Welcome to the huberman Lab podcast, where we discuss science and science based tools for everyday life. I'm Andrew huberman and I'm a professor of neurobiology and Ophthalmology at Stanford school of medicine. Today, my guest is dr. Robin Carhart Harris, dr. Carhart Harris is a distinguished, professor of Neurology and Psychiatry at the University of California. San Francisco. He is one of the leading researchers in the field of psychedelics and how they change neural circuitry in the brain.
In his laboratory is responsible for understanding, for instance, how psilocybin also sometimes referred to as magic, mushrooms change in neural circuitry in the brain, such that new ideas and new forms of learning occur. His laboratory is also responsible for carrying out various clinical trials. Some of which have demonstrated that appropriate dosages of psilocybin can alleviate major depression in more than sixty seven percent of people that take the drug. Now, this is not to say that everybody should take psilocybin and today's discussion describes both,
Clinical trials and why treatments with psychedelics in some cases work and in some cases do not work in order to treat major depression as well as discussions around psilocybin lysergic acid. Diethylamide sometimes also referred to as LSD as well as DMT and how these change the brain and how those brain changes can relate to changes in mental health as it relates to depression and other psychiatric challenges as well as how psychedelics are being applied. In order to change a neural circuitry for sake of expanding different aspects of
the human mind, including creativity intelligence and much more during today's discussion. Dr. Carhart Harris teaches us about the history of the study of psychedelics, as well as how the legislature that is, the laws surrounding psychedelics, are evolving in the United States and Elsewhere for the use of psychedelics to treat psychiatric challenges. By the end of today's discussion, you have a thorough understanding of how psychedelics work, both in the short-term during the actual Journey or trip. In fact, much of my discussion today with dr. Carhart Harris talks.
The different aspects of the Psychedelic journey and how those relate to therapeutic outcomes. And of course by the end of today's discussion, you will also understand the long-term effects of psychedelics that is how they can actually rewire the Brain before we begin. I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is however, a part of my desire and effort to bring zero cost to Consumer information about science and science related tools to the general public in keeping with that theme. I'd like to thank the sponsors of today's podcast. Our first sponsor is
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In Carhartt. Harris. Dr. Carhart Harris, welcome. I've been wanting to talk to you for a long time. I certainly known who you are for quite a while because I place you in this very small, but very special, and important category of researchers who has been pioneering the use of psychedelics for the treatment of specific clinical conditions and really carrying the torch for essentially the entire field. So I want to start with a
Voice of gratitude and say thank you for doing this incredibly important work. Could you tell us a little bit about what psychedelics are? In fact, I'm curious as to how the name psychedelic ever came to be and what you think they potentially reveal about the workings of the brain and then we'll talk about the clinical
applications. Sure, well, even that one is kind of hot one because opinions differ on how to define
Eric, but perhaps a good starting place is to start with the etymology. Where did the word come from? And it was a Brit excommunicated living in in Canada, humphry, Osmond who was due to present a paper at a National Academy of Sciences meeting on psychotic, memetics drugs that mimic aspects of psychosis in their
And and certain drugs like mescaline. Let's see, 1956 and LSD were on on the bill and he felt dissatisfied with them being under this category of psychotic memetics and felt that the signature psychological effects of these compounds went beyond just mimicking psychotic symptoms and so he wanted to find a more apt term to speak to in a sense, the principal
Moment of their action. And he jotted down a few different possibilities about a dozen or so. I think, and one of them was psychedelic, actually, it started as an ended up being psychedelic and he had a correspondence going on with another Brit, also, living in the u.s. Aldous Huxley, where they were playing with some terms to refer to these compounds.
Sin. And in the end Osment, one with psychedelic and he had this little ditty of to Fathom, hell or saw Angelic. Just take a pinch of psychedelic as we put the disclaimer in and so, what does that mean? It's to ancient. Greek words, psyche means the human mind or if we're being actually true.
Due to the ancient Greek, it means soul. And then the other component means to make clear, or to make visible, or to make manifest, or to reveal. So, all of those work and it's a neologism, it's a made-up word, but it does have that ancient Greek origin. And it's speaking to this principle that these compounds reveal a
Specs of the psyche.
Of the human mind, the soul that are ordinarily, not entirely visible. And so that's the etymology, and it's wonderfully, poetic, but I happen to think it's also very accurate. It's a useful term because it's sort of, you might say valence nonspecific. It doesn't say you're gonna have a great time or that, you're going to go mad. It's more that it reveals the psyche and it could be hellish but it could be heaven.
Lee and so that's the etymology and also a bit of the psychology and sort of, you know, pointing to the phenomenology, the subjective experience. But there's also a pharmacology here and quite recently, there was put out a consensus statement about psychedelics, that's really referring to what we call the classic psychedelics to say that these are all compounds that
Work on a particular receptor in the brain, the serotonin 2A receptor. And that's another way that we could Define these compounds. I said this one's a little hot because I'm of the view that while the pharmacology is really useful, how the drugs work chemically, you can't avoid the phenomenology. And if we're true to the etymology where the term came from, then we must recognize and we cannot neglect.
The subject of experience.
Thank you for that beautiful description of what brought us to today in terms of using the word psychedelics. And now it's thrown around all the
time. Yeah she much.
Yeah too much and I'm guessing I'm not guessing I'm certain that it's also used to describe many compounds that don't touch the 5H 2 if I HT to a the serotonin 2A receptor. So there is a broader categorisation by most people and we
See where all the nomenclature naming goes for the time being. I'd love for you to tell us a bit more about this idea that psychedelics, however, one defines them can reveal something about the mind that can't be revealed. Otherwise, are you talking about the subconscious? I mean, you know, psychologists and most famously, Freud but also young and all also neuroscientist I think think about subconscious processing. I think perhaps the most Salient example for me that's
Outside the realm of of anything psychedelic would be blindsight this phenomenon that you take people that are blind but still have some connectivity in their brain and you present them aboard with your computer screen with different number of dots on each side. He say how many dots are on each side of the screen and they say, what do you mean? I can't see the screen. I'm blind. He said we'll just guess and their guests rate is accurate far. More than Chance wouldn't would predict. So they have so-called blind sight.
People have said, well, this is the subconscious revealing itself. There's no psychedelic drug involved but what you're describing is a pharmacologic and do state that reveals something that normally should we assume is masked or that. We are oblivious to even though it's expressing itself. What what, what does it mean for these drugs to be reviewed? Revealing something about the workings of the mind? That would not be obvious to us. Otherwise,
Why's yeah,
so the example of blindsight is interesting, but it's different Blindside would be referring to non conscious processing. May be implicit processing so stuff, going on in the mind, in perception, in a sense that is below the threshold of conscious awareness, but yet is influencing you. So it's sort of It kind of related, but it's different. So in in depth, psychology psychoanalysis, psychodynamic
Gee, you know, Sigmund, Freud, Carl Jung and so on, we talked about the unconscious and there it's more about the kind of Blood and Guts of The Human Condition and the human nature. Both the personal unconscious, say things that you might not want to necessarily be conscious of because it's painful. So that that's the repression aspect pushing it out of conscious
awareness or
Repressed memories in particular. Yeah,
like, traumatic memories difficult relationships, could be complex trauma and not necessarily just the specific, you know, index trauma, but a series of trauma. And then you have the collective unconscious, which was really Carl Jung's contribution to say that, you know, there's a transpersonal quality to the unconscious. There's aspects about humans
Not just this individual human as aspects to our Mount. Our minds, our psyches that are not fully available to conscious awareness but can come up in certain States. You know, psychoanalysis went crazy for dreaming as as their Royal Road to a knowledge of the unconscious that was Freud. But we now know with
psychedelics. And this was what
drew me into the area was discovering.
Literature. That was speaking to this particular action, the Psychedelic action and was saying that when these drugs like LSD psilocybin found in magic mushrooms when they're used in in Psychotherapy material, comes up that maybe may have been repressed, that is of, you know, therapeutic value.
An awareness and insight of this material, seems to catalyze the therapeutic process with strong, emotional release, these cathartic experiences, and, and insights, you know, whether their insights that are personal or whether they're transpersonal. But for me, this is really where the meat of it is with psychedelics and classic psychedelics in particular, the likes of calm
Compounds like LSD and psilocybin. I would say that if it wasn't for this action by classic psychedelics, we wouldn't be so interested in psychedelics. I think we only had compounds like ketamine MDMA cannabis there. Just could be said, broadly speaking to be psychedelic, like I don't think it necessarily would have captured the world's attention as psychedelics are right now.
As you think is a major Gap to fill? Is this principle action of the classic psychedelics? What does what does this mean that I'm referring to psyche revealing? What is that? And as well as where I'm going with this is what is that in terms of the biology as well? What's going on in the brain and the body? When people become aware of things that previously, they weren't fully aware of
I'd like to talk about some of the clinical trials that you've been involved with, in particular looking at psilocybin. The, as you mentioned, the principal hallucis hallucinatory, psychedelic agent in magic mushrooms. I'd like to start with a kind of nuts-and-bolts question. Just so that everyone is on the same page. I've read the papers that you've published and others have published in this area and typically on the dosage is used in these trials are
25 milligrams of psilocybin, and we talked about one recent trial in particular that compare 25 to 10 milligrams to more frequent use of very small amounts, 1 mg over 3 weeks, for instance, however,
When people talk about magic mushrooms, they often talk about G doses of the mushroom because I'm assuming that they contain mg dosages of psilocybin here. We're not encouraging. Use of any kind, these are clinical trials, but for clarity of understanding, what is the conversion? Typically? Like one gram of magic mushrooms will contain? How many milligrams of psilocybin on average? Because of what I
What I'm trying to do here is is calibrate people to this idea of micro dosing, versus macro dosing. And that's fairly straightforward to do with respect to the clinical trials. But then, in the lot of the lay discussion around this, you hear about heroic doses versus micro Doses. And so, I think there's a lot of confusion. So if you would educate us on this idea of what's a microdose and perhaps also, how many milligrams of psilocybin,
Ivan are contained in a gram of quote-unquote magic.
Mushrooms sure. Well, a micro dice is. Neither of these are that simple but the fun. It's a fun challenge. But microdose, one definition is that it's a dose of typically a classic psychedelic like LSD or psilocybin that is that has sub perceptible psychedelic effects like you, it doesn't put you
To a noticeable, altered state of consciousness. That feels like you're tripping. And if that was LSD, it looks as though the threshold is around about, let's see, 10 11 12
microgram, microgram microgram? Very clear here. Yeah Rogue. Yeah, so 10. So, 10 micrograms of LSD are you saying will not induce visual hallucinations in most
people? So it's
That's threshold level. That's about the level that that some people who are sensitive, could feel it. But if you were to talk to the micro dosing gurus, they might say that that's kind of the ballpark for an LSD dose that you would consider a microdose and then you would take sort of semi-regularly. It's typically something like one day on one day or for one day on two days off this kind of thing.
There's different protocols and yeah. So you know some like Jim fadiman, one of the popularizers of micro dosing I think would say that a true microdose should be sub perceptible, you shouldn't feel it yet. The assumption is it's going to change you in some way on a kind of trait level more than a state level and maybe behaviourally. And
And the typical Story Goes it will improve well-being and maybe maybe it could improve certain aspects of cognition, say related to creative thinking. I emphasize the may be there because that's another angle with micro dosing. We're kind of waiting for some compelling evidence as things stand right now, I'd say we lack that compelling evidence. There's some suggestive stuff, but often the study design.
