bruxanolone from the pilot paper, the effect size, was greater than one. But in phase three of the study, Sage didn't publish it because they're main, and they didn't publish the effect size of it compared to the placebo because it was so small. And they tried to hide it. So it's like this idea of sometimes early studies have a bigger effect size.

And then when you actually do a bigger study and you compare it to placebo, the effect size drops quite a bit. I don't know. You don't like that. No, I do. actually, I pulled some, a paper called Antidepressants versus Placebo and Major Depression, an overview by Conan Brown in 2015, to talk about this as well, because we have this graph here that where you have antidepressant trials, and when they're blinded, they do a little bit better than when they're unblinded.

And then when you compare that to the FDA analysis, you know, you go from, you know, about 50% efficacy to about 40%. Like it's, you know, that's, it's pretty significant. And it's the same thing. If you look at treatment as usual, which would be the placebo group in large part, like the placebo group, if they know they're in the placebo group or the treatment as usual group, they do, they don't do nearly as well. Yeah. You know, expectancy for treatment and the effectiveness of the treatment is very powerful. It's been going on since mesmer, you know. I got to do a little bit of the history of psychiatry. He's, you know, he took these women, upper middle class women. He did this like, he created these rituals and even like evoked like seizure like activity and all, a lot of different types of things. He had, you know, you, you know, he created, you know, he created these rituals and, um, he even like evoked, like, seizure-like activity and all, all the different types of things. He had, you, you know, you know, you know, you know, you know, you know, you

know, using powerful magnets, you know, and, and, uh, you know, that's where this idea of, like, mesmerize, you know, and he got this incredible effectiveness and he had this, like, following, you know, so it's kind of like, you know, people want this kind of, like, miracle, you know, they want this mystery, right? And they want you to have authority and all of this kind of combines together to create this, like, placebo response. Okay. Yeah. And again, I mean, I mean, the person who you're talking about also notes about the placebo's hard. With SSRIs, like some people feel nothing when they take an SSRI, where with these medications with psilocybin, it's impossible.

Like, you know what you're getting. Right. So, you know, there's this idea that with an SSRI, when you take it, you might not feel anything, which kind of allows for a placebo to actually work, potentially. Because with a placebo, you don't feel anything. either. Whereas if you take ketamine, you take MDMA, you take something like psilocybin, you know you've just taken something, right? Yeah. So then how do you create a placebo that's like an active placebo? Yeah, we already touched upon that a little bit. Yep. There was some also criticism about the exclusion

criteria with nobody with a first degree relative with the psychotic illness. Yep. But I think that that's just safety. And, you know, the same thing, they were also excluding people who were, who had active depression and needed to either be hospitalized or required to be on antidepressant, anti-depressant medication in order to, because of concern for suicidality. And that's just the way that trials go and experiments go. It's like, you just, when you have a new drug on the market, whether it's psilocybin or it's a new SSRI. You just are really cautious about who you put in your study because you don't know what's going to happen.

You don't have that much evidence for it. Right. So, you know, the critique of this could be, is it ready for the general population? With this small of a study, you know, do you think it's ready for primetime? What do you think, Nadav? We'll talk about it later.

Well, in the conclusion, I talk a little bit about it. Okay. Okay. Well, we'll hold the suspense. You guys have to listen to the end. I would say it's not ready for prime time, but that's just me being like, you know, a little bit more. Show me, prove it to me, change my mind, right? I'm going to try.

I'm trying to do that. Okay. Let's keep going. Oh, you know what? And in the article, I'll put the data for my program here, which should. shows our effect size in our treatment. And it's around three to two, two to three, somewhere in there for different types of mental health

components of the measure that we do. So that's to show like look, in and without a control group, right, getting an effect size of three with a good program is going on right now, right? Like this is prime time right now, there's patients going through my program, every day. And by the end of the program, their effect sizes two to three somewhere in there. Actually, interestingly, it's been going up since. Yeah, I was curious about that. Like,

how are you getting so much better? Like, every month you get a little bit better. A little bit better. You know what? We have gelled as a treatment team. We've brought on a couple new therapists. We've had some therapists leave. And there's just a good culture. And that's been something that's been maintained. So that's probably for a little bit of the change. I mean, we're talking about an effect size change from a year ago of almost one. So we've gone from like two to three somewhere on there. The other aspect is I think people are a little bit sicker right now with COVID. And so when people come in, they come in literally starving for connection. They're starving for connection. And that's very unusual. And so we're seeing better effect sizes because of that, because we give them,

you know group therapy starts off five days a week and then it goes three days a week it's over like a couple months so that's probably why we're getting such good effects right now and i think this is going to happen is whenever you have a motivated population who are going to show up every day and stick to it you're going to get benefits like those people are going to get better or they're way more likely to get better partial works partial works i think across the board and you know it's crazy because I'm in moving to Florida I'm talking to them and they're like oh we don't do as much partial here it's like what like this is like what really is effective like this needs to be everywhere so I don't know I'm on board with partial I've got patients who I push partial and they don't want to go and then they end up having to go for one reason or the other other and then they come back and they're like that was so helpful yeah so great yeah because think about like how do you get that much therapy condensed into such a short amount of time like if they're going seven eight hours a day, five days a week starting out. And if you look at every study, whether it's DBT, mentalization, CBT, and they're partial,

all of them, huge effect sizes, huge effects sizes. Okay. Yeah, and I wanted to, this was kind of like after, right after you talked about that, it's like where I feel like, you know, these effect sizes, you've got huge effect sizes. And when we talk about SSRIs, we've got like, you know, small effect sizes. And you can't, you can't compare the two, though, because I'm doing medications in this program, right? I'm not only putting them on the right medications. I'm taking them off of things like benzos, marijuana, opiates.

Like, all of that is happening in this partial program. So it's a mixture of medication psychotherapy. But anyways, go on. What were you going to say? I was just, you know, it's difficult for me as a new psychiatrist and someone who's just, you know, sinking my teeth into all of these kinds of papers. And like, what's the difference between like a weight list and a placebo and an active control when you're comparing that across studies? And when you're getting, you get data with like, you have a P value of 0.001 and then you

have an effect sizes, which seems significant. But then you have these differences between like, you know, what about the provider in the therapeutic alliance or if something's industry sponsored or non-industry or government sponsored? Like, what are, the differences are all really significant and it's really hard to have hard data that you're like this is like you have to compare every there's all these different fruit like apples and oranges it's just and it's just not so it's hard yeah and i think that's why having this conversation on this podcast over and over again about like what is effect size how to understand the different effect sizes i can tell you a lot of people don't understand it because i do this self-assessment

quiz and a lot of people miss some of these effect size questions like people have been practicing so i think like like with my program i'll be critical of it look there is no control arm this is this is the effect size change if you compare how this measure is done to the general population there's a bell curve and so how many standard deviations do you move people who are really sick down three months later on the effect size it of course they they get better i i can tell you it takes them usually about three to four weeks to start feeling better and maybe two months to start feeling good and then somewhere around three to four months they start feeling gratitude towards being in the program and and that's really a lot of fun it's a lot of fun to see that change and if you're a

resident and you're in the thick of it and you're not feeling that gratitude every day and in day out that's really hard too comparing different groups is really really difficult i'll say with like with medications, one thing that's hard is like, you know, are you comparing mild depression or severe depression? In severe depression, compared to the placebo, the medication is going to have a bigger effect size, like 0.7, 0.8. That's where you're going to get the biggest effect sizes for that. With like something like TMS. Are you comparing it to sham TMS or just wait list? There's going to be a big difference in the effect sizes there. In exercise, are you comparing it to, if you compare cardio and strength training, you might see a little bit of a difference, but, you know, if you compare

it to a weight list, you're going to see a huge difference. So that's effect size. Yeah. And I think it's, we'll bring us back to this paper because all of the studies that we looked at, they all have like moderate, moderate severe depression. This isn't, those are the effects size we're looking at. It's not severe depression where you might be able to see bigger differences or mild depression where the differences are not going to be as much. Wait, so you're saying that most of these papers are more moderate to severe. Is that what you're saying? They're not severe, severe.

These aren't like suicidal. This isn't like psychotic depression with like catatonia. No. Right. And honestly, like those are some of the hardest patients to treat. You know, who is going to get referred for this type of treatment is probably going to be the person that like the psychiatrist is like, okay, I've tried like six or seven different things. nothing's working, you know, the person doesn't want to do ECT.

Okay, Nadav, you're doing the psilocybin stuff. Would you take on this patient? And he'll be like, oh. Yeah, that's exactly right. It's like, thanks. Yeah. Well, you know, I mean, but we need to find other options for people who are in the very close to death place, right?

the place where they're like they're going to commit suicide or they're going to try some option that's like different because I have a lot of patients that come to me who are like I take their medication list and they've been on 20 different meds and I say hey you know medications might not be the solution for you it might be meaning into their lives it might be a partial and I have some people who have gone through three or four partials before and they're still struggling so it's like okay what do you do Okay. We digress. More digression.