That strong. It's really hard to do a study with micro dosing because you need to have permission to give people a microdose that, you know, for practical reasons, they would go home with and otherwise, you're requiring them to be in the lab, say, three times a week for X number of weeks to meet the criteria of a course of micro dosing, which might be, you know,
No two or three times a week for say a month. And that's a hard thing to do in a lab study. It's expensive. You need to do that against a suitable control so a placebo control and there is a study that's been done in New Zealand. That has some interesting preliminary data that did I think kind of did the design right? But it hasn't been published yet.
I've seen some positive findings presented around improvements in mood, but it's a bit early to get too excited about that. Needs to go through peer review and all that. But as things stand, you know, the evidence is pretty thin. And and we have to be honest about that. We did quite a creative study, with my colleagues at Imperial, the guy leading that battle Ash. She gets it
See, Hungarian chap did a really Creative Design, very much his brainchild. He instructed people to do their own blinding, their own placebo-controlled, blinding of their own micro dosing. So this was a classic citizen science study like do-it-yourself science where they would get their LSD tabs and chop them up, put them into gel capsules opaque and have other capsules that are the placebo is that they just closed empty capsule.
And then those, the whole bar code scanning technique, so that you at your kind of shuffle them up, you know, but they've got the barcode in the QR code, so you can break the code later on, but once you've shuffled them up, you no longer know which one's had have the microdose in, and which ones are empty. Was this LSD, this was LSD. Also tried it with mushrooms but the issues with the mushrooms was people with burp, sometimes it Belch and then they have this mushroom.
Tastes. So then instructed people to get some like, non-psychoactive mushroom material to put in. So it's really not an easy study, golden easy study and it was I love that kind of science, you know, real creative first mover kind of Science and the results are fascinating because the short story is that the micro dosing didn't compellingly beat the placebo. Did not it didn't and
Controlled because he asked, he controlled for expectancy. So people's positive expectancy which is in a sense of the vehicle that carries the placebo response. It's why you have a placebo is the positive expectancy can drive a therapeutic effect to you know, a large extent. So he measured that pretrial and then used it to kind of correct for the response and how did it work? Those who got a placebo.
Whoa, but thought they got in microdose did as well as those who thought they got a micro Dice and did get a microdose. So it was the bigger effect that the majority of the effect was in thinking that you got to microdose. So in a sense, it was a victory for the power of the placebo response and it's created all sorts of controversy people don't want to believe it, you know, that kind of thing. But that's the beauty of science, isn't it? That science is not about
You want to believe that right there is the beauty of science, really?
I love that experiment kudos to them. I'm not going to attempt to say his last name, right? Yeah. No, no. You got it. You were involved in a clinical trial that was published last year. Comparing 25 milligrams of psilocybin to 10 milligrams of psilocybin. Is a very
To drug called escitalopram
yeah, Lexapro, yes
a pro. And this one milligram over three week dosage in wanting to discuss the results of that study a bit. And some of the other trials that you've done involving psilocybin for depression, the treatment of depression. Could we calibrate ourselves? 25 milligrams of psilocybin is, is that what wouldn't it's going to be a perceptible?
It's presumably hallucinations and all that. And is that what one would find in? I'm guessing here if I'm accurate. This does not mean that I have experienced here but 22 grams of
mushrooms we think. Yeah. Sorry. I missed that. Do not miss. That one. Went off on a tangent. But yeah, 25 milligrams of psilocybin would be, we don't know. And, and it's important that I say that because I wouldn't want people to hear my answer here, and then use it.
To calibrate their own dosing and mushrooms and get it way off. So it's guesswork and I would love to see someone do proper study on it and you know look at the psilocybin content in a given mass of philosophy. Mushrooms magic mushrooms. But to my knowledge that hasn't really been done. Someone like Paul stamets with would give a better answer here, but I think the percentage
Within the mushroom mass is some of psilocybin in the mushroom mass and psilocin which is the metabolite of psilocybin is something in the 1% little bit higher, maybe
range. Okay? So 11 G, 1000 mg of magic mushroom would contain about 10 milligrams of psilocybin. It's all right.
Broadly speaking.
Yeah great that helps calibrate and I
Think again just allows the layperson to understand a bit more where we're headed with these psilocybin trials and the results. So we don't have to restrict our discussion to just that one clinical trial. But if we include that one and and compared to some of the other trials that you've done, I mean your laboratory is seeing phenomenal in my opinion phenomenal results in the treatment of otherwise, intractable depression, major depression, which so many people suffer
From from to, I suppose, there are two sessions of using psilocybin in these ranges of 10 to 25 milligrams. Do I have that correct? Yes. Okay, could we talk a little bit about what people typically experienced during those sessions that allows this phenomenal transformation of mood and state and trait as well? And I'm especially interested in
Whether or not it is the experience during those sessions that is the trigger that's necessary for the transformation from a depressed to a non depressed state. Because with the, the impulse is to think it is that what one thing since he's and hallucinates is and here's is so vital, but of course, these drugs can create neuroplasticity changes in our neural wiring presumably for long periods of time. So what are your thoughts on the The Experience itself? And
Maybe for those who have not done these compounds before you can explain a little bit about what's typical for people and what you think is leading to that incredible positive and pervasive change in mood State and trait.
I would say that it's more than impulse. That is leading us to think that the experience is important. It's really data and and converging evidence now. So independent teams, independent studies are
Verging on the magnitude of certain kinds of experience rated. Yes, with subjective rating. Scales is predicting. Therapeutic outcomes, pretty pretty strongly and very reliably and so that's guiding us. Now could you say, well maybe those experiences are some kind of epiphenomenon of say, a central brain action. Well absolutely but then all experiences and epiphenomenon by that principle.
Yet we care about it, you know, and it matters to us and then our human relations with each other. So I think it does matter to a human being when they're in a say, a psilocybin therapy session. And as the drug effects begin to come on, and body starts to feel a little strange and tingly, and there's some initial anxiety and then in their minds eye, they
Start to notice patterns and maybe colors and then maybe those patterns deeper and their Dynamic and they have this fascinating organic
quality, are they patients in your studies typically using a i mask? Or so, they're in the, I'm aiso eyes closed, that's why you said Mind's Eye as opposed to looking out into that. And that is, of course,
one of the major differences to psychedelic therapy versus taking. A psychedelic, is you shut your eyes, you know.
It's so it's a world away from taking a psychedelic. Yeah, a rave or something. You know, in a sense. Good luck with that. But in psychedelic therapy. Yeah. It's, you know, settled conditions, there's music playing and what I'm describing here is very much, the default, there's actually, you know, very little variability between the different sites that have done this work on these conditions.
Typically it's two people, ideally mental health professionals, at least one who's a psychiatrist or a clinical psychologist or some other kind of psychotherapist or psychiatric nurse. But ideally to who meet those criteria with a individual, who's ingested, the drug and music playing throughout kind of Runway, into taking the drug and then throughout so there's continuity.
Music with lyrics or
without lyrics to begin with. And the music typically is spacious to begin with and then builds and becomes atmospheric. There might be, I don't know some tribal drums in the distance or or something as as it develops. I like the sound of a bird in the distance, you know, Birds call and then as it gets
It's into more stronger, drug affects the music starts to coax emotion and very intentionally, you know. Strings for example, would come in and it's an inch, it would be an interesting experiment and one that we love to do, actually to see whether if you were to pull that out, whether the Psychedelic experience would be as
Really intense as as it is in psychedelic therapy when you have music, there is a default and across the board. People should find this remarkable because it kind of is all of the published studies that are now, you know, having such an impact on Psychiatry and Beyond have music there as a staple component. And we just take it as a sumption that it needs to be. I tend to share that assumption but it's
markable that it hasn't been tested properly, but it's there and, you know, if you were to run with that and if you were, you know, had a kind of Critical Agenda, you would say, well this is music therapy, you know, why are you making all this fuss about psychedelics who had it? It's music. That's there. In all of these trials is all these fantastic findings so there is something to that, you know and this will T me up, probably to talk about psychedelic therapy being a
In treatment, we have a hyphen between the two because I share the hypothesis. The assumption that should be tested better. That there is a positive interaction between the two, that there's a Synergy between the two.
That's why it's psychedelic therapy. Yeah, life and just like cart heart Harris. I'd like to take a quick break and acknowledge one of our sponsors. Athletic greens, athletic greens. Now called a G1
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extremely useful to hear.
Because I think most people think, okay, psychedelic, whether or not they have experience with psychedelics or not get some visual hallucinations, some auditory hallucination, some synesthesia, some visual auditory blending somatosensation, you know, rubbing a surface and being able to elicit, The Sounds in one's mind.
Of course Etc. But so seldom do we actually hear about the specifics of these clinical trials in a way that for instance, points to music as one of the perhaps key variables. Now you mentioned that as people enter these psychedelic states that. There's a little bit of initial anxiety about a year and a half ago. I had a discussion with dr. Matthew Johnson, who's running some psilocybin trials. At Johns Hopkins, has, you know, and he mentioned the
Well, importance, at least in his mind to this idea of the patient, quote, unquote letting go or allowing the experience to take them someplace mentally as opposed to trying to constrain their sensory and cognitive experience. I'm curious what your Reflections are on that, on that idea, and why it might be so valuable clinically and this ties back to the
Earlier discussion, we were having about the unconscious or about psychedelics revealing something that's there all the time, but that we don't have access to, you know, it's and again I'm I'm struggling to find the right language for this because we don't really have a neural mechanism like, you know, top-down inhibition or something like that. To explain how this, you know, unconscious might be Uncorked in the Psychedelic experience but to make it quite simple and direct. How important do you think it really is?
For the patient to feel like they are quote unquote, letting go. And what in the world is Letting Go in biological terms?
Yeah, yeah. Well I think we'll get there in terms of having the neural correlates of the Mind revealing itself to itself, you know, the emergence of unconscious the unconscious into Consciousness or unconscious material into conscious awareness. It's a, it's a wonderful.
Food challenge. It's a huge challenge, but it's a challenge to embrace and letting go very much is again, a staple component of how the different teams do this work in terms of encouraging a willingness to let go. And when we started out doing our depression work and did that first trial was the first trial of psychedelic in formally diagnosed.
Diagnose depression. You know where that was the target population and depressed population was the first modern study to do that and we visited Hopkins friends there and and were mentored on how to do The Guiding Bill Richards. Meri Kasam on. Oh they were just so brilliant. And and you know why is in
They're in the guidance to us as to how to do The Guiding in our trial. And so this Fraser trust, let go be open, you're here a lot. I don't know who fairly it should be attributed to but I would attribute it to Bill Bill Richards meth. Yeah everything's borrowed you probably got it from some 11 hours, but it's such a key principle and it's almost like a mantra
That you're trying to instill in people trust let go be open and those different components where the trust is about the therapeutic Rapport that again you know this goes beyond just intuition. Now we formally measured therapeutic Rapport, we do it even with just a single item of visual analog scale. Items. Subjective rating scale item on the morning of dosing and we find that it's a
It's a significant predictor of the quality of the experience that you have under the drug in the Psychedelic therapy and then the therapeutic outcomes X weeks or months later. So, very powerful kind of chain of sort of predictive components there, but trust essentially important. And again, not just doing tuition, but the data pointing to that let go, there's a Readiness, a red
Enos to surrender to let go to not resist and we do measure that too and see that it's predictive of response. And then the being open is about a willingness to go there to confront to be inquisitive something that's easier said than done can be terrifying. You know when you're dealing with a very vulnerable population.
It's probably more the rule than the exception that they're carrying some significant adversity, life, adversity, or Frank trauma that they've suffered. And so, that message of the open be willing to confront and to go there is really, you know, it's really powerful and that, that's how it plays out. And, and often there is struggle, there's something going on. That is, I don't want to be feeling this. Make,
Kitt stop. That can be nightmarish at times but it's very, very strong and with these big doses that we give, it's it's very strong. And actually a student that I've worked with I think now doing a PhD re Brauer is working on a fantastic project characterizing. The different phases of the Psychedelic experience where the early phase is.
By negative emotions and negative - Avail instead feelings of anxiety and struggle and then it's a different story in the latter half
could ask about the eye for. So I think that's fascinating and important to analyze the different phases. And again, I'm delighted here because people typically hear about a psychedelic Journey but we never really hear about the kind of stereotypic components of the beginning middle, and end of that Journey. We know that there's a peak and that there's a kind of a
Shooting down and etcetera. But when you say that typically, there's an anxiety, may be some negative valence, in the early stage. Do you mean about the sensations? People are experiencing or about some prior event. That's being called to mind that they're remembering likewise for the positive phase of the Psychedelic Journey or trip are people? They still called a trip? Yeah. All right. For the I guess.
We'll use trip for the psychedelic trip. Are people feeling positive about the experience like ah, like there's been some sort of breakthrough or they're in a, in a calmer state or is it that they tend to be focusing on prior events that were positive? So in other words, is there a Threading through of some concept that comes to mind for people? Maybe about an earlier trauma or maybe about a sense of self or a sense of other forgiveness you know, could be any of these things.
But what do we know about the kind of finer details of all
that? I would say, the initial struggle is more against the general drug effects. Then pinning it on, on something specific. It's more that, you know, normal waking consciousness. We have a sense generally speaking if we're well or well enough as a sense of assurance about what what is a table here and and so on and and and we have that issue.
You're innocent to an extent about ourselves as well. It might be illusory, but we have it. And what the drugs doing is, it's breaking down all of that, and it's scary as hell, you know? And if it's a big dose it's just like human nature to boot to read, you know, rage against a bitten and a bit like dying. You know. I don't want this. It feels like I could be dying.
I might lose my mind. Yeah. That it never
comes to the classics is all but
I might, you know, I might know that I've taken a psychedelic and I might even know of a bit about psychedelics but I still fear that I'm going to go mad or that I know they you know generally speaking these drugs don't have a high, you know, fertility risk. I still think I'm going to die, you know, and it's just it's very
Palpable in that and that comes up. So yeah that's that. I mean, those are the core fears that those two and very reliably that comes up and it's really like, a basic drug action, it's those dependent. But it's a basic drug action. That is forcing something about the nature of the mind. And the way it's made up, that makes it feel that way. I'll, but it feels like I'm losing my mind if it feels like I could lose my mind or that I could go and say,
In all that maybe I'm dying here and this is bad.
Yeah, you've talked many times before and I've done really wonderful work. Looking at the changes in communication between different brain areas. While under the while, people are under the influence of psychedelics and I think the Gestalt of those data, correct me if I'm wrong. Is that compared to the non psychedelic state that under psychedelic influence, there is far more. Let's just call it interconnectivity or
Ian between a brain areas that typically aren't communicating which probably is not surprising to people given the the subjective effects of these of these drugs. What is the evidence that after the Psychedelic journey is over that some or perhaps all of that, enhanced communication across brain areas is maintained. And if so what role do you feel that could play in these incredible positive therapeutic
outcomes. Yeah, so we've had a
Some recent findings in, in that direction where yes, it's true. And you know, the picture that says a thousand words of some people might be familiar with. Are these two circles project that we did in collaboration? With some researchers, where ordinarily, the communication is going on within systems, like other regions of the visual system will be.
Be speaking mostly within the visual system, they'll be a kind of clique East cliquish nurse or a modularity to the quality of the communication in the brain. And then the cool finding with psilocybin was the first paper? Is that the communication? Yes, it's sort of transcends, these modules and becomes much more into modular crossing different modalities and that affect correlated with the magnitude of the
The facts. And then we replicated it with LSD using different methods. And new paper will come out soon where DMT showing a similar effect. It's a bit of a debate about what regions and most implicated, but the general effect of an increase in global functional connectivity, is what we call it or Global Communication in the
brain. And this is while Under the Influence, this is under the use of putting people into a brain scanner while they are under the influence of the drug.
Right. Yeah, that itself must be a quite an experience given that these scanners are small tubes, you're in a b bar, you've got a B Bar in your mouth. That's a quite a quite a study.
You don't always have a, by far at least with the psychedelics. But yeah, you got to keep your head still and and you have the loud Mr. Scanner noise going, but because it's regular there aren't too many surprises. So it's actually surprisingly tolerable earlier in the
All settings. So you're not worried about what would happen if you had a cardiac
event, Uncle professionals around. And you know, most people generally tolerate that setting quite well surprisingly well, but yeah, we do all that. And yes, we do see that opening up of the communication across systems in the brain, and it does speak to kind of intuition about the subjective experience that, you know, different modalities might be blending with each other.
It is sorry for interrupting, but I have to ask, is it thought that the activation of the serotonin 2A receptor? Is what's responsible for the increased communication between brain areas that under normal circumstances would not be
communicating. Yes. So there's a few reasons why some modeling work that computational modeling work. That first identifies whether to a receptor is and then looks at models, its basic effect. On Ural activity will recapitulate.
Late the the or recreate the effect that we see actually in the data with the scanning. So doing the computational modeling, you can see the same effect by knowing whether to where the key receptors are and then making them do a certain thing that we know psychedelics
do. I can imagine two possibilities and I think it's important to distinguish between these two one possibility. Is that the activation
None of this serotonin 2A receptor leads to increased connectivity and thereby auditory and visual hallucinations emerge changed. Patterns of thinking emerge, Etc, that sort of the obvious interpretation, but the scientist in me has to ask, is it possible that
All of that increased connectivity is occurring and yet that is a distinct phenomenon. Layered on top of some other effect of the Psychedelic drugs, impacting access to the to the unconscious hallucinations. In other words, is it the increased connectivity? That's leading to the subjective experience. Or are those two things happening in parallel? Well, they happen in parallel, and they map to each other. But the question of causality, what causes, what is the tricky thing?
Where I would suggest that the said that the causality is circular, that they influence each other and this gets a bit philosophical, but it kind of matters because otherwise, you know, there's a trap that it's easy to fall into where you're thinking that it's all about the brain action causing the subject of experience. And that's typically what we do in cognitive Neuroscience. It's kind of like the sort
Of first Port of Call kind of materialist approach but one can be a materialist essentially, but still appreciate that circular causality. That mind also interacts with brain and it's so hard to pick the two apart. And there is a kind of essential dualism where subjective experience is the thing in and of itself, but that's not to divorce it from what's going on on the biological
level. The reason I ask is because
As I understand it, nowadays there's a bit of a movement within the scientific community that study psychedelics to develop drugs that can essentially cure or alleviate many of the symptoms of depression, or trauma that are built off our understanding of how psychedelics like psilocybin. And here I'll throw MDMA in there. Although classically, not a psychedelic. It's kind of gets lumped in when you get back to that later but that do not produce.
The hallucinations or massive changes in subjective experience. I should I think this is what initially got us into conversation on Twitter, as I had learned about this paper published out of a group at UC Davis that essentially modifying psychedelics so that they have potential therapeutic application for the treatment of depression. But zero,
Hallucinogenic properties. Yeah, and I thought, wow, this is going to be a very controversial thing in the world ride because the the history of psychedelics as you pointed out has been one of people accessing different modes of thinking feeling seeing things these in letting go trust etcetera, therapeutic relationship. And here we have I don't want to say farmer because it's not really Pharma but we have Laboratories who are trying to tease apart, the activation of receptors independent, of all
Subjective experience in order to essentially treat the same conditions, I'd love for you to comment on this where you think it might be going and you know whether or not you think that's the right or the wrong approach. If it has any validity,
all it is Farmers just smaller Farmers sort of startup farmer
but okay so because the farmer would like to have drugs that can cure depression but don't make people hallucinate is that
cause a woods and patients might and the system would love it because the system is used to it. It
Edison
right and it doesn't give this this mental imagery of you know the summer of love and San Francisco or of you know kaleidoscope eyes, right? It's more. Yeah. You could imagine the more to be careful with my wording here. Those who would not be inclined toward that would might might Embrace a therapeutic that that is strictly effective at treating depression with no
hallucinations. Yeah. And it doesn't look like, you know,
No, an individual lying on a cipher crying their eyes out about, you know, the life that they've lived and that deep catharsis being life, transforming the very different from that model. I'm skeptical of it. I thought for a few reasons
And one is that I can't see the logic. I can't see the pieces fit in a way that's compelling and I'm also skeptical because I think it could easily be wishful thinking because of that point that patients would like it and the system would like it. And I just can't you got to bear that in mind as well. So wouldn't it be
Alliant, you know if it were true and you could get the therapeutic action without the Psychedelic
effects one away, that's a little bit of what micro dosing seems to be designed to do. Like you said take dosages there below that that perceptual or some you know awareness of some effect threshold over a longer period of time in an attempt to Ping the circuits or twist, you know, alter the circuits but not hallucinate. Yeah, not have a
catharsis. So if, if Mike reducing could do that,
And it's a perceptible and Mike reducing isn't psychedelic action? Because where's the Psychedelic action when psychedelic when defined means psyche, revealing you're not getting that effect. You might be getting the pharmacology might be getting some direct serotonin 2A, receptor agonists. Mm! That could be driving a therapeutic response, but you can get that with ssris as well, you know, and so my point is what, what's new? Okay, maybe it's a bit new.
New in people are now developing direct to a agonists rather than indirect, through a serotonin release her like the selective serotonin reuptake Inhibitors ssris, like, Lexapro and I,
are there any ssris that selectively agonize, which Folks, by the way, means activate in a good way. I get a gurney. Sounds terrible to put those an unformed might think that mean that a disrupt but that can activate. The serotonin 2A receptor. Are there any
Drugs that will do that. That are not psychedelic.
I'm not aware of any, but then again, I'm not unless
there are any other. I needed a licensed in used, as medicines in Psychiatry, actually had this debate recently on social media. And I couldn't see, I couldn't see a compelling example. I saw to a Agonist that we use for other things. You have a compound, like, Lissa ride, used him in treating Parkinson's, but actually it's more of a dopamine
Agonist and they're always having other things.
The right? Yeah, yeah, I
said tapping other nerds that being transmitted for other things. So is there a is there a selective serotonin 2A receptor stimulator and Agonist that? It isn't psychedelic that is therapeutic in Psychiatry and the answer firmly is no, I haven't seen it yet, will they develop one well for patients sake? I hope so because it would be great. Let's wait and see if they do. I doubt it will be psychedelic and I doubt it would have much.