It's a good digression. Okay, let's keep going now. Okay, so our next study, we've got a, we're moving on from depression. We're at a depression now. We've got a pilot study. It's called the pilot study of the 5HT2A receptor agonist psilocybin in the treatment of tobacco addiction by Johnson et al in 2014. And this is also part of the Hopkins group.

So in this study, they had 15 participants, 10 men and five women, five of whom were psychedelic naive. They were all motivated to quit. They had all been smoking for an average of 31 years with an average of six failed past attempts. And they integrated the psilocybin therapy with smoking secession CBT. And they had three sessions of psilocybin. This was open label.

The first session was 20 milligrams per kilogram. 70 kilograms, which is the moderate dose, and then two sessions with the higher dose of 30 milligrams for 70 kilograms, unless they opted for the lower dose, which I think only happened with one or two participants. And the outcomes are pretty significant. So 12 out of the 15 participants, which is 80% of people, remained abstinent at the end of the study. How long was that? How many months? I believe it was six months. They do have. follow-up study that had 12 months, and at 12 months, 10%, or 67%, so two-thirds, were completely smoking abstinent.

That's impressive. Super impressive. That's impressive. It's like quitting nicotine is very hard. Very, very hard. Okay. So, it's a small study, but it shows me like, hey, we should maybe do some more studies on that.

That's right. I'm slowly going to get you. No, I don't know. I know. Oh, okay. Okay, nicotine. Okay, let's go. Let's do this.

The smoking. That pushed you over there. That pushed you over the edge. Oh, okay. Like, we can do anxiety depression. I do that with, I do that in my partial, but nicotine, we're out. We're like, man, good luck. Okay.

No. Yeah, so again, 73% of people are rating them among the top five most spiritual significantly experiences of their lives. 87% or 13 are reported as personally meaningful with increased life satisfaction as a result of the psilocybin sessions. And the reason why they talk about why they found that it was helpful was the participants found that they were thinking more long term. They had increased self-efficacy. They had changes in their life priorities. And that helped them lead to change and stop smoking.

All really good things. All right, let's go on to the next study. So this one's psilocybin-assisted treatment for alcohol dependence, a proof-of-concept study. So again, it's an open-label study, and this was by Bogan Shoots at All in 2015, and this is part of the NYU group. And so they used, they had 10 patients, two sessions of psilocybin, and the two sessions, the first one was 21 milligrams for kilogram, so that moderate high dose. and then the 28 milligrams per 70 kilograms, which was the high dose, which was eight weeks later. And they combined that with 12-week motivational enhancement therapy, which is the standard of care CBT for alcohol use disorder. And the take-home message for this was, again, significant improvements in reductions of both total and heavy drinking days after psilocybin with effect sizes between 0.86 and 1.38.

So again, large to very large effect sizes. Wait, what did you say the effect sizes were? 0.86 to 1.38. Okay, yeah. Well, I mean, that's, wow, okay. So, you know, no real control, small study, but promising nonetheless. Yeah, similar to the tobacco study.

And, you know, similar to other things like people are measuring it. It correlates with the mystical experience that they're having, which it's just an interesting thing and something that we don't really look at in psychiatry is, you know, and this is a substance that seems to be creating some kind of powerful mystical experience, which is helping people get better. M.EQ 30. Yeah. Mystical experience questionnaire 30. 30 questions. I don't think I've ever seen that one before. That's cool.

Okay, yeah, let's jump to the next study. Cilocybin assisted group therapy for demoralized older long-term AIDS survivor men. Open-labeled. Open-label study. Fresh off the press. This is from a UCSF group. And so this was a pilot study with three treatment groups of six participants. So this was group therapy.

which each group with six participants, and there were three of these groups. So over seven weeks, participants with moderate to severe demoralization underwent three hours of individual psychotherapy, 12 to 15 hours of group psychotherapy, and one eight-hour individual psilocybin administration. So this is kind of mixing PHP a little bit with psilocybin.

Oh, man, this is, you're trying to hook me now. Like, look, Dr. Feudor, you could do this in your Ph.P. I, you know, I've never seen researchers more excited. Can you imagine like these? Yeah, so there was, there's no placebo group because, and they said it was because of the difficulty of actually blinding anybody. They were like, you know, the blinding isn't really happening anyway, so let's, it's too complicated.

It's a small study. Yeah. I mean, but the treatment, people get better, right? That's what they're finding. They're finding people get a little. bit better. It wasn't, it wasn't like a knock your socks off difference. They had effect sizes of 0.47. So it's like a small to moderate effect size comparing it to baseline with the end of treatment in three months. And they're looking at demoralization, which is not something, again, that we have any

treatment for. I mean, you know, there is demoralization mixed in with everything else, but it's not something that we measure in psychiatry so much. Well, it's, it's, it's something that probably most people listen to this have been like, oh, I don't even know what questions they would ask for demoralization. Or, you know, you might guess, but if there's like a measure for this, and so they follow the measure. Mm-hmm. And they get a little bit better. That's cool. And this is a tough population, by the way. Chronic, long-term AIDS patients. So this is, these are all men who lived through, the AIDS crisis and had AIDS themselves and survived. So there's a lot of survivors guilt, there's a lot of trauma, there's a lot of grief, and it's been something that they often don't

feel comfortable sharing with anybody else. Yeah. Yeah, so there were some side effects that I wanted to highlight here because there was some, there was one significant adverse outcome here. So 14 out of the 18 people had expected side effects, which we talked about, headache, nausea during the session or the day after. So one participant in particular had generalized anxiety disorder, panic disorder, and borderline personality disorder diagnosed before the session. And decades of heavy substance use. and he initially right after the session, right after the medication session, experienced improvement in his anxiety. However, 10 days later reported severe anxiety in which he described as a deeply felt

sense of being rejected by the other group members. He then, after learning that a former partner had suddenly died, had a lapse in his methamphetamine use and cocaine use after having been sober from all substances for one month prior to the study, which was a requirement. And as had occurred once before previously in his life, he developed a brief psychotic episode subsequent to methamphetamine use. During this episode, the participant made a suicide attempt, which did not harm him. So there was no physical damage, or there was only very minor physical damage, but had a high potential of lethality that could have killed him if he had gone through with that, even if he had medical care. And he withdrew from the

study at that time but completed the subsequent assessments. And yeah. This is what I love about researchers is they publish even the bad stuff, right? I mean, I wouldn't put this guy's suicide attempt on the psilocybin. I think this guy had a lot going on in his life. He was pretty severely ill. Lots of drug use, meth-induced psychosis. I mean, this is the kind of person that we see quite frequently in our inpatient

setting here. Borderline personality disorder. It's a really... It's a difficult combination person to treat. Yeah, I mean, what I was saying about researchers published this, they know they have to, right?

They're trying to make sense of it. I don't know if you could antidotally attribute the psilocybin to a lot of what went on. So what they do address is that for all the participants, there was no change or improvement in the alcohol use or overall drug use scores. So they don't think, it doesn't seem that his return to methamphetamine or cocaine use

was because of the psilocybin, because it's not being shown on any other studies or in their study either. It makes me wonder about borderline personality, sort of, though. Like, what is, because a lot of these patients were seen so far, cancer patients, these are not the typical, you know, psychiatric patient. you know something like 50% or so of our inpatients probably have borderline persuasor so it's like what what is that going to be like in that in that population you need specialized treatment and you need people who are really familiar with what's

going on you'd yeah you'd have to you know this is where like you take you take some nice studies on depression anxiety but you've kind of excluded people with the borderline perisor or maybe diagnosis or you haven't I don't know but maybe you have Maybe you have. And so what's going to happen in that population that dissociates very easily? Is the treatment going to sort of dissociate them? Yeah. So most of the studies did have exclusion criteria for people with disassociative disorders.

And some of them did also with borderline personality disorder because you need a higher level of care. I mean, the best therapies are like transference-focused psychotherapy where you really need people to have really strong relationships and be able to build that really strong relationship before you can really push people to get better. Right, right. So, I mean, it's a good risk to put out there, right, to our psychiatry colleagues, to our psychotherapy colleagues. You know, if this person has a history of psychosis, bipolar, borderline personality disorder, we don't know what would happen at this point. So maybe some more. studies are needed.

Yeah. Okay. Let's keep going. Well, one of the things, the other thing that's unique about the studies, it's group therapy. And when you're talking about any kind of intervention, which requires two therapists per participant, you're talking about huge amounts of time and huge expense. And so this is creating the group therapy model and saying that it's feasible, which is both effective because group therapy has its own unique, beneficial. effects and would decrease the cost of the treatment overall.

Yeah, and yet the effect size is not as strong as the individual therapy. So do you think that part of it had to do with group versus individual? I don't think so. I think they were looking at a really difficult population. I mean, that's what my intuition tells me. Yeah, like I haven't done group therapy, and even though I haven't done group therapy, I have an affection for it, having read Yalom, and just knowing that people respond to, like, if you can live out the dynamics of people's personal lives in a therapeutic setting, then that just seems awesome.