Do with psychedelic therapy and it would be much more like the system we're used to of chronic pharmacotherapy, take your drug every day. Let's let's hope they find it and it works for patients sake, but as things stand right now, I'm a little skeptical. Now, some of the findings that are being seen that are really exciting. Fantastic work being done showing things like
Creases in the communication components of neurons. Dendritic growth spine growth synaptic, spine
growth. Yeah. By the way, folks, just I'll interrupt for the Dada necessarily spine, the bone, you know, the not the cerebral column. But spines, are these little, like little tiny Twigs with bulbs on the end of neurons that are allow for communication points between neurons. So neuroplasticity, is often associated with growth of dendrites and
And so, of course, which is what Robbins referring to that reminds me. I just want to make sure that we close the hatch on the earlier answer because I interrupted you is the increased connectivity between or communication between brain areas. That's observed while people are under the influence of the Psychedelic. Also observed later, after the effects of the drug wear off, and then I'll just throw in another question there because we're on to this topic now, to what extent do we think that neuroplasticity?
City structural changes in neurons functional changes in neurons are responsible for that. And how long does that last? Let's say I take, let's say I come into your clinic, I'm a subject in your experiment, I'd take do come in in the morning. I do my psychedelic Journey five, six hours later, I'm parachuting back to reality as we call it. And then I go home, increase the connectivity last for how long, and how long are the structural brain changes occurring? Well, you're
asking fantastic.
Students and partly because we don't have the answer yet, but we do have some, we do have some data. And so we have looked first of all the in a sense, the function plasticity or what we assume it to be or at least the functional changes the increase in communication across systems that increase in global connectivity. Functional connectivity, do we see it after the trip? We know, we see it during the trip pretty well. Replicated correlating with intense drug.
The effects. Do we see it after the trip? Well, the answer is we've seen it in two different depression cohort, psilocybin therapy for depression. In one study where we look the next day we saw it kind of residual effect similar to what you see acute least being seen the next day and then in a subsequent study we saw it. Also three weeks later so we've seen it in two.
Independent data sets. This decrease in modularity is how we measure its the same thing, essentially, broadly speaking. It's the same thing in increasing Global connectivity, functional connectivity, and actually unpublished we've seen it in healthy, volunteers on a correlational level not on an absolute change level. But if you look at its relationship to a mental health outcome and this is an important thing to stress with the depression work. We
Or a relationship between the magnitude of that change the decrease in modularity, or increase in global connectivity and the Improvement in symptoms severity.
So interesting. Yeah, I mean wait and just to stay there different ways. So what Robbins referring to as way to rock modularity is neuroscientist. We think of the different modular networks of the brain that, you know, the I talks to a region of the thalamus involved in Vision, which talks to the visual cortex, which, you know, eventually converges with auditory
Formation. Of course, but there's a separation or modularity of function. This increased connectivity is cross modular in during the trip but afterwards as well. And you're saying that that correlates very strongly with the strength of the therapeutic outcome for depression. I mean the The Logical extension of that is that extreme modularity of brain function is depressive in some way. Now, we don't want to go too far but what does that mean that increasing crop?
Crosstalk between different modules of the brain is so strongly correlated with a positive therapeutic outcome.
We don't know other than as a relationship. I mean this is this is the thing. We need to be a little careful, not to run with it too far. I mean, there's some things that it suggests I think it suggests a more
Flexible mode of brain functioning if you're not getting stuck in modules or the modules on excessively cut off from each other. But you see different things with different presentations? If you were to look at cognition sharper, cognition is actually associated with more modularity. So it's a rule that a little slippery, and we need to be careful with it. I just again, I'll forgive me for
Trying, but I think of I have friends who are, I would say are on the Spectrum who are very linear in their thinking, and extremely intelligent, and it in the kind of classic sense of being able to ratchet through hard problems, to arrive at a solution. And then I have friends who are just calling with her from the creative communities outside of science that are very expansive. They see connections between many different things but you sometimes you have to
Not all of them. You have to catch their ideas with a butterfly net and oftentimes what they're saying doesn't sometimes just doesn't make any sense. Now they also produce incredible creative works but to have a conversation with them is anything but a linear experience. They are not random thought generators but there's a non-linearity or Randomness to their processing. That's distinct from these other folks that I'm describing as on the Spectrum. And of course, it's a spectrum, there's some whole range in between sounds to me like
There's some therapeutic value to being able to move along this Continuum from the more linear to the nonlinear. Is that is
that well I think so. Yeah. You see, it's resonating what you're saying. It's speaking to my intuition that you know, you could be very Posse you know passing things up chopping things up like an analytical scientist. Like I kind of
litter as we say inside you're either a lump or a splitter. Yep,
you know, the way I'm being very particular about
What what, what, when to call something, psychedelic, you know, that kind of pasty analytical way of thinking you would. You might associate with a more modular system, you know, whereas the system that's more globally. Interconnected and open. Yeah, might be more flexible and creative and Divergent in the association's and so on. So, yes, that's speaking to my intuition to how you're describing it. And I imagine if you take severe Psychopathology severe,
Mental illness like a depression. I've always thought there's something intuitive about the term itself like a depression in the landscape, you know, which is a whole cigar depression physical depression that it's easy to fall into and if you do, it's hard to get out of. So almost, if I understand what you're saying, correctly almost like getting stuck at what location on this Continuum, because most people don't reside, it one or extreme one extreme or the other full-time and kind of migrate back.
And forth between expansive States and more linear States like like you do with low mood, you know, if you're healthy and inverted commas, you can feel your low, mood your disappointment, but you can spring back but someone with no you can spring. But yeah, right. Whereas the suicidal depressive person or to aside Ali depressed person somehow at least it my understanding. There's something about that. Extreme depressive States and extreme anxiety States.
Laboratories a bit more familiar with anxiety, which Alters the perception of time, such that people feel like that - state is going to go on forever or that if it goes away that it's going to return at random. Yeah. Kind of a vulnerability to the time
domain. Yeah. Yeah that's in its I tragic. But that cognitive bias in depression that everything's hopeless and and there
There is no light at the end of the tunnel. Yeah. So, you know, if you were to get stuck in that rot and have that bias, then you're cut off from other things, other sensory, modalities or modules, you know, cut off from the world cut off from other people, stuck in your inner rot. And so, yes, I think we're sharing this intuition that a decrease in modularity or an opening up of the system, the brain.
Could relate to an opening up of the mind that is kind of enduring after the, after the Psychedelic dosing session. And yeah, and, and the third replication was to see in health. He's an improvement in well-being because they're healthy. We don't look at
depression, so these are people that are healthy walking into the trial. Yeah, take psilocybin twice.
Well, actually, they do, but the first dose is 1 mg, which they don't feel. It's a placebo
do micro. Yeah, we have
Sticky G on their heads to measure their brain waves during each dose and one milligram, you see? No
change. So we think that you may grow dozers. No I'm just kidding that. I got nothing against microdose is I've always just been a little bit skeptical based on my conversations with the scientists actually doing the work was with with psychedelics it seems like the answer keeps coming back do
One or two maybe three macro doses in a controlled safe setting.
Well, that's compelling the evidence for that is compelling and that's what making all the difference right now and microdose is just appealing. But again you know, science isn't about what we want to believe it's about what's actually coming through and what seems to hold up. You know, to testing, I'd like to just take a brief break and thank one of our sponsors.
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That's LMN t.com huberman to claim a free element sample pack with your purchase. Again, that's drink element. LMN t.com hubermann. Would you say that's right? That one or two or three sessions, and how far apart of those typically spaced in time?
Yeah, typically one to three weeks across the site is the way people are doing the Psychedelic therapy. Dating sessions two sessions, you know, Hopkins Imperial. And why you
You that's being a kind of default to we actually use three and a current anorexia trial. Psilocybin therapy for anorexia to patients left to see after 19 who've gone through the trial. Very exciting results. They're
using the alleviation of the, the obsessive thought about food in a, willingness to consume even healthier amounts of
food. Yeah, even improved. Wait.
The long follow-up. So
so critical eye, when we did an episode on eating disorders. And I learned that anorexia nervosa, which by the way folks the rates of are not increasing. It's been pretty stable Through Time despite what said, about social media and Etc. But anorexia nervosa being the most deadly of all psychiatric illnesses which is a big statement, because, you know, manic depression so called bipolar depression as a
20 to 30 times that the typical suicide rate, basically, many anorexic, or people with anorexia. I think it's how it's now. You is what one says not anorexics but people with anorexia often die. Many of them died.
Yeah, so tragic. So often young people as well and similarly with suicide in terms of premature death. So the tragedy with Psychiatry is so strong and and there so it's it.
So rewarding to be doing that trial and to be seeing good results, I had to check myself a little bit that I'm, I'm reporting on it in this really promissory way and the trial isn't yet publicly released and publish, so it's still ongoing as
well. But that was three, doth researches
three sessions and I can't say what the dosage is because we still have, there is a blinding component, but there are three dosing sessions and there.
See now I think they're two weeks apart.
And we do the follow-up. Yes,
I'd like to close out this description of the of the journey and the trip by extending past the day when people actually take the drug into this, what I've heard described as the integration phase, you know, you have to reintegrate right on the all this love all this increased connectivity during the session hallucinations insights anxiety, letting go, maybe.
Should maybe Epiphany? Okay great. At what point is that Consolidated? Meaning are these patients or subjects and studies having daily conversation with their therapist are they journaling every day? And you know I want to keep in mind that most people are not going to be part of a clinical trial. And of course, here we're not suggesting what people do or not do. But let's just put it this way, we're people to use psychedelics.
What is the way that people can maximize on the neuroplasticity and the Brain changes in a positive way in the days and weeks afterwards. In other words, how long does this so-called integration last? And, you know what, how far can we take this? I mean, I could imagine that how often one chooses to think about the insights could also have an impact. Yeah. Right. Because clearly people went to Raves clearly people did psychedelics in the
Yes, we don't know if clearly people do psychedelics now, but we don't have data on those people. You have access to the understanding of how they're spending their time and the therapeutic outcomes which we haven't gotten to the numbers yet. But again are incredibly impressive, you know, in upwards of, as I understand it, 60% or more people getting relief from depression. Yeah, 70 years, 70 percent incredible, especially when compared to the typical
Depressant treatments and so on. So what is this business of integration? How is it done
properly? Yeah. Yeah gosh. Well, how long does it last as well? A lifetime you know life is a journey like a trip is a journey and there's always work to do and I was Jack kornfield says after the Ecstasy the laundry. Yeah there'll be other good ones.
As well. Forget them. But yeah so the works on going and and and yeah, but this gives you a footer, it enables people to do the work more easily and that's true of the classic psychedelics. It's also true, very true of MDMA therapy for post-traumatic stress disorder. It's really giving you a leg up making it easier to do. Very, very difficult work going back.
The trauma, trying to digest it process, it integrate it. So it's such an essential component of the treatment model, but one has to be realistic as well. So, you know, by saying, O, integration lasts a lifetime. Well people delivering a service. Can't be there for a lifetime. So what's the answer there? And people are wrestling with that.
Issue right now and I think one of the solutions might be that it's in a sense on you to a point you know the therapeutic team can treat you to a point and then it becomes what you might call practice in a similar way. That meditation is a practice. It's something that you have to keep up and if it slips then things could slip and and that's the way it is.
Or you have a another psychedelic treatment, you know. So people have even used this term of practice in relation to psychedelics, where there's a psychedelic practice like there's, you know, a meditation practice but I'm using meditation intentionally here because they actually think that meditative practice spiritual practice elements of spiritual practice could be a
A very important complement to psychedelic therapy and I think it's probably doing something similar in terms of promoting inability to sit with a former colleague of mine, said it quite well in relation to psychedelic therapy versus chronic pharmacotherapy or like ssris being on them all the time. It's a psychedelic therapy allows you to sit with rather than sit on and I thought that's quite good.
Yeah. Say you know the meditation the mindfulness ability to yes be present centered but also present centered and accepting. So if things come up, you can watch and process. And then let go
that Holy Grail of mindfulness. Yeah, you know, you know, awareness without reactivity respond. I, you know, I grew up in the Bay Area and you'd hear this.
Language. Right? And I'm not being disparaging this. I have friends that are on the board of esalen and work down there, you know? And I've gone there and it's, you know, and yet you hear these terms, right? Be responsive not reactive which to a neuroscientist, is like grates on me, which probably just means I have issues, but and surely I do. But you know, it was like what does that mean? Right is sort of saying like oh to a be the Observer but not be drawn into the experience, you know. And and again I don't want to be overly reduction.
What I find. So compelling about the emerging data that really is data on psychedelics as treatments for depression and Trauma, namely psilocybin and MDMA is that it really seems to allow people this space. That that is so commonly thrown around, you know, giving space between stimulus and reaction when Viktor Frankl talked about this, but, you know, I've been reading a wonderful book called The Prince of medicine. Good, two dates, back to the origins of medicine, very dense, book human talking about
Stuff. And thinking about this stuff for thousands of years.
Psychedelic seemed to give people access to that better version of self, which is remarkable. What's also remarkable? It's perhaps worth pointing out. Is that five years ago, I never would have been comfortable having this conversation. I would have been afraid to lose my job. Stanford magazine this week just published an entire issue about psychedelics with how ketamine Works MDMA psilocybin with the appropriate cautionary notes in there. But clearly times are changing.
Speaking of which, I know you're doing a trial on first time use of psychedelics what inspired that and what are you observing and as you tell us that please give us a few of the key Contours. What's the dose? How old are these subjects? I'm assuming it's men and women, are they suffering from depression or not? What kind of, what's the landscape of that study? And I realized this is still early days of the
Study or maybe it's close to completion. It's not yet published. However
correct. You know, it's not published, it's not submitted, it is completed. So this was one, another one of our covid studies in a sense, meaning covid hit and we had to finish the study and it was hard to finish the study because the covid that was true about psilocybin therapy versus escitalopram Lexapro trial, which is published New England Journal of Medicine. But the, this was 20 that paper. By the way, folks will provide a link to in the show, no captions.
As well as some of robins other papers. I think the 2022. New England Journal paper is really fabulous given its the different dosages and the comparison to essentially, what is micro dosing and the comparison to
Citalopram. Hmm. Yeah, that's interesting that you link the way. We gave small dices of psilocybin to micro dicing. We didn't think of it that way. We thought it was just the necessary Placebo for the big big dice, the 25 mg said,
Yeah, so that we could say to everyone with giving you psilocybin and not be lying. Yeah, for those who got Estella pram, Lexapro for six weeks, they got a very, very low dose of psilocybin but it allowed us to standardize all the Psychotherapy and so on but the the other study that you're referring to was in health, he's healthy, volunteers middle-aged, average age, I think was 40 so not your typical student study that is so often the case in Psychology research.
Yeah, well, the undergrads and up volunteering to your study. So this is more of an age range and also I think it was an equal proportion of male and female all the staff actually were female, which the staff were very proud of
them. Although it produces its own potential confounder right to have all 11 sex of Staff possibly. Yeah they did a
good job in the sense that we saw
Significant improvements in well-being, at the end of the trial, so let me describe the design. It was a repeated measures design. Meaning people come in, you collect your Baseline data and do a brain scan and you give people a placebo. We gave people a placebo. Now, as she let me rewind a little bit, everyone's healthy volunteers, middle-aged never taken a psychedelic in their life. None of them entirely, you know, fresh virgin people coming.
In and and the plan is to give them their first ever psychedelic experience. So that's what we did in this study. But to do it, we have this repeated measures design where they'll first get a placebo and we have the placebo. So that we can do all the procedures, all the therapy, all the music listening, but not give a whopping dose of psilocybin. We again, we gave them a placebo dose of psilocybin 1 mg. We stick EG headsets on during the experience.
To record the brain activity from the scalp, the oscillating, electrical activity. And we do the MRI scanning before and after to see deeper into the brain. And we can look at the functional connectivity that we were referring to earlier and also properties of brain anatomy which we did in this study. So there's the short story is that all of the changes that we saw both psychologically and
Euro biologically was seen with the 25 milligrams. It all happened with that big whopping dose. And what did we see? Well, we did see significant improvements in psychological well-being. We saw what I call the entropic brain effect, which is actually formally quite accurate. We see an increase in the informational complexity of ongoing brain activity, recorded with the G on the dose of psilocybin.
Then the activity becomes more complex. It's harder to predict across time. It's more information, Lee rich. And that affect correlates as it does very reliably with the magnitude of the subjective effects. So the bigger the trip, the bigger this entropic brain effect, now pretty well replicated finding, but then the Mr. The MRI sink deep into the brain. Was probably our most exciting result where
We didn't just see some functional brain changes, but we've seen some anatomical brain changes as well and we used a technique called diffusion tensor Imaging. That looks at the cabling of the brain, the white matter tracts and we saw a change in major track. So we sort of limited our search space to really thick tract, really thick fibers. And the fibers that came through as changing the ones that traveled
Between the prefrontal cortex and the thalamus and the striatum there were two tracks to prefrontal tracks that changed and they changed in the direction of the decrease in axial diffusivity, which could be interpreted as tract Integrity where a decrease would be an increase in tracked Integrity. It is something that you see in the developing brain that axial diffusivity.
Reese's as a brain goes from being a baby to being a adult. Axial diffusivity goes down and then in aging and pathologies of Aging axial, diffusivity goes up.
So this is in the opposite direction of the results you talked about earlier, in terms of brain connectivity of sort of increased communication across areas, if I understand correctly, and I'm perfectly happy to be wrong. By the way that this decrease in axial, diffusivity is translates to a higher Fidelity of communication between the prefrontal cortex and the thalamus and striatum as opposed to less and your description of this is somewhat like the, the
Transition from babyhood and childhood to adulthood speaks to the same where we know that there is a massive culling of connections as opposed to growth of connections. So in other words, as we get older, we get better at doing certain things and less good at doing potentially. Most, everything else is that right?
Ish, because the change was anatomical and not functional. So the other stuff was is really measuring.
Caishen in, in the brain by looking at how the activity fluctuates across time and whether those fluctuations in activity, a synchronous between regions, and if they are, we say they're functionally connected and we infer that they're talking to each other because they go up and down in synchrony. But when it comes to the anatomy, we're talking about the just static you know, material stuff. And so we're seeing the
Fibers in a property of the fibers change. At least that's what we think. And recently we had an independent person come in and reanalyze the data because, you know, one of those things, incredible finding requires you no credible evidence, really, strong evidence. And and I would say the evidence of the Moments One study. So we need to be cautious on that. But we did rien analyze it and use this.
Action procedure, free water correction to be more sure, that it was a change in in the actual micro structure rather than something to do with the extracellular space. That the water surrounding the fibers and it came through it. In fact, the the change was strengthened by doing this correction step.
So these are our, this is neuroplasticity as the consequence of one first time session, with 25 milligrams of psilocybin.
Yeah.
Yeah. Yeah. So we're excited and the until we see two different you know the second analyst coming in, wasn't sure she believed it and then she you know, thought this correction technique might kind of kill the result and then it came through and she's like, okay now I'm excited too. So we'll see we don't know what it means. What what does it mean? Functionally we don't know. How did the people change? Well psychologically, as I said, well-being improved, we did look at that cognition.
And we used a cognitive flexibility Paradigm. That looks at people's ability to notice a rule change and then flexibly adapt their behavior. Based on noticing this rule change and people improved after the 25 mg and didn't significantly improve after the placebo dose, there weren't correlations with the DTI change that the cabling change, and the psychological outcomes. But
No, with these studies in smaller, sample sizes. You don't always see those correlations come through. So it's something we don't know what it means, but it's a change in brain anatomy. That's in the opposite direction. To what you see in an aging brain or
with pathology of aging and it's what you see in a healthy brain as it goes from, you know, normal neuro development into adulthood. Very, very exciting and intriguing and I appreciate that.
Highlighted that, it's just one study. Although from everything you said, it sounds like been done with immense rigor, so we will eagerly await the publication of that study and so we can peruse all the data and the subsequent studies. I want to hear a bit about the study that you have been carrying out on the use of psilocybin, for the treatment of fibromyalgia. I'm intrigued by fibromyalgia because because I have a good friend who also, I won't reveal who it is and no.
Not me, this isn't that. I have a friend thing who also is a scientist who sits at a fairly High position in the National Institutes of Health who quietly has expressed to me that they are incredibly frustrated with the fact that the standard medical community has largely ignored fibromyalgia and that for many years, it was kind of lumped with things like chronic fatigue syndrome. And other so-called, again, so-called I'm not saying this but people often refer to these
So it's psychosomatic. That's all in your head which is a neuroscientist is a ridiculous statement to hear because it's all in your head. Your brain is in your head. After all your physiology and your psychology are influencing each other. Of course. And and the world is starting to appreciate that more. But first of all, maybe you could tell people what fibromyalgia is, what inspired you to do? A study on fibromyalgia, using psilocybin of all things because that's surprising to me and if you
Are allowed to or if you have access to the data and in mind share with us a little bit about what you're discovering in that in that study
sure. Yeah. Happy to. So again, it's Silas up in therapy and population is Fibromyalgia syndrome. So, this is people presenting with a generalized, chronic pain. So unlike some other pain disorders where the pain is focused, you can say it's my lower back which is very common, chronic lower back pain.
Is more generalized and it and for that reason, it's hard to sort of know what it is and that's why it's been a controversial space in medicine, and it's been. Yeah, it's had that charge thrown at it that maybe it's psychosomatic and just to your point is anything ever, you know, independent of of the Mind anyway, but this is actually a fascinating space for how, you know, subjective experience to live.
And experience and the mind can influence the body because there's some really interesting literature around the etiology, like the how the pain has come about in a sense, like, what caused the pain, what's the story there and ahead of the trial? I would say to my colleagues. Let's just be careful because there is some fascinating literature around things like a background of trauma. And
How that can relate to issues related to inflammation and how that can express into things like fibromyalgia syndrome. I just said be very careful there because if you go in with an assumption that there's some very trauma for example, then there's that whole other side of psychoanalysis that massively tripped, it up around false memory and so on. And so please don't hold prior assumptions. That
You're going to run cover Barry trauma in every case. Now, the team of treated, I think eight people and it's going it is going very well. Again I just want to be careful with how I described it to Matt, you know, to manage expectations and not get too carried away. But I check in with the team every week and they're still based in London, doing the work. And
And it's remarkable what I hear about the profound experiences that people have under the drug. In this study, we only give one dose. It's a very mechanistic study, we actually have the EEG cap on in the sessions like in the healthy volunteers study. But this time now taking into a clinical population
And
so they're in the I'm there they are wearing an eye mask under the influence of 25 milligrams of psilocybin. Most of them probably have not done psilocybin before so it's a little bit like the first time study in some sense they have fibromyalgia. That's debilitating in some way they don't, they want, they don't want it. Obviously, and during the session, are they thinking about their
Pain. Are they being told to think about their pain.