Yep. So I like group therapy, at least as an idea at this point in my training. Good, good. Well, even though you haven't done group therapy, you've interacted in groups most of your life. And so learning the group therapy stuff. can help you when you're leading a treatment team. All right, well, I think that that is a ton of information. And if you're still listening at this point, you are truly curious and willing to put up

with our sort of going through some dense material. It's so much material. Oh, yeah. Well, it's monumental. It's almost like a book that's like in audio form. It's better than a book on this Because I think like most books Will have a lot of emotive language

You'll have the charismatic leader Pontificating about how amazing this is And here you have a skeptic and a person who likes it Joint together Okay So at this point looking at those studies I would say the effect sizes were good The treatments are promising

I think it's not ready for prime time That's my sort of big takeaway is that I think there needs to be there needs to be some more studies. But are people starting to put this in prime time? Like, what are your thoughts? And I think it's a fair assessment. This is overall, the research is really in its nascent.

I think it's, there are phase three trials with what I understand of hundreds of patients where they're going to be studying, in depression, studying psilocybin in depression. And when that data comes out, I think it's really going to show us what it looks like on a population scale. I do think that regardless, it does show it. What have you looked at so far indicates that there should be changes in policy around psilocybin, that at the very least. I would agree with that. I would agree with that. and I would agree with the need to have IRBs relax a little bit,

how they might look at these types of studies. And I would agree with the idea that we need to compare this to other active treatments. And so we need patients who are willing to potentially be in the psilocybin arm or the active treatment arm. And we need some, I would get excited by that kind of study. Like, show me this first partial, you know, like a like a, like a, a university partial program. Like, compare it to that. What do you thinking?

You're smiling there, no? Yeah, it's so hard, though. You're, like, talking about, like, psilocybin is sexy in psychiatry right now. And partial, while incredibly effective, it's not sexy because it's so... They're both time-intensive, but there's no, like, specific, like,

crazy experience that people are, like, this is the experience that is the most significant experience of my life. And it's hard to recruit people. I talk to patients every day leaving, or not every day, but every week someone leaves my partial program. And inevitably they said this is one of the best experiences I've ever had. At first, I went into it. I wasn't excited. I didn't want to be here. But Dr. Peter, thank you so much for convincing me to stick it out because this has changed my marriage. This has changed my relationship with my friends, with my family. I hear that every week. You should team up on one of these studies and you should run the partial arm. I'll run the partial arm.

Yeah, we'll randomize the patients. Yeah. The other thing is like, honestly, it's a lot of work to do research. So I get why there's some, and, you know, there's not drug money in this, right? There's a lot of private donor money. People are interested in it. But there's not like, Big Pharma is not going to make billions of dollars off of this. There is a for-profit company that is in the business.

business, which I was planning on touching on later, but called Compass Pathways, which released, which went on to the public market about a month or two ago. And so, like, there is money in it. You know, we can talk about a little about, like, where the money actually is, because there is a non-for-profit company that's at the same stage of development. And psilocybin itself, like, once it's legalized, then, or what? once it's not criminalized at the very least, is like, will people be able to use mushrooms for their sessions, or will you only be able to get psilocybin from a lab?

Like the lab psilocybin can be marketed because there's a special way that you create it. Yeah, okay, so maybe I'm wrong about that. Maybe this will lead to new industry and new studies from these industry leaders. and this is a nice review of the big studies. And I would like to see some control arms that are active control arms

that are six months long so we can compare it six months what's going on between like CBT versus psilocybin therapy. That's what I would like to see. Do you think I'll see you this? I definitely think you'll see it. Yeah. I think I think that would be what it takes

to really like, change my mind. You're going to have some of the same issues in terms of like you're going to know, everyone's going to know which arm they were in or where they were. So you're going to have, there's going to be bias, which is unavoidable. Yep. And that's good. It's good you're thinking like that.

It's a good, good researcher here. Yeah. So let's jump into this article we're looking at this 2011 Stradius, Stradius. article. Yeah, so we are after talking about the psychiatric disorders that psilocybin has been used to treat, these are the secondary effects and experiences. And so this, this article called acute, sub-acute and long-term subjective effects of psilocybin in healthy humans, a pooled analysis of experimental studies. This was a study of, that we've looked at before, but a different part of it, with 110 overall healthy individuals getting a total of 227 doses between high and low doses.

And I would just pull out here the different kinds of experiences that people had. So 90% of the people who underwent the experience found that it was enriching. Two-thirds found it influential. A quarter of people found that it led to changes in relationships with others. 56% found that it had changes in attitude to altered consciousness. whereas about a third of them, third of people found it frightening or unpleasant. Medium frightening, 30%, very frightening 5%. Yeah.

So, yeah. Yes. You expressed a little fear of yourself there as I said that. Sorry, I'm reading your micro expressions here. Yeah. You cannot see this watching this podcast. So what we're showing here, I think, is that for the most, part people have very positive experiences with the psilocybin experience but some experiences can be

really intense and doing it in an unsafe space can be really frightening and unpleasant now this study was of a safe space though right this was but they had support so you're still they had support so you're still finding that you know 90% of people are finding it an enriching experience right okay yeah let's talk about this second article mystical experiences occasioned by the hallucinogen psilocybin lead to increases in the personality domain of openness mclean 2011 so as you discussed in your openness podcasts openness the domain of openness is where people have um where it leads to new ideas and values in imagination aesthetic appreciation novelty-seeking, non-conformity, and creativity. And in this study, they had 52 hallucinogen naive participants between two studies, and they found that there was increased in openness that remained over the course of a year with a significant P-value, with an average increase in openness of four points,

which is half a standard deviation after they had a high-dose psilocybin. in session. Yeah. So just to break that down, part of openness is fantasy. So people who are higher in openness have a very active imagination, fantasy life, enjoy entertaining fantasies, daydreams. The second domain is aesthetics. They get absorbed into music, experience chills of excitement while reading poetry,

fascinated by different types of music, intrigued by patterns, feeling, is they may experience many emotions and feelings, and the mood may be influenced by sense or names of distant past. Actions, you have, they believe in a variety of things that they enjoy doing. They enjoy new and foreign foods. They enjoy learning new hobbies, ideas, they enjoy entertaining theories and abstract ideas. They enjoy mind-twister puzzles and games, a wide range of interests involving. intellect and values, they believe the laws and social policies should be flexible,

unlike the Nixon presidential. That's probably why he was so against it, right? Yeah. Broad-minded and tolerant believes everyone has a different version of right and wrong. So that's what it means to be flexible with the values, whereas someone who's low in openness for values. use. They may rely on religious authorities. They may stick to ingrained principles. So all of that being said, a half a standard deviation shift, is that a lot or is that a little?

I think it's the question that I have is, is it a half standard deviation shift every time they use this? Is that just from using it one time or ten times, it's still a half a standard deviation shift? What do you think? I would guess that it is of diminishing, diminishing returns after, like the first time, maybe you have an increase after the second or the third time, but it's going to be less and less. I don't think, you know, it's, it is a difference, and it's not particularly clinically impressive. But at the same time, over the course of a lifetime, generally people get less open. And in this paper they talk about, over every decade people have one point decrease. increase in openness on average. So this is reversing that effect by the equivalent of 40 years

of openness change, which that's what they say. And then, and this is the only discreetly measured experimental condition that they know of that has caused an increase in openness. So if you want Well, there's an MDMA study, right? Wagner 2017. I talked about that one in my openness openness one. I think that increased openness from 56 set baseline to 59, so not as much, and the P value was significant.

Okay. So similar. So similar, there was also in that one a decrease in neuroticism of one standard deviation, which is kind of interesting. But yeah, this one definitely has a bigger shift in openness, so psilocybin more than MDMA.

And they found that there were no significant changes in conscientiousness, extroversion, agreeableness, or neuroticism. And as a caveat, they note that the people who participate in the study were already high in openness, and they were low in neuroticism. And so they wonder whether or not there's a sealing effect. I almost wonder if someone who is lower in openness would be less likely to want this type of treatment. you know like is there a certain degree of openness that leads to kind of the openness to try something new like this you know yeah i think that would be where having a really strong therapeutic alliance with somebody to try something new

even with same thing i think with something like php where people are like i want to just stay in my comfort zone and the idea of sharing is with a group is too intimidating i'd rather not do that and so just having being able to the trust that people have with their providers is crucially important. So looking at your own openness and you scored for ideas and values, you scored about almost two standard deviations above the mean for aesthetics, feelings, actions about one standard deviation and about half a standard deviation for fantasy. So would you like to be higher in these? How would you feel about being a,

half a standard deviation higher. I really like the idea of openness being already open. You want a more rich fantasy life? Let's, uh, yeah. I feel like, you know, fantasy is linked in with my own playfulness. And as long as it is constrained and it's not going to leaking out into other domains and causing impediments to my life and my work, it's I think it's good it's openness to other people and experiences and yeah I scored pretty high

I scored about a standard aviation to two standard deviations above the meaning most of these except for actions I scored one standard evasion lower because I probably like I go to the same they asked a lot of food questions and I'm pretty happy with my food choices that I've kind of become accustomed to yeah so that's that you know one of my my friends, Adam Bereke, he's a resident, he's, he's doing an ethics paper on psilocybin and asked him what he thought about, so this article. And he specifically said, one thing that he's thought about is, do we give informed consent that your personality may change? How would you give the informed consent? Like looking at this article, realizing like, okay, these people shifted.