So no big tell to think about the pain. In fact as I understand it, while there is a therapeutic model around acceptance of the pain, it is an unlike some of the PTSD work, you aren't encouraging them to focus on, you know, the index trauma. And then, you know, work through it and try and digest it. We don't we don't do that with the pain. So the pains there,
But there isn't an invitation to focus on it. And that's probably one of the differences with classic psychedelic therapy versus MDMA therapy. Arguably, MDMA therapies. More like bit closer to traditional talk therapy where there is more dialogue. People are able to talk on MDMA in the MDMA trials. Do you know whether or not they used, I masks.
Or they because this seems to be an important distinction between, as you describe the therapeutic trip versus the trip that one. Does you're going into the woods and taking Scylla, take you Scylla. So, I've been in the woods or at a party or while staring at a poster, or, or, or a leaf. Again, I'm not trying to trivialize those experiences. I mean, obviously they can be profound, but so I'm told but the MDMA trials.
Seemed to involve, as you said, more directed dialogue and sometimes, even kind of empathic connection between people by they're actually looking at one another, you know, the eyes and eye contact being such a key, part of the human social cognitive connective networks. So, do, you know, if they put eye masks on people during the therapy? Pretty
sure that they have the eye masks. They're right?
Because a lot of the
A work. And I was part of an MDMA trial was, as I understand geared toward developing, because it's an empath Legend, empathy toward the
self. Yeah, I'm pretty sure they have the eye masks there but they probably and it's a great question because you can formally test this if probably don't use them as much. The thing is with the classic psychedelics, if you're looking at your guides your facilitators and their faces are melting or whatever
MDMA you just wait, really start to feel more connected. Yeah, it might look
especially beautiful and you know and and yeah there's that fascinating effect of loving, you know, the people that you're with and so yeah I'm majan. They talk more and used the eyeshades less and it is more interpersonal rather than like intrapersonal going inside. They do use a fascinating terminology that some people have critiqued but
It's a very interesting phenomenon and and it's this notion of the, in a Healer they use that language a lot. It's been critique because it sounds very suggestive, you know, and that's probably one of the vehicles here. Driving the therapeutic process is suggestion. I think I have to be honest about that, but so when they go inside, that's another term that we use, very much in the classic psychedelic therapy, work you go inside, you know,
Put the eye shades on and people are encouraged to go inside, you know, but when they do that in the MDMA work especially they might be told explicitly and listen to the inner healer, you know, and that kind of language. So you could see how a cynic or a skeptic could come in and see that some kind of like suggestive priming or biasing. I think they have a point Skeptics often do but I don't think it
All of the story and and just briefly because it's an interesting point. Speaking to that point of bit in our psilocybin therapy versus Estelle apparent trial. We measured pretrial expectancy and we did it for both conditions. So you know what kind of improvement do you expect with the Lexapro? The S Attalla pram at the end of the trial and what kind of improvement if you go into the psilocybin arm and get a big too big
doses of psilocybin, what kind of improvement? Do you think you'll see in that in that? And of course, it was a coin flip as to what armed people went into and there was no crossover and what we found was that it was true that we had a sample bias. So most people had higher expectations on average, there were higher expectations for psilocybin and its efficacy or Effectiveness versus the yes.
Saray, the Lexapro. However, when we looked at the correlation or the predictive relationship between pre-trial expectancy and response, we saw that pre-trial expectancy for the esoteric. Pram predicted response to a Citalopram across virtually every single measure, all these different measures of depression, and anxiety, and well-being. And and I think none of the scales. I'm pretty sure it was none of
About 12 or so. Mental health rating scales was there a relationship between pretrial expectancy even though it was high, it didn't predict pre-trial expectancy didn't predict response to the psilocybin therapy. So that was a bit of a, you know, smash on the head for the idea that the classic psychedelic therapy is some kind of placebo response, I think it's so important to address that question.
Jen. Because if it doesn't come through as it didn't, is it didn't come through, then it it opens up even more intrigued about well, what is it? Then if it's not just a placebo response or a super Placebo response, like an amplification of the placebo response, then it must be something else. And how intriguing it has a direct therapy to action. It must be something and we don't yet know what it is.
I talked about the residual, you know, increase in global connectivity, that's one possibility, but the truth is, we're just scratching the surface
and yet the therapeutic outcomes are again, just so marvelous, marvelously impressive, I'm curious as to why us, well, there are that many Labs but the Laboratories that are focused on classic psychedelics for the treatment of depression. And now, as you mentioned, promising results for anorexia
Fibromyalgia as well. Although preliminary prompt very promising. Why the lack of attention toward LSD? Is it that the LSD trips are just too long? Is it that they are qualitatively different? Are there any data on non micro doses of LSD? And here I want to be very careful because I learned through my interactions on social media that this term microdose is very misleading.
And in some cases can be dangerously misleading, because, as you mentioned earlier, the effective psychedelic dose or you know, the effective meaning that can induce a real trip with hallucinations Etc, of LSD is actually in the micro gram range. So some people here microdose, and they think microgram of LSD is a micro grams is a micro dose when, in fact, a macro dose of LSD can be measured in
Right. So this is where you know in the absence of scientific training people can really go go astray or even in just in that lack of understanding of the metric system and since now you're a yeah, you're a recent arrival to the yes. Fortunate for us. Sorry, England's losses, that is the US has gained by Robbins lab moved from from England to the United States recently. So score one for us, but why isn't there more use?
He's of LSD in these trials,
I think it probably is the duration of the trip. It used to be stigma and it was easier to get your psilocybin study through because others were they were getting that true. So there was still likes of Franz volunteer leader in Zurich, and Switzerland and then Roland Griffiths coming along and doing the psilocybin work at Hopkins. So you could appeal to that presidents and say, Well they're doing it over there, you know?
Can we not do it in little England? So that's how it worked for us. We did actually go on and do an LS d-- study once we kind of laid the foundations for doing this kind of work and it was a brain Imaging study. It was a really extensive one actually where we use both MRI and another modality called Mig sort of super EG in a sense. But you know, why didn't we? Why didn't that?
Turn our heads to think. Oh should we not be doing our trials with LSD? Its it does have something to do with the pragmatics like a study day with psilocybin is long enough
so four to six-hour trip.
Yeah. And the FDA asked us to have the people in the lab and until eight hours post dose with personally, I think could be quite excessive especially if it's a low dose and
You know, if you have that in the placebo condition as well, it becomes
impractical. Yes. Scientists are not paid nearly enough to Warrant the, there's no such thing as overtime in for The Graduate students. And
postdocs, it's often. As you know, more junior members that are doing that really hard
work. It was described very well to me by a student. When I was a graduate student said, to me, they really can't afford to pay us by the hour because we used to work. He was at electrophysiologists so he would run experiments.
No joke, folks, 3 to 5-day experiments, sleeping in bouts of two hours here or there in a dark room with a bunch of equipment and recording. So these are long long acute of physiologic physiological, electrophysiological recording so yeah. No, no scientist does it for the money? I promise you that there is money in Pharma, there is not money in personal income. It's not lucrative if for the basic scientist,
So yes, LSD is what anywhere from 8 to 15 hours.
Something like this team would be a little long. You'd be bit worried. If you were still tripping at that time, maybe with a really
big text, so that's good.
But yeah. 8, h plus and dose-dependent? Yeah, if it's a bigger Des, it's a longer experience. But, you know, if you're gonna dice say, you know, 10 a.m. in the morning, which is more or less, how it often goes, then at six pm
You're feeling the effects. And then, how long do you wait now, to kind of close things out before they can go home, even with psilocybin, you have people still work into the evening, and the staff were always there later, of course, because they got a pack up. And yeah, so these are long days in it and it it's just it's too much and
they don't make sense of your practicals. Constraints, I learned from a recent guest on this podcast that we were
Word with dr. Sachin Panda, who is a colleague of mine when I was down at the Salk Institute is pioneered, a lot of the studies on so called intermittent fasting. That the reason the intermittent fact that the eating period and these studies in animals and now on humans is eight hours. This are feeding window in these days is because the graduate student was going to otherwise lose their relationship because their significant other says, listen you can be in the lab for 12 hours, that meant some hours before the experiment, then eight hours and then some hours afterward, but you
Stay in there longer and and many people use the 8 Hour feeding window as a consequence. So the science has to exist in and be carried out in real world frame. Yeah. MDMA is a little bit a little bit shorter. Right. It's about a 42. It's also about four to
six abstract kind of similar to psilocybin. Yeah, it is. And actually in the maps work they read ice after a certain point, the Boost boost have a beast are optional. Booster, ya say so, there is that and now
Plus thinking, well, even the psilocybin sessions, long and expensive. And if you have to have two staff members there all the time, that's expensive. That's where most of the expense is, is in the Staffing. So can we Bridge The Experience? Make it shorter and get away with it and get get similar kind of therapies outcome. So there's a lot of interest in that direction.
They asked about, sorry to interrupt, but I want to make sure I don't forget to ask.
About combination psilocybin and MDMA therapies. The reason I asked about this is in here, truly, not me, but I know people who do self-administered combination psilocybin and MDMA. I think I have this, right? I think it's called a hippie flip. There's another one that involves LSD to again, I'm not suggesting people do these kind of drug combinations, but the way it was described to me was that the psilocybin because it's so
Energetic sometimes can be not a downer but can have a bit of a kind of a kind of a murky. Feel to it, some real deep introspection sometimes in the the darker Realms of one's psyche, depressive thoughts Etc. Not that it necessarily stays that way throughout the trip but that the MDMA because it has a very strongly serotonergic but also dopaminergic. I mean, so it has an amphetamine component cocaine. Like in fact, if you've ever seen someone on MDMA there,
Pupils are about the size of quarters, for reason they're in, you know extremely extreme autonomic arousal compared to a sedative which by the way, would construct the pupils. So they describe the use of MDMA to kind of balance out the kind of effect component of it. What are your thoughts on combination psilocybin? MDMA does this hold any therapeutic potential? This is obviously a backyard chemistry.
In the sense that people are or, you know, kind of cowboying this stuff on their own, which again, I don't really recommend. I like to see the science go first but I understand this is how it works in the real world. Yeah what are your thoughts on combining compounds?
Yeah, well I guess the cowboying it in recreational context but also underground therapists do work with this combo.
That's what I'm referring. Yeah, I'm not talking about people partying with this stuff. I'm talking about there are
thousands now of therapists that offer psychedelic therapies illegally, really because it's not legal, at least, not in the u.s. to possess her cell, but that are doing this. Yeah. So that's really why I'm
asking ya. And, you know, I think there's something to be said, for one has to be careful with this as a scientist. But, you know, if they're doing it, are they using somekind of trial and error? The same is true. Of course, with the you no longer history of psychedelic, plant medicine, Yusuf by plants. We
Glued the fungi as well. Say in the extended sense, plants. You know, there will have been trial and error there. It might not be as systematic as the science we do today, but maybe there's been a learning process and maybe what they do, they've come to because they found it works. So, by that principle I'm interested in that combination and whether it does offer some advantages maybe in certain patients, you know, if we one of the buzz terms in medicine these
Is precision medicine, Precision medicine, and personalized medicine. So maybe there are certain cases, where, you know, introducing say psilocybin after the MDMA or the other way round, could offer some advantages and the differences are interesting. You know, psilocybin can get you to deep places maybe, you know, the colonel of your suffering and
And major life experiences complexes that are cause Ali link to whatever the pathology that you're presenting with. But it can do sometimes quite aggressively, you know, and if it's a post-traumatic stress disorder it can be overwhelming and you can fight it and really it's that it's that, you know, the resistance is really challenged and they fight
Back and the therapeutic breakthrough and the progress isn't happening because you've agitated the defense mechanisms, whereas what MDMA offers is something arguably more directionally reliable. In terms of, in terms of the valence like more directionally positive generally an MDMA
experience. Our Dev a bad time on em. Yeah. To be quite blunt, I mean, but one of the concerns I had with them.
MAA. I've never done it Recreation. I have had not and have not ever done it recreationally but when it was done in this therapeutic setting, I realized because there was a music on at the beginning, I asked, I actually asked them to turn it off because I realized that the music was becoming such an attractor to my attention that I suddenly was starting to think about music and my love of Music, which was not the focus of the session that I saw was there, you know, for and I'm glad that they did turn the music off because the moment they did I was able to draw
Been within the eye mask to this, the sort of go Inward and address some certain issues that at least to me felt key and productive. So that seems to be the kind of Hazard with MDMA, is that it's such an empath legend, that one could start to. You could go down any number of different rabbit holes.
Yeah. Yeah. But but it's also it's a strength because you well you know the classics like psilocybin can take you there very reliably but maybe a bit aggressive.
Civ Lee. MDMA makes it easier to go there and and that's its strength and that's why that marriage of MDMA therapy for PTSD. And particular is a is a good combo. It works because you are going to go there in a sense you have to, to Really make the therapeutic progress, you're going to have to go back there, but we're going to set it up so that you can go back there and feel safer and more
Saying and be able to go back there. Whereas you've never otherwise, been able to go back there without, you know, dissociating or having, you know, horrible flashbacks and so on. So, that's the strength that it offers, I guess the limitation would be that, maybe it doesn't take you as deep as the classic psychedelics and I tend to think I'm biased on this one that there's a kind of honesty to the classics in that it is. It is hell, as well as heaven.
You know, and that's the psyche, it isn't all roses,
I really appreciate that. You bring that up because I think that there's such a fear of so-called bad trips. There's such a fear in non-psychic states to, to avoid the painful and everything, everything we know from trauma and the treatment of trauma. And we've had several guests on here, my close colleague, close, close colleague at Stanford, doctor.
David Spiegel or associate chair of psychiatry's clinical hypnotist amazing, amazing. Human being in scientist and clinician is as really just, you know, like embedded this in my mind that the only way to deal with trauma is to get right up next to that trauma. To the point where some relief is experienced, there is no other real way as so, I really appreciate that. You're saying that the classic psychedelics may offer the the with a very strong nudge perhaps the opportunity to
To get into the uncomfortable in a way that MDMA or some non-classical psychedelics, perhaps do not. We were talking about time frames or duration of trips and these different compounds and how they differ and how they're similar. I'd love for you to educate me on DMT and some of the work that you're doing with DMT. My understanding is that it's a very brief trip minutes. People, I know who have done this again, therapeutically actually.
I'll just point to one very exciting, I think group and initiative which is the veteran Solutions initiative which is a group. This is the carried out in Mexico. But in conjunction with Laboratories at Stanford and elsewhere who are evaluating the neural changes and this involves ibogaine, which is iboga, which is a very long duration, psychedelic 22 hours or more followed by a I think one or two doses of DMT. This is for veterans with to deal with.
A number of issues appears to be working with great success. And I've spoken to several people have gone through this and the way that they describe DMT almost across the board, was quote here, I'm just pulling quotes, right? Anak data, the most profound experience of my entire life, even greater than the birth of my children, quote, like being attached to the shock wave of an atom bomb quote. There's no way I'm a would do another dose because
The first one was so unbelievable. Interesting. By the way, I think most of us, including me would think why wouldn't you want to do it again then but this idea that that was just beyond anything. So these are significant. Excuse me. These are significant statements coming from individuals who have existed at the extremes of Human Experience to begin with, right? These are so-called Tier 1 operators within the Special Operations who exit and may or may not have trauma, but DMT sounds like,
Big deal. Yeah, short duration, really, big deal. What do we know about its chemistry? What do we know about how? It's impacting brain networks? And what in the world is going on? That people are describing it as the ways I just mentioned a few moments
ago yes it's a it's a rocket ship if if the psilocybin is like a ship leaving port and yeah this is this is a rocket ship into craziness.
Is that I'm
58. Is it serotonin 2A?
It is. Yeah, so it is a classic psychedelic. It's a direct Agonist the direct stimulator of the serotonin 2A receptor. It's a an order of magnitude less potent than psilocybin but potencies a funny thing because dose-dependent, so that doesn't mean that the experience with DMT is less than that of psilocybin. It's just that you give more of the drug.
But has that's matched by its stickiness for the serotonin 2A receptor, which is this kind of golden rule in, in psychedelic science, is that it was discovered in the mid 1980s. This tight relationship between the Affinity or the stickiness or The Binding potential of a psychedelic for the to a receptor. In particular serotonin 2A and its potency and the sticky of the drug, the more potent. So LSD, really sticky very, very potent. You only need those tiny micro
Ram doses. So DMT by its Affinity is a little less potent, but by its effects when you give a standard dose it's just in in it's just wild and DMT because there's another compound called five methoxy DMT, which is a bit different pharmacologically and subjectively it's it. Similar, in terms of its kinetics, it's another rocket ship both compounds.
Pounds in the wild. So to speak smoked often TNT and 5m e. O, people of vaping. Both. Actually, now that there are Vape for vape pens that have been developed for people to administrate administer this but more traditionally. It's been a smoking thing. This is clinically not recreationally.
We're both obvious and now you're coming, you know, underground practitioners that using the vape pens, they like them because people titrate the dosage, they get a feel for what it is to be going into this state. So that they feel, they can let go and go into it. But and actually I think some of the veterans work might be giving five Meo after the ibogaine phenomenologically. If there's a difference between DMT and
M5 M e0 people might put it on five, Meo being more of a reliable ego, dissolution experience, less Visual and more kind of all round immersion in the greater whole loss of self identity and just in motion and everything.
Maybe we could just talk about ego dissolution for a second. She's such a sticky interesting idea. I can take a step back as a neuroscientist and, and say, oh,
Ego dissolution. This idea that the that, you know, from a very early age, we have a concept of self and that, you know, I wake up every morning and I know I'm me and not somebody else. And presumably, you do the same. In most most people do the same. I would hope but that, and that there are objects in the world and people in the world Beyond us. But every time I hear about ego dissolution, it sounds like it's a kind of a temporary elimination of the of the idea that things stop. And
Start and stop between us and everything else almost like, you know, in a kind of a here, I'm not trying to sound philosophical or metaphysical but they're sort of the molecular continuity of life, right? We're all at all just little little bits, which is true, which is true, right? Not a functional way to go through the day, right? Because you want to make a cup of coffee. You don't really want to get lost in that if your goal is to make a cup of coffee. But but you know what is
Is the what is the power of ego dissolution? Is it the idea that we believe that we like belong? Is it a sense of meaning? Is it the sense that we're not as important as we think which of course could be a wonderfully useful way to go through life you know to think that we're not as a as in like where we are vitally important but we're not the only thing right? Because I do believe connection is vital as most people do. What is ego dissolution and why would this
Serotonin 2A activation cause that, that's remarkable.
Yeah. Great questions. I mean what what is it
You alluded to it with the start-stop, I think you know because you could Define it by boundaries in a sense. What it what isn't me is as valid here is as than, you know, a developing sense of what is me that a child develops at whatever age. And so, a major characteristic of the you go dissolution experience rather than just a - the thing going away.
My sense of self going away is, is the positive? Oh, now, I feel interconnected with other people and the World At Large and I realize, you know, that there is that molecular continuity. And actually that's a ground truth and all maybe the ego thing is somewhat illusory, or at least the construction of my mind and indeed it is right. Well, it is. Yes, yeah, I mean, there's no transcendentalism about that. It's just
It's like
logic. I think we are about it a little bit like family and we all know what immediate family is, but you know, sort of like forgive me for interrupting myself. I do it all the time. Anyway, when I teach neuroanatomy, you know, some clever student always figures out. Okay, well, that's connected to that and that's kind of but ultimately everything in the brain is connected to everything else. Yeah. There's just no way around that. That's a true statement. Yeah and so you really just have to decide where you draw the boundaries between Legend truly are
Where What? Where are the modules? What are the model? You can say, the brain is just one big macro module. Yeah. And then you also want to include the body. And now, fortunately, people are starting to embrace this idea, that it's not mind body. It's both because the nervous system extends through both, of course. So as the same could be said of family, like we're related, right? Not just by virtue of the fact that we're human beings have, we did our genealogical charts? We would find a convergence at some point. Yeah. And of course, you know, this becomes
Of a game but then one realizes that where you draw the boundaries and if you draw them at brother sister parents, biological parents, Etc, that's a game too and so it is just a construct.
Yeah, I mean it is a fun game, you know, where do you draw the line? And when to pass when to collapse, it's also a classic consideration in science when to pass when number versus the splitter you can really yeah.
The u.s. is question like well why does psychedelics do it and there we think psychedelics do it because the target receptors at least, you know, classic psychedelics, do it and that's important to stress. So MDMA doesn't really do it in the same way. Might soften the ego a bit. But yeah that's
debatable. My experience with MDMA is that it's such a strong in pathogen. Yeah. And and that it can indeed cause
Empathy for others. Yeah. Certainly you could imagine situations where one in MDMA journey and afterwards says you know these these my oppressors or you know are the people that harmed me they and here I'm not referring to my experience but you know, they did the best with what they have. Actually have empathy for them. Forgiveness, but also for oneself, that there's an empathy for self. I know, I said this earlier, that is very hard for most people to access, perhaps not the narcissists out.