Now, interesting, do you see this mediated by a mystical experience? Yeah. Some people who had incomplete or no mystical experience during this did not make a shift, whereas the people that did feel like this was a mystical experience had even a bigger shift. And so this is the pattern that we've seen with the other studies where the people who have this complete mystical experience. And I think it's related to a dose response. or the people who have higher doses tend to restrain more strongly, and the people who are having more powerful experiences

are probably having more insight or more psychological benefit. So it's kind of this is another thing that plays out with that. Well, come back to my question now. Like, do you think that we should give informed consent? Like, that potentially, if you have a mystical experience, you could go up a little bit more than half a standard deviation in your openness. Yeah. Yeah.

What do you think? Well, I think that for most people, if your partner is higher openness than you, it might actually be a good thing to be a little bit more open. But if there's already a discrepancy in your openness, I find that partners when there's a big discrepancy in openness, like one. very low, one's very high. It can create some conflict, some new conflict. I mean, the thing that comes to mind for me is that with any kinds of therapy, there's always side effects. Like, sometimes people gain insight into the dysfunction of their relationship. It's like, do you give informed consent and whenever you start therapy that it might change the dynamics in their relationship? And it's possible that they will have increased anxiety and may decide to get a

divorce because of the insights they gain or they might get closer it's like both of these things happen it's it's hard to give informed consent for everything that could happen yeah i i personally um probably don't give that informed consent when i start therapy i mean there's a lot of things that you could consent people on and i think sometimes it's a if you need to consent someone on something, you end up with like a huge terms of agreement form that no one reads. Yeah. So there was actually one study where they looked at could therapy, certain types of therapies, change openness.

And they found that there was this one, that they, there was this one study where they looked at, it was Jackson 2012 where they looked at, could you change openness with, it was like an inductive reasoning training. and they did find that they could increase it. And so there's other things that could potentially change openness as well, I guess. That's what I'm thinking. And probably if you were giving induction reasoning type of training, you probably wouldn't consent them for openness.

But I think it's something to think about, you know, like how is this going to, how is, you know, your personality may change permanently. And it's not a huge change from just, just one dose. Half a state of aviation isn't huge, but it may change. Okay. I don't know. I don't feel very strongly about it.

It doesn't seem like such going to be like, you know, a little bit more openness, I think, is a good thing in general. Well, if you're listening to this podcast and you're thinking about doing this type of therapy, you can consider this and you're sort of overarching thoughts on the treatment, right? Yeah. So our next study we're looking at is the effects of psilocybin therapy on personality structure by Eritzo 2018. And this was a study measuring 20 patients with moderate to severe depression.

And they did a baseline score from with the NioPI to a three-month follow-up. And they found that there was a significant decrease in neuroticism, increases in extroversion and open. and then increases also in conscientiousness that was trend level. It wasn't particularly significant and no changes in agreeableness. And they found that the changes in neuroticism, agreeableness, and conscientiousness were similar to pharmacological therapies with the treatment of depression like SSRIs or SNRIs. But in contrast to those for openness, openness, which was already high in this group, They were more than three times.

The increase in openness was three times when compared to the SSRI or SNRI group. And there was an increase in extraversion twice as much between the SILAOcian group and the SSRI group. Wow. Yeah, that's, I'm looking at, I'm looking at this table here. If you get a chance, go on the website, psychiatrypodcast.com and check out this blog that goes with this. And yeah, in this study they showed specifically with openness, about the same half of standard evasion increase in openness. And in neuroticism, they showed about a half a standard evasion

decrease a little bit more than half a standard evasion, which is pretty cool if you think about it. It's pretty cool because you want to decrease that neuroticism. I think that goes with the treatment. I think any good treatment, whether it be psychotherapy, your medications will decrease neuroticism a little bit. So cool. Anything else on that one? No, they make a, the only thing is they make a note that other therapies, just like we mentioned before can result in personality change. It's not as stable as we once thought, but none are doing

it as quickly, or I guess maybe the MDMA ones are as quickly, but in this article when this was published as psilocybin. Yeah, they probably, this is another 2018 article. so pretty recently. So yeah, it's cool. Okay, let's keep going. Silocybin, this was a Griffin's 2018 article as well. Yeah.

It was called Silocybin Occasion mystical type experience in combination with meditation and other spiritual practices produces enduring positive changes in psychological functioning and in trait measured measures of pro-social attitudes and behaviors.

Yeah, so in this study, they were basically measuring the changes in psychological function between healthy participants. And so they had 75 healthy participants where they were evenly split between a low-dose psilocybin group with standard support for spiritual practice, a high-dose psilocybin group with also standard support for spiritual practice, and then a third group of high-dose psilocybin with a high-support, spiritual support. And so the difference was, for standard of support, there were five hours of preparation for the experience, and then one

hour the day following the session, followed by 10 minutes, two weeks after each session. And for the high support group, which was a total of 35 hours, there was 10 hours of preparation, three hours between the sessions, 10 hours of individual sessions, and then group therapy for a total of 12 hours. That was a group that met for a group. an hour or two for a few weeks afterwards. Well, that's actually a lot of treatment. A lot of treatment. That's a lot of treatment, 35 hours.

Yeah. So I would expect like a good effect size. Yeah, so they found like basically they're both the higher dose of lysine and the support both added a lot together for increases in personal meeting, spiritual satisfaction, well-being, life satisfaction, life meaning and purpose, gratitude, interpersonal closeness, forgiveness, and death transcendence. And the fact, this is just more evidence that just, you know, with just psilocybin and psilocybin plus psychotherapy in-depth, like intense psychotherapy, the psychotherapy adds a lot to the therapeutic

effect. Yeah. They also did the NioPI and they did not find significant changes. of the factors. Interesting. And then like other studies, mystical experience appeared to mediate the change that they found. Yeah.

So you see quite a bit of increase in life meaning. Forgiveness increases significantly in the high dose, high support. Yeah. Interesting. Like if you compare the low dose standard support with a high dose standard support, like for forgiveness, it's not much of a difference between the two groups.

Some of the other measures, a little bit of a difference. But yeah, that high support, high dose, that does kind of move a lot of the people into a better positive psychological space. Yeah, and I think that's one of the things. Like, you're looking at like trait forgiveness scale, but then they have like a subscale of benevolence motivation where having the high dose standard support

was very similar to the high-dose. dose high support and both of them were much higher than the low dose standard session. Okay. You want to tell us about this next study? Also by Griffiths? Yeah, so Griffiths, this is the, yeah, the Hopkins group. So this was mystical type experiences occasioned by psilocybin, mediate the attribution of personal meeting and spiritual significance 14 months later.

And this study in particular was given to healthy individuals with who, who already were involved in religious or spiritual activities, such as religious services, prayer, meditation, or study groups. And it was to understand the religious component of the experience, the mystical component of the experience, which we've been talking about. And so this was 36 individuals, and they had eight hours of preparation for the psilocybin experience. They had three sessions, one session of psilocybin,

and two sessions of methylphenidate or ridolin. And essentially, like, these participants were already low in neuroticism, fairly high in extroversion by half a standard de-aviation, one-and-a-half standard deviations higher than average in openness, half a standard deviation, higher in agreeableness, and were already pretty low negative affect. At the 14-month follow-up, 58% of people rated the psilocybin experience as among the five most personally meaningful experiences in their life. Two-thirds, 67% rated among the five most spiritually significant experiences of their lives.

64% indicated the experience increased well-being or life satisfaction. 58% met criteria for having a complete mystical experience. as rated by the MEQ30, which is one of the survey that they used. And 61% rated the experience was associated with a moderate to extreme positive behavior change. And then one of the limitations is a fairly homogenous population, mostly white and educated. But I pulled out, I wanted to pull out some quotes here about the way that people describe the experience itself.

Okay. So, yeah. So one person said, these are like moments during their session. So when I confronted my shadow and yelled, what do you want? It disappeared in a puff of smoke. So people talking about confronting the dark parts of their lives and feeling like they're gaining insight. The next person said, to cease to be as I understand it, was not frightening. It was safer and much greater than I had words for or understand. Whatever is larger than the state of being is what is holding me.

So this I pulled out because I think it's speaking to the existential anxiety of existence and feeling held in existence. Someone wrote, the knowing was so powerful and yet personal, experiencing the beloved and falling in love. And then the last quote I pulled out is, my conversation with God, which they viewed as golden streams of light. assuring me that everything on this plane is perfect, but I do not have the physical body or mind to fully understand. So it's kind of like, I mean, one of the things about the experiences people talk about it being ineffable and difficult to explain. And, you know, these are kind of abstract, these are abstract descriptions of people's experience,

but they're describing very powerful experiences when they're either feeling really connected or to a higher being or with the world around them or feeling much less frightened by their own shadow, which are, you know, I think all things that we deal with in an existential subconsciously or unconsciously. Yeah. Well, thanks for sharing this article. Well, I think it's like this one person said, it opened to my third eye. I could see many spiritual beliefs that I hold held and linked them. A more cohesive and comprehensive spiritual landscape became apparent to me. And so I think my question there is like, is this, what they're observing?

Is it real? Or is it like a myth of sorts that they're creating inside themselves, you know? And are they linking things which should be linked? I don't know. There's a part of it that lacks a sense of control, like in therapy, normally, you know, you can slowly kind of, you can slowly take apart, right, things. Or is there something about, like, not knowing exactly what is going to happen? I don't know, that's a little bit of anxiety provoking for me.

Yeah. The way that I think about with these individuals is that they are all, they already have a deep spiritual life in some people. And coming with a speech, deep spiritual life comes with oftentimes is a cognitive or intellectual understanding of the personal understanding. And what that person is describing in the way that I understand it is an experiential component of the belief that they have intellectually. Okay.

Yeah. Well, I mean, it sounds like it was powerful for a lot of these people, you know. Yeah. I mean, they're rating it. I mean, 50, 60%, 70% are rating it as the most personally meaningful or spiritually significant experiences of their life. Yeah. I also think back to like doing some therapy with some people. During the therapy, I would pause. We'd have, we'd have pauses. And they would have a sort of very vivid vision, vision like things that would come to them in the pauses. And one patient in particular was a vision of, like, at first it was feeling a disconnection with God.

Like God was like up the stairs and she couldn't reach God. And then as we sat in the silence, she felt like she could walk up the stairs type of thing. So it was a deeply spiritual moment for her. And so I think some of these things are possible just in the midst of a deep connection. I wonder about that. Yeah, I mean, I don't think that,

from what I understand about these experiences, is that these experiences are not unique to the psychedelic experience, but they tend to promote them or make them more likely. Like, the mystical experiences that people have are similar to other religious mystical experiences, but this brings it out a little bit more. Yeah, I mean, myself, I've had spiritual experiences.

Like, I feel like I've had them without any substances in my body. And so it's like one, it's just kind of like a quandary that I have, I guess, is like, okay, are we manufacturing something that should be potentially not manufactured, you know? You know, I think these experiences are the reason why people, find such benefit from them, benefit from them, is that they're gaining insight. They're feeling like they're gaining insight. And the insight itself is the powerful experience. It's not necessarily the experience itself. That's the special part. Yeah. I mean, there's like people who have psychotic connections, right? When they go manic, they connect things that are really normally

connectable the mind count i had one patient like connect the mind calendar with quantum physics and she was like looking for a physicist you know like how is this you know those are things that i don't think should be connected right like are are we inducing connections where there should not be connections at times i don't know like how i make sense of that quite yet i mean that's why we would screen i mean and what they do is they we'll actually talk about that a little bit but you know they screen people out who it's a concern for people who are too open already or too they're not anchored enough in reality because this tends to lead to more more mystery and less grounding. Yeah, there was this person that I know about. It wasn't one of my patients, but they were in a city

and they were doing like sex webcams and then they got a hold of some, you know, That was their job. And then they got a hold of some psilocybin and started doing that. And then just kind of wandered the street for days, was eventually taken into a church and just kind of passively, kind of like, it was like a total like mind shift in their mind. I don't know. Maybe it was too much.

Maybe there were some other drugs involved too. But is there a place where openness has a, a, or not openness has a protective factor as well, like, of just, like, not falling into some sort of, like, cult like thing, like, where we should be guarded against, you know, connecting things that maybe are not connectable. I don't know. I think there's risks there. Yeah, I would agree. Okay, tell me about this next study. Yeah, so now we're moving on to the neurological effects and either studies, like, bench research or neuroimaging that they have done with psilocybin. So this study is psychedelics

promote structural and functional neuroplasticity lie at all 2018. And this was a bench research study where they found, they used neurons from a couple of different organisms. They use drosophila at early and more mature development, zebrafish and rat cortical neurons. and they found that in these non-human models, psychedelics can stimulate neuroplasticity and neurogenesis with increases in BDNF, dendritic growth, and increased inaptic activity. And they found that it was dependent on the 5HT2 receptor, and there's 2G protein mediated growth proteins, TRKB and MTOR dependent mechanisms. So, and they, in this study, they used a control, which was just saline, and DOI, which is an amphetamine that was, they wanted in place of MDMA, LSD as the 5HT2A receptor and DMT, which is also a 5HT2A receptor agonist, but it's a tryptamine analog.

And so basically they showed that there was an evolutionarily conserved mechanism with increased neuroplasticity, increased ender to growth, and increased ineptic activity. And we, you know, as psychiatrists, we're always looking for medications that do that. And we have medicine, like lithium does that, does those things really well. And so we're always looking for improvement. So that's what this study shows. So, yeah, we know that there's other things like exercise. or diet can increase BDNF brain-derived neurotrophic factor, which is like miracle growth for the brain.

And so what you're saying is that psilocybin increased that as well in this study? Yeah, so these were non-human neurons. And so they found with just neurons using Ben's research techniques, they found that just the stimulation to the LSD or the DMT or the MDMA analog, there was increases in neuronal growth and dendritic growth and synaptic connectivity between neurons. And there's this other article which discusses the difference between meditation or therapy and how it can work with psilocybin. So in the article it talks about how psilocybin offers bottom-up BDNF promotion while mindfulness meditation or therapy. induces top-down beat and BDNF promotion.

And psilocybin offers cognitive flexibility and disinhibition, whereas meditation and therapy offer enhanced cognitive control. And basically, all those things together offer more therapeutic benefit. And they're additive in effect and benefit. it well so i think that the conclusion was that you know this is this is sort of some of the framework behind why they think it might be important to try this for the treatment of depression yeah basically that it stimulates neuronal growth and in whether that's depression or anxiety we want learning and we want neuronal growth and it's just that it does that

or it seems to in this condition. Cool. Okay, yeah. So, Nadav, talk to me about the default mode network, and what is that? We hear that a lot, but maybe just break that down, and then we'll talk about how psilocybin relate to that. Yeah, so the default mode network, I have a quote here from Wikipedia, because I think the Wikipedia said it really consistently, is a large-scale brain network, primarily composed

of the medial prefrontal cortex, post-easternal. posterior cingulate cortex in precunius and angular gyrus, and it's best known for being active when a person is not focused on the outside world and the brain is in a wakeful rest, such as during daydreaming or mind wandering. So this is essentially where most of us, what's going on in our brains most of the time. So in Michael Pollan's book in How to Change Your Mind, he describes the default mode network as the orchestra conductor for our minds in general. It's involved in self-reflection, self-criticism, being when we're just running on autopilot, when we're thinking about the future or the past or how we think about our own thinking. It's

experiential, it's our experiential or autobiographical self that's narrating our experience as we're doing it. It often suppresses things that are keeping things in our subconscious that we find threatening or thoughts and emotions that we find threatening. And yeah, so that's kind of where the default, that's the default mode network. The default mode network is kind of a, from what I was talking with one of my attendings, and it's essentially what we see in an fMRI machine that's lighting up when our brains are at rest. There are not necessarily neuronal connections between them, but people talk about.

about them as functionally connected because they're they're just all lighting up in that state. And so it's more of a theoretical, it's a theoretical connection in those states because the way that they study these things is they put people into an fMRI machine and they measure deoxygenation in the brain with the assumption that if you have more deoxygenation in certain areas, that indicates more neuronal activity. But brain science is in its nascent. And, you know, we only are able to do so much with imaging, with brain imaging at this time. I think it's a good summary of it. That's really helpful. And then, so if we're going to extrapolate from that, there is, we do see, there tends to be hyperconnectivity of this default mode network with when people are particularly rigid,

or hyper-stable, and this occurs in depression, anxiety, addiction, OCD, or anorexia disorders, which are also the same disorders that people have been exploring the use of psilocybin in. So now we can move on to the studies. Okay. So our first study is a 2012 study by Robin Carhart-Harris, where neural correlates of the psychedelic state as determined by the fMRI studies with psilocybin. and the take-home message is essentially that during the psychedelic state, there is a down-regulation of the default mode network structures, and that leads to the psychedelic experience and therapeutic benefit, and that this decrease is associated with increased openness and increased cognitive flexibility. What they find specifically is they find a decrease in blood flow to,

the thalamus and the thalamus is essentially the filter for our brain where if we were having all kinds of sensory experiences and the thalamus decides what actually comes into conscious experience so there's a less blood flow during that time and in addition they show decrease in the anterior singular cingulate cortex and the posterior cingulate cortex. And essentially what they're indicating is that there's a decrease in the typical structural rigidity of the brain, of like how our brain typically works, there is less of a filter and a decrease in our own, maybe even our own ego state of our own sense of self. So that's what this is showing. Yeah. So, yeah, that's interesting.

That's interesting that the prefrontal cortex decreases that kind of inhibitor, governor, the critical mind of sorts. So in CBT, you know, we activate the prefrontal cortex by getting people to think, you know, look at your cognitive distortions. How do we put these cognitive distortions on trial? That's a very prefrontal cortex activating activity. TMS transmitting cranial stimulation. They stimulate this frontal cortex with magnets to activate it.

Interestingly, in this one, it's kind of the opposite. They want to decrease that. Yeah, and so this is really just during the experience itself. So that's when they're studying. They're not studying the effects afterwards. Yeah. Okay. Yeah, what else do you find in this, the next article here?

So the next article is also by Ross. Robin Carrard Harris, it's a 2017 article called psilocybin for treatment-resistant depression, fMRI measured brain mechanisms. And here, as far as I could tell, there was no psychotherapeutic intervention. They just did f-m-I imaging. They did a pre-treatment, and then one day post-treatment. And they found that they did, it was 19 patients. They all showed some decrease in depressive symptoms, 12 met criteria for some kind of response.

and nine of those 12 continue to show response after five weeks, and then at five weeks six remained in remission. One of the things that I think this is important, which isn't, again, not an imaging component, but the studies that have therapy, a therapeutic component, seem to be much more successful than this study, which has about a third of patients being in full remission without psychotherapeutic intervention. Which it's hard. Of course, you can't tell how many would have spontaneously improved. Right. There's no control condition, but it's just kind of an indicator that I saw. So in this study, they found that there was a recalibrated amygdala response where there was

increased amygdala activation when emotional stimuli were presented post-treatment and an attenuated amygdala response at rest. And what they say is that both of these outcomes are expected when you have successful depression treatment. So people who have a hyperactive amygdala response chronically will generally, even without stimulation, it'll be increased. And because it's increased all the time, even when there is an emotional stimulus response, they tend to have a response, but it's not as the difference between baseline and having an emotional response is less. And so they're saying that the amygdala was recalibrated in the day after, showing in the day after treatment.

So decreased emotional blunting, essentially. Okay. Well, what else they find? They also found that, interestingly, despite the previous paper which showed a decrease in the default mode network being reduced. Afterwards, they found increased resting state

functional connectivity. So there was a, seemed to be a tighter bound between the default mode network centers, which was surprising to them. And what they argued, and this is kind of the thing

where it's like, they're just searching for things and we don't really understand the brain science so much, but they argue that this is similar to ECT, where there is like a digital,

disintegration of the default mode network because you shock the brain and then a normalization and you kind of reset the neurological connections. And so that's what they're saying might be happening here. Yeah. Well, I think it's highly theoretical. Highly theoretical. And, um, you know, like, why does ECT work? People don't really know. I mean, at the end of the day, we don't really know, right? It's like people have ideas. People have ideas. People have ideas. but it's like proving those ideas to be the causal agent is like, how do you do that? Okay. Yeah, so this next paper, this is a theoretical paper, and so we can take it or leave it as we want,

but this is they call a rebus, which is relaxed beliefs under psychedelics and the anarchic brain towards a unified model of the brain action of psychedelics. And in this paper, they basically argue that psychiatics. psychedelics work to relax higher-level priors. And sensitizing them to liberate bottom-up information flow, which with the right intention and context can help guide and cultivate the revision of entrenched pathological priors. So in simpler language, what they're saying is that, and the way that I understand it,

is that when you have a depressed brain, basically whatever the sensory input is that people have, they interpret it in a negative way or they interpret it. And we tend to interpret things in the way that we've learned to interpret them. And people give examples of like having certain glasses or they're looking at the world in a certain way.

And basically psilocybin reduces those ruts basically reduces the typical way that we think about ideas or the way that we interpret sensory input and it allows for a revision of our experiences. Does that make sense? Yeah, I mean, this is how I think therapy works to some degree. You have a person in connection with you, decrease shame, experience, right, over and over again. I think the therapist's action to decrease the internal critic to decrease the internal shame that they feel is paramount for any therapy to work. And I would say separates the best from moderately good therapists. It's like how well do you reduce the shame experience?

Do you reduce that internal critic? Maybe this is like what we're talking about with kind of decreasing that frontal lobe, the critical parts of the frontal lobe, right? There's good parts of the frontal, the sort of self-criticalness, that super ego, structure. Yeah. Exactly. So they talk about how the 5HT2A receptor signaling is enhanced, and they see this receptor also

enhanced in children and who tend to be more sensitive to the environmental influence. And it basically creates an acute period where experiences can be re-experienced and viewed in a different light. Yeah. They do express some caution where they talk about how the loss of ego, while it can be useful for people where their ego state is hyper-stable, where it can be a concern for people who have poorly integrated experiences or selves. So if you have a poorly integrated experience during the session, often when people come back down into reality and they have to make sense of it, they sometimes, if they don't have any groundedness or they don't have someone to help make sense of it, they end up explaining things with potentially delusional beliefs in order to help protect them from the

uncertainty that these bizarre experiences have. Yeah. Yeah. So I think that that's kind of what I was hinting at earlier with the spiritual experiences connecting things, which may be, should not be connected, right? I think about this high stress environment we're in in the world right now with COVID and everything and the political unrest, political divisions that are more polarized than ever. And I think about how people to maintain or to make sense of the world,

maybe to stay in a flight and flight mode, they are jumping to connect things which may be not connected. I know I have a tendency to do this being highly open. And I have, maybe that's why I'm like, there's a part of me that's very guarded of not wanting to jump to conclusions. Show me the evidence, right? Stick to the evidence. Stick to the things that we know and not get too far in trying to connect things because I'm naturally seeing the connections. That may not be there, right? Yeah.

And so, I mean, I would argue that for a lot of people or for most people, people want to experience more connection. and there is a sense of loss of ego in the psychedelic experience. And it often leads to feeling people feeling really connected with other people in their lives or the world or nature. And that could be really beneficial. But for people who are not grounded enough, it could lead to more uncertainty and possibly more delusional beliefs. I think part of the problem with a new treatment like this is when it's dead. done. It's done usually on people who have moderate depression, who don't have personality types of conflicts, right, disorganized attachment, borderline personality disorder. And so you have

like people who have good ego strength to start, right? And then when this gets out into the mainstream, it's going to be given to everyone indiscriminately by some people. Like as much as you don't want to hear that, like if you look at ketamine treatment, who are the people opening the ketamine treatment centers right now? Often it's people who are, they're not psychiatrists. They're not even therapists, right? And so they may not have the selection criteria to say, okay, I'm not going to give it to this person because they don't have treatment-resistant depression. Now I'm going to give it to anyone who wants to pay for it. Okay, and they may not, they may not be screening people and thinking,

does this person have a good ego strength coming into this treatment? Yeah. Or like they won't even know how to determine if someone had good ego strength, right? Yeah. It's a difficult thing to really balance. Like you have to, in everything that you do, it's hard to tow the line perfectly. And you want to weigh the risks and benefits.

and you want to provide the most benefit and you want to limit the amount of risks and the detrimental effects that you have. I guess what I'm fearing is that this gets, there's a capitalist nature of humans, which are not always altruistic like you are. So there are some people who are going to enter this who are more capitalistic than others, right?

Yeah. Like a good example of capitalists with some of the like multi-level marketing and they use a lot of psychological tools to get people fired up to sell their stuff and then they don't make much money, right? Now, not all multi-level marketing is to the same degree as some companies

that have started and failed. So if you're into that, hear me out here. But there's powerful psychological tools that they use for the profit of the people who are at the very top, right? So with something potentially as powerful as this, that's just something going on in my mind is like, okay, you know, you see this as like this could lead to a utopia, you know, I see this as like

you're going to have people who are who are trying to make money coming in and potentially marketing it better than the people who are altruistic, you know? I don't know if that's how I would, I would frame this as I view this as a really powerful and potentially beneficial tool, but one that should be used cautiously. and carefully and with intention. And I know that you can't legislate intention.

Right. It's going to be on the free market. Yeah. And it's already on the free market in Oregon, right? No, nope. It's going to be,

no. So they have, in Oregon, they have two years to develop a psilocybin psychotherapy and a way for people to have it accessible to them. But it is not going to be unregulated.

But it is decriminalized. Okay. Yeah. Well, because it's decriminalized, like what's stopping someone from opening up a center? Well, I mean, cannabis is decriminalized in almost everywhere, but that doesn't mean that it's available in the stores or available for anyone anywhere.

Like, it's decriminalized, but it's not legally sellable. In California, people go into places to buy. So in Ohio, it's decriminalized, but it's not recreational cannabis isn't legal. So, yeah. Okay. Well, let's keep going. Okay. I'm sorry to be such a...

We're balancing each other well here, Nadav. Yeah. Okay. Yeah. So this next study, we've got emotions and brain functioner altered up to one month after a single high-dose psilocybin, and this is Barrett-At-All in 2020 this year. So this was a study of 12 volunteers, open-label pilot study using 25 milligrams per 70 kilograms, which is a, on the higher side, moderate to high-side

dose of psilocybin, two preparatory sessions for a total of eight hours, and with one follow-up the day afterwards. And they tested cognitive function. One week, after and one month after the psilocybin session. They found that there was increases in openness and decreases in neuroticism, but I couldn't find any effect sizes in the study itself. And they found that there was an effect size of increased conscientiousness of a moderate to large effect size of 0.74 one month after the administration of psilocybin, which is, you know, that increase in conscientiousness was not something that we, that was noted in other studies comparatively to the like other psychotherapeutic treatments.

Yeah. The other thing that they found was that there was, initially there was a decreased amygdala response to negative stimuli, but that this returned to baseline after a month. So it wasn't maintained long term. And they found that after a month, there still continued to be increased responses in reward learning, attention, decision-making circuits, increased responses to somatis a sensory and the fusiform gyrus during high demand incongruent trials in the emotional conflict struped task. So were they able to better perform the strupe task?

That was my understanding of the study, is that they were better able to perform the strupe task after a month after the psilocybin session. Yeah. And then, yeah, and the last thing that they found was that there was a global increase in functional connectivity at both one week and one month post-silocybin. And it's hard to really, you know, give an objective understanding of what that is, but they found that there was more kind of brain connectivity. Okay. All right.

Let's keep going. Okay. So here we, I have two studies, which kind of joined together, which is one is the entropic brain revisited, which is a Robin Carhart-Harris, 2008 study, which is a theoretical study, and a non-theoretical study with serratrix called serratrix. energetic psychedelics, LSD and psilocybin increase the fractal dimensions of cortical brain activity in spatial and temporal brain domains by Varley et al in 2020. And so essentially what they are discussing in these two papers is that they notice through a study of

an fMRI machine and EEG measured brain changes that there is an increased in entropic or disorganized brain activity and essentially an entropic or increased disorganization in brain activity means that there is more uncertainty and that it's more content-rich, unpredictable, and uncertain. And they compare this to the creative process when there are lots of disorganized ideas, but out of that entropic experience or those disorganized ideas, it leads to more creative, more exploratory, or more divergent conclusions, which allows for more diverse cognitive outcomes, kind of breaking people's kind of rigid states that they're in with, you know, in the things that we were talking about with depression, anxiety.

And they, you know, in this, it's a, it's theoretical, again, and they argue that, you know, whenever you have, you, we measure increased entropy and entropy equals changes in consciousness. And when you look at, like, the lowest level of brain entropy is when people are in vegetative states. And then you have slightly increased entropy in a coma, then in sedation, then to sleep, awake. And then higher than that is the psilocybin or LSD experience. and yeah and so it's kind of just looking at the disorganization and saying that it leads to more diverse changes and it leads to more creativity yeah i'm reflecting on uh stephen hayes was just on my podcast talking about acceptance and commitment therapy and he was talking about how he really thinks that psychological flexibility is a big thing that leads to change

when you're treating depression anxiety. And so these people are saying, look, flexibility occurs through this substance, right? Mm-hmm. So there's some commonality there. Okay, what about this, Priler at all, 2019? So this is papers called Effective Connectivity Changes in LSD-induced Altered States of Consciousness in Humans. And in this study, they talk about specifically functional shifts in the corticostriato thalamocortical pathways. And what they are arguing and what they show is that LSD, which is the substance of study in this paper,

selectively opens the thalamic filter. So there's increased information flow through the thalamus, which we described as the filaments. of the brain from the sensory stimuli to the posterior cinglet cortex and other certain areas of the cortex and it loosens experiential gating so people are having more diverse experiences based on the sensory input that they have and you know with all these papers i you know i it's a lot of these are theoretical it's hard to like purely neurological biological interpretations regarding brain activity during the acute phase of the psilocybin experience doesn't like whatever's happening during that doesn't necessarily tell us what's going to happen

afterwards and it doesn't capture the variety that can unfold in the weeks or months after the therapeutic experience so everything all these studies are basically a moment in time either you know it's during the experience or a week after or a month after or a month after. after and they're trying to make sense of what you're seeing in brain imaging. But it's all, it's difficult to do at this stage in our science. Yeah. Yeah. Cool.

Well, I think it's kind of, it adds something to go over these things of kind of where the field is and what, what they're thinking causes these effects that we're seeing. Yeah. Yeah. And so that's the end of our neuroimaging part of this talk. And so this next part, you, we've kind of touched on all the, all the individual trials. So maybe we'll leave this type of systemic review for, for people to digest if they want on their own. Is that okay?

Or is there something else that you wanted to pull out from that study? The thing that I wanted to pull out was just kind of an overview where, you know, there were a lot of studies we looked at were looking at openness. And they, like, of seven studies that they were looking at, that looked at openness, four of them showed increases. And of the nine studies that were assessing well-being, all of them showed increases. Of the 10 studies, there was increased in spirituality. There was, out of the 10 studies that were looking at spirituality after psychedelic use, nine of them showed increased ratings.

And then all four studies that were looking at psilocybin, adduous psychotherapy for substance use disorders showed positive absent effects. So it's kind of just like a global idea of where what we've gone through. What's going on? And they mentioned that the studies where they already had people with high openness may not have improved as much as the people who are medium of the road. So maybe there's a ceiling effect there. I found that interesting. Okay. And then this other systemic review that I wanted to look at was a review in the American Journal of Psychiatry earlier this year, Rife at All, psychedelics and psychedelic

assisted psychotherapy. And the main thing that I wanted to look at here was the editorial concerns that they had. Okay. Yeah. Which I think might be in line with your own concerns. Okay. Let's read it. Yeah. Sorry for getting excited about.

Yeah. So one of the things is they were concerned that a lot of these studies, they have really broad diagnostic criteria of who they're allowing into the study. And so they're questioning about whether or not, like, while they're seeing benefit, there are improvements in depression and anxiety and substance use. It's like, who are the patients that are going to mostly benefit? Like, how sick do they need to be? Are people with sub-syndromal illness going to get this?

And is it actually going to help them if they have milder illness or more severe illness? And so that's one of their concerns, which I, you know, I think that it is. It's like there has been broad diagnostic criteria for entrance into these studies. In response to that, I think there is, I tend to be more of a lumper than a splitter. You know, I actually, you know, I go back and forth. The truth is it's not always so clear. But I feel like there, there's a real focus on DSM diagnosis, and they're sparsing between adjustment disorder with anxious distress or depressive symptoms

or major depressive disorder or persistent depressive disorder. or persistent depressive disorder. And yeah, I don't know. It's like these are all people with very similar kinds of symptoms at the time of diagnosis or entrance into the study. I'm kind of, this one for me is not that big of a critique in my mind. It's not like the critique that makes me have concerned, have concern. Because I'm probably like you.

I'm like, well, you know, these people could probably meet criteria, depending on the psychiatrist they see for MDD and GAD, you know. So, and they're, you know, they show the Hamdys scores and they show the the different anxiety scores and stuff like that. They also mentioned concerns about those limited and blinding, which we've talked about, and we'll talk about a little bit more in the conclusion, and inconsistencies in how the therapy is done, which is true. I mean, it's all of these things have had different.

they've all had slightly different therapeutic models. They also, one of the things that they mentioned, they talk about a desire for, they're like, they view the mystical experience and the experiential component of psilocybin as a side effect. And in my mind is like, you know, the medical community

doesn't really know what to do with a therapy with a strong experiential, or consciousness, like, what do you do with a mystical experience? And so they view that as a side effect as almost undesirable. And I kind of think that where like a lot of these papers are saying that that's one of the mediators of the benefit. And you can't really separate those two. And if you're wanting to separate the two, you're kind of missing the point. Yeah, I think there's, that's an interesting criticism. I hadn't thought about that one. I think that for you, that's part of the treatment. That's part of the desirability is like you're going to give someone one of the top

experiences of their life, right? Yeah, it's dramatic. There's something dramatic. There's something dramatic that just took place. Yeah. Yeah, they're also concerned about it being a drug of abuse and about whether or not it's abusable or increased substance use. I think a lot of this caution comes from the medical community being responsible for the opiate epidemic or abuse of benzodiazepines or Ambien or other sleeping aids of the Z drugs and whether or not there's also within the psychiatric community some mixed feelings about ketamine and the FDA approval of ketamine. And it's like, is this just the next ketamine?

Yeah. I think from the early papers that we looked at in session one together, you know, it seems like people who were using other drugs were also more likely to use this type of drug. So there's no causal relationship between that association, but the association is there. I think as practitioners, we don't want to do anything to harm patients.

so maybe that's a little bit there I think it's going to be a little bit different than the opiate epidemic though because unless this is when it comes out unless it's a very expensive drug and drug reps are knocking on our doors like they were with the opiates

Purdue Pharma and stuff like that you know I think that some of those incentives aren't going to be there the incentives might be more patient-driven honestly patients might want this type of thing they might be searching it out yeah i mean i think that that's very possible and people will because i you know i already hear people people do talk about and are really interested in this um but i'm not

really concerned about this being a drug of abuse as we've we've talked about it before um even on the population studies in the survey studies and in the when they were using this as a treatment for substance use it's like they should benefit on all in those things So I'm not really concerned about this being. It's not addictive. Not in the same way as like nicotine or cocaine. It's very, I don't think it's addictive. But nevertheless, if they used, you know, psilocybin, you know, 95% or so,

we're also using things like marijuana and some of the other drugs. So, you know, what do you? So cocaine, 40%, 40% we're using cocaine, you know, is that just the culture of people? who would have access to it, maybe. And so maybe it'll be very different for people who do this type of therapy. I think it will be. That's what I expect, given all the other data that we looked at. I think it's more of a, like, who has access to these things or who's looking and seeking

it out when it's illegal. Okay. Talk about the future. What is the future? Okay. So in late 2018, psilocybin was designated by the FDA as a breakthrough therapy for treatment-resistant depression. And so that expedited the development and review of psilocybin because of the preliminary clinical evidence that we've reviewed over the last couple of episodes.

And so basically it's fast-tracked and whatever, you know, usually everything's slow-tracked. So this is a little bit, it's not quite slow-tracked. So there's a little bit more leniency in the development of third of phase three trials. for this Schedule 1 substance, which there was a lot of barriers for. That's a few, that'll be a future episode maybe. Yeah. Yeah, future episode. So we mentioned Oregon.

We mentioned Oregon already. So they had this past election, the population voted to decriminalize plant and synthetic psilocybin and they established a two-year developmental period to create the groundwork of making a program for administering psilocybin products, such as mushrooms. to individuals age 21 or older at things called a psilocybin service center, and they have to define what exactly that will look like. They have therapy. They say it's going to require preparation, supervision during the session, and integration sessions,

and it's going to be available to anyone that it's not contraindicated for. Okay. Yeah. So we'll see what those contraindications are. Yeah, sometimes it's good to have these like kind of individual state trials to see how, whether or not it makes sense to expand it for everybody else. There's a couple of companies that are working to make this happen. So there's a company which we've mentioned called Compass Pathways. This is a public traded for-profit company with investors and it's backed by Peter Thiel, who is a Silicon Valley, big Silicon Valley investor.

they are spoke spoke for president trump right st peter theo yep at the at the republican convention a couple years ago i remember that speech yeah so this group they're conducting a randomized controlled phase two b study of psilocybin therapy with 216 patients with treatment resistant depression and 20 sites across europe and north america wow 20 sites yep wow to any control control arm? I believe that they're doing a control arm, but I don't know the, I don't know the details. I would, if I was to guess, they might be doing. Yeah, I mean, the other ones were also controlled, but only up to like four weeks or eight weeks. So it might be a similar situation. Then USona Institute, which is a non-for-profit organization that's in the same boat. They have

also developed their own way of creating synthetic psilocybin. And they have, they're also doing a phase 2B study with 80 participants. And they've got a lot of the people who were in the first study. So the Johns Hopkins groups, the NYU group, they also have UCSF group, Yale, University of Wisconsin, Great Lakes Clinical Trials in Chicago, and Segal trials in Miami are all participating in this trial that's supported by the USona Institute. Okay. Then there are, I want to talk about the current studies that are undergoing on. So Johns Hopkins University, they've created a whole center of psychedelic and consciousness

research, and they've got ongoing studies in depression, smoking cessation, Alzheimer's, and anorexia nervosa. So we looked at a couple of studies with depression and smoking cessation, but not the other two. There are ongoing European studies in fMRI imaging, attention and cognition and visual changes with psilocybin. And there are other studies that in their future that I've got links to either the maps or the, there's a database, a national database for ongoing or future studies. And so there are studies using with healthy volunteers exploring the experience, depression, anxiety, cluster headaches, cocaine use, alcohol use, opiate use, and op.

OCD. So those are ongoing or future studies as well. So that's where that's where we're at in terms of research and a few things that we can expect down the line. That was incredibly comprehensive. I think this is the most comprehensive, the most amazing podcast that's ever been done on this topic. I just want to give the people the information that they're wanting to. They're asking for it, and I want to give it to them. That's awesome. That's really good. I know I'm not being sarcastic. I really I think it's very comprehensive. And if you look at, if you look at on the website and the resource library, you look at the handouts we're going to have from this, you'll see.

It's like all the studies are here, up to date. I mean, this is as up to date as it gets for when this was released. Let's talk anything. Let's kind of wrap it up. Any other big things you wanted to talk about before we kind of bring this to an end? Yeah, I wanted to just try and just talk about how this is a really active. treatment. It requires, like, therapy, I think. I think it requires patient motivation. And it's a different model than I think psychiatrists are often useful outside of the therapy model, where it's like,

it's not like, I'll just give you this and you'll get better. It's like you need to be, you need to participate. And I mean, I think we see that, you know, our current drugs are limited in a certain way. And I think having a mixed model where we have medication and therapy and in a safe space, I think it could be really beneficial. This is like a tool that we don't have and it could be extremely beneficial for, you know, depression and anxiety, OCD, addiction, potentially. All these are really potential. And the thing that I'm most excited about is the changes in like boundary experiences when people are experiencing big shifts in their lives or facing existential questions or grief in palliative care where you know we don't really look at this and we don't

really have that many tools and that's what i'm really excited by that's cool i'm glad i'm glad you're able to share your excitement with the with the psychiatry psychotherapy community i can reiterate i can reiterate in this kind of idea of you know these are these are therapists and And in psychiatry, there are some programs that do not emphasize therapy. And so how do we as psychiatrists sort of regain this place where we really love therapy and do therapy and feel like we're capable of that? I mean, it's like I know our program, our residency here at Loma Linda, it's like attracts people who are interested in therapy because we kind of like value that so much.

But not every program does. And so can we get programs to value that more and see that as part of like what it means to be a psychiatrist again, you know? So yeah, cool. Well, hey, this has been a really great experience learning this with you and diving into this. I definitely want to have you come back. I told you that before. I think this is a, if you guys take a look at this handout, this is phenomenal. I mean, this is just really top-notch digging.

and it's fair, and I also think it's very fair. We try to look at every angle that we could. And if you feel like we missed some angle, please let me know. If there's some piece of critique towards an article or maybe something that we missed, let me know. You can reach out to me through my website, and I would love to continue to learn with you as we kind of keep going.

I want to just thank you so much for kind of giving me the opportunity to, you know, this is very much a passion project of mine. Like I'm, I'm, you know, I don't know the outcome, but I'm really excited about it. And I'm excited about the possibilities. And this is a, uh, an outlet for me to share that with a lot of people. And, um, you know, I'm really, I'm really hopeful. I'm really grateful for the stage of my career that I'm in and where this is heading. I want to also think, I think without my, uh, like, my attending support. Like I've talked with a couple of my attendings about different aspects of this and how they look at different studies and they've been really supportive. And I think it was one of my

attendings. It was one of my attendees who reached out to you initially to share with you that I was interested. And without that, I wouldn't be here. So this was really fun. And I hope to be back at some point. I think you reached out to me and she reached out to me and it was sort of the continual pursuit which was helpful. I get really busy and so I think it was like like oh okay let's try this out you know let's put together all the research let's let's create a good handout and we'll go from there and I think you did an excellent job and your high conscientiousness really brought it through to the end. Thank you.

Yeah. I think what were you like? I think you were two standard deviations, at least in some of the conscientious things, which is like definitely evident. So it's fun to work with you, man. And I really appreciate it. I hope that I wasn't too, you know, part of this is,

this is very new to me. Like I think you've been thinking about this for a long time. But, and I think it's new for a lot of the listeners. It's like we haven't been thinking about it. like what it means, what it doesn't mean. And so I think it's good to just have a discussion where we kind of like are honest with where we're at and okay with not completely arriving yet, but exploring what the research shows and what may come in the future.

So I hope you guys enjoyed this conversation. If you send me a message, I will also let Nadav know what your thoughts are. So unless you're very critical, then I will not be sending that onto them. unless you were only critical of me, then I'll probably will. All right, we'll leave it there for today.