They're listening they'll be like of course everybody for self but everyone else I think all the other healthy people or the healthy people other than Narcissus and not picking on nurses. I have to imagine they suffer to. In fact I think that's the root of their narcissism that empathy for self is not something that comes from reflexively for most people and the here, I'm not sure about self-love or self-respect, but this notion of being able to see the self as not just deserving of
Love and care but actually holding that in place while in confrontation with something challenging in a way that allows a more not less access to Adaptive responses to that challenge. I think that's the way I kind of conceptualize
it. Yeah. Yeah. But I mean drugs offer a great, they offer great, they are great scientific tools for tackling this question. What is ego dissolution and why do drugs modulate it? And what does that tell you about the brain? You know,
Because other drugs like cocaine, releasing more of a different neurotransmitter, dopamine more than serotonin. The opposite is the case with MDMA is more of an ego. Inflator
I oh, absolutely. People become hyper linear hyper linked to their own desires and wishes and future outcomes become an obsession. It's the stuff of kind of American Psycho and the kind of clichés and stereotypes of the
80s cocaine
culture? Yeah. Yeah. We did a study once actually looking at dose dependent relationship with ego, inflation on one axis and ego dissolution on the other and saw that it just massively past or differentiated between cocaine and the psychedelics is quite a neat
study. So cocaine makes people's egos super inflated. Yeah. And so it doesn't
touch dissolution. And the opposite is the case which with psychedelics at
least into your Imaging to to
Explain how cocaine does
that? That would be a great study. Yeah, great idea. Sure do
that. I have a sabbatical coming up. I've got 12 months of sabbatical coming up. Yeah, yeah that one I'm going to show up in your lab. Yeah,
that's a really good one. If it's right to finish the thread done on why psychedelics and he go dissolution, we do know some things or you know we have some hypotheses and it's that the target receptors are serotonin. 2A. Receptor is a classic psychedelics? Hit are heavily expressed in what these days. I like to call
Recent brain because the evolutionarily its recent brain. It's cortex that humans have more than any other species. If you look at a mapping of cortical expansion from Save macaque or chimp to human, it's the very same map that you'll find the to a receptors in. So that's the target. It's and and it's just easy to think that I'll well that could be the goack brain, you know and
And the classic psychedelics come in, they kind of they scramble up the activity. That's the entropic brain action. And in terms of you know the start-stop the boundaries that entropic action sort of spreads out the system, it doesn't shut it off. It sort of spreads it out, you know, just solution. Yeah. And you know that you were talking about the head space as well so that fits if it's you know if it's more
Asia's it sort of fits the big qualifier with psychedelic therapy that people rightly bring up, is it doesn't last, that's the Paradox of it, the Paradox of ego dissolution, so that you go might go away during the trip. And you have these profound insights about the molecular continuity and how we're all one and interconnected. And then you come down and however,
Furlong later, you know the ego comes back but maybe with a Vengeance and sadly you know things can go awry when people haven't done the work. Perhaps haven't done the integration work and maybe ego defenses, come back and you know and it's not it's not a pretty picture.
How often do you see that in the trials that you do?
What percentage of the the app of people coming through? What do you think end up with worse than they were before the trial? It's very rare in the trials that we've done.
Yeah, but you see defenses, come back. So you you do see people relapse, that's more, you know, if you are pushing out to like three months plus in something like treatment-resistant depression, that's more the rule than the exception. Sadly people relapse, if their histories are, you know, histories of chronic depression, then while you might give them a window of Wellness. Sadly, it doesn't last, that's not to say that. It doesn't.
Just it does and we have people who are in our first treatment resistant, depression trial, who well to my knowledge today back at work doing fantastically well. But sadly, the majority of relapses to my
knowledge and need to do more psychedelic
Journeys. Well, they can't because it's illegal that's been the really difficult situation that we've been up against is that we do a trial where all of a sudden is schedule. 1 drug becomes a medicine in the trial or at least an experimental medicine. We give
The treatment works fantastically well gives people a remission that they've never really had for however, long and and then the trial ends and they're denied that treatment and were still, if they were to have that treatment, they would be committing a crime, it's sort of a sick joke in a way. But that's, that's a situation that we've
been here. And that's a perfect segue for what I want to talk about now, which is what is the current state of
Legality in terms of or the progression towards legality. I'd also like to touch on the role of, let's just say, incoming big Pharma. There are a lot of startup companies. Now trying to capitalize on these discoveries that you and others have made. You know, the landscape out there is very unclear to Me. Maybe I'll just call out some silos as I see them, and maybe we can draw some bridges between them if they exist.
At the ground level, not the Grass Roots, but at the ground level. I Look to Laboratories like yours. Matthew Johnson's Roland Griffiths some Laboratories at Stanford Nolan Williams, Laboratories doing studying the effects of psychedelics in human beings. So not animal models in terms of their clinical application for the treatment of depression anorexia and now, no. Fibromyalgia trauma let slump MDMA in there as well.
Assuming that it all works in an equivalent way at the level of kind of where the legislature is taking things. Okay. So Labs using government money philanthropy, Etc then there are the sort of the therapists out there that are accessing. What we believe are, clean sources of MDMA psilocybin LSD to do this. They are doing it illegally. This is in the US or other Western European countries.
Obviously it's going to differ by country who are administering, these things sort of on the basis of what they're reading in these studies that you all are publishing but also expanding on and experimenting hippie flips and combination drugs and ketamine and etcetera. But let's leave ketamine out for right now because it's legal. But there's that then there's the I don't want to say it's sort of recreational / open market black market. And here, I want to raise
A flag to the fact that dr. Peter Tia did a terrific podcast on this recently and his own podcast, the drive, the fact that fentanyl lacing with fentanyl is now showing up in MDMA and psychedelics that are purchased on the street. So serious caution to those getting it from uncertain sources and and then you've got Pharma and then as an umbrella, for all of this, you've got the FDA and law enforcement agencies, which currently say this stuff.
Is illegal unless it's being used in a clinical trial selling it? Or possessing, it can get you charged with a crime ranging from. I don't want to say, because I don't know, but I'm up to felonies, right years in prison. Okay. So
Can't take it through. Airports can't don't get caught with it. Don't buy it. Don't sell it kind of thing. So where are we going from that picture of the silos?
I know things are in, clinical trials. Now, most people including myself are not familiar with how the different phases relate to the proximity to legality. Could you just kind of give us the landscape and touch on how long you think it will be before the people that come through your trials? Could then go get a prescription for psilocybin or potentially buy it without the risk from a reliable source, when would hope? But without the risk of getting thrown in jail, I used to live in Oakland California.
Yeah, my understanding and please correct me if I'm wrong. Folks. Don't trust this information and get in trouble. My understanding is that psilocybin is decriminalized in Oakland but that's not the same as being legal. So what is going on out
there? Wow well so
much I just asked 55 questions but but but feel free to answer. Just a subset of them if you
like well Oakland's, a funny one. I live close to our Clinic. There are head shops in Oakland.
You know the might be selling cannabis and you know cannabis related paraphernalia that are selling mushrooms as well. Psilocybin mushrooms. Over fact openly
yeah that's a fact. I can I can verify that. I haven't purchased them but I've gone in and got checked it out like what's going on
here? Yeah, yeah. So you know the police aren't going to prioritize that activity the purchasing of
Those mushrooms as a crime now, in Oakland, because of the decriminalization. So those head shops shouldn't strictly be selling. Well, they shouldn't be selling, they won't have a license to be selling licenses. Don't exist yet for that here but let's see whether they get shot down, they probably will, I don't know, but there's a, there's a church, you know, in Oakland at a sort of
Say that they're selling and it's part of sort of religious rights that they're using that church model as loophole. You know, the way that Native Americans can use po2 a and they have a more genuine case, I think because there is a history there, they're trying to kind of piggyback on that the anyway that's that's sort of, you know, close to where we are right now. But federally, which is really the
Major inflection point is the FDA and the licensing of psychedelics as medicines to be legally prescribed across the country across the u.s. and beyond that is closed because the key phase there are different phases of clinical trials in the key. One to know about is phase. Three phase 3 trials are licensing. Trials if they're successful and typically have to do at least two.
Successful ones, show the results to The Regulators, who are the FDA, the medicine regulators and say, is this good enough. Now for you to give me a license so that I can sell and provide this medicine that we've demonstrated is the medicine. So that work has been done with MDMA therapy for post-traumatic stress disorder, maps have led that work and done to face three trials. I think they've already publicly announced that the second
Trial had results consistent with the first. We know the results of the first because they're published and they were remarkably good. Something like sixty, seven percent, remission
rates. And long-term my understanding is some of those remission rates for trauma or years, which is different than what you're describing for psilocybin. Where people might need ongoing dosing. That's true. Yeah, yeah. But of course, just for trauma in those trials, my understanding is those. MDMA trials were not focused on depression, yes,
Yes, focused on on the trauma. So that's something because that data is being filed. Now to my knowledge like as we speak and they're anticipating a decision, maybe this year with rollout happening as early as next year mean, that sort of best case I
think could ask you when you say roll out, who's Rowena to the appropriate term for MDMA has a so-called rolling about
Scent of my audience, maybe 50 will understand that. Not funny joke that I made who's going to roll it out? Is this, where would one get the MD at the clean source of ndma meaning not laced with fentanyl? Not laced with methamphetamine, not undergone any chemical conversion to some other drug which can happen with extended shelf-life etcetera. Are people going to go to their psychiatrist to get MDMA and who's going to be
Writing. It, is it going to be some big major Pharma the seems like a serious set of
issues? It is? And I don't have all the answers. I do know that Maps would be providing because they've done the work and they have set themselves up in a sense to potentially become the provider, whether as a Pharma company, which is the big question they're wrestling with. At the moment, it's very expensive to become a
Farmer company.
And yet they probably deserve to make the choice because they put in so many years of hard work. When all this stuff was considered, like raver culture party drug, they were the ones that spotted the therapeutic potential. The, I mean, we knew there was therapeutic potential based on work going back many decades, but points to them. And I think that I think in my opinion they should have the agency to make those decisions. Yeah,
it makes the remark such a remarkable thing that's been achieved. And I
I think they've done it all on philanthropic donations, I think so. Yeah. So there are, there is this? Yeah, big question mark in the FDA are also asking questions about to your question, you know, who can provide this. Because in the phase three work and up until this point has been a map straining, a Maps therapist trading and you have to do this formal
training in order to be a practitioner within the trials. But now there's a question from the FDA, whether that map's training could be the training that a clinician has to have to. Now be a provider. And when I say roll out, it's like offering this as a service essentially. And so where would the referral come from? That's a good question that I'm not 100% on the answer, whether it would have to come from a
tryst whether someone's General physician could do that referral, but they will be going to a provider who is licensed and certified and we'll have done some training and there will be a consensus on, you know what constitutes good enough training to provide there will also be some stipulations on the basic underlying professionalism of the clinician who
Ides. So I imagine, they'll have to be a mental health, professional? I don't think they would have to necessarily be a psychiatrist. They could be a good clinical psychologist for all the Dos. Things. I think without question there would have to be a physician present or at least within ready access in case of an
emergency. Yes, especially with MDMA because of the propensity for cardiac issues. Yeah. Because of the amphetamine properties, and where is psilocybin in terms of
Phase trials is it in Phase 2? Phase 3,
it's in Phase 3. There's psilocybin therapy work being done for treatment-resistant depression by a company called Compass those trials, which are always multi-site. So there's always a bunch of teams or labs in a sense geographically spread out that are each contributing to data, that then gets Mass together and is then submitted as part.
Out of the phase 3 trial results. So that's happening with compass right now. It's psilocybin therapy for treatment-resistant depression. Those trials have just started. And I think the earliest estimate that I heard in a, in a journalistic article was because I don't think Compass would say or they wouldn't say publicly something like 20, 26,
26, what? Wow, so MDMA is ahead of
so yeah, yeah it's good quite a few years ahead.
And it's more of a not a certainty but it's very very strong position with MDMA. Whereas The Works Only Just Begun with with psilocybin in terms of the phase 3 trials. But then you have this other situation over like however many psychedelic research centers. There are now across the globe. It was nice to you know we had the first one in London in 2019. First one in 2019 is 2023 now and I don't know how many there are
But so much has happened in such a small space of time. Yes. But you know all these different indications. I've been able to tell you about anorexia and fibromyalgia syndrome trying to do a trial with a colleague of mine at. UCSF in methamphetamine use disorder, he's got a trial going on in Parkinson's disease and chronic lower back pain and bipolar disorder. I mean, there's so much going on. I see
D, Almost the full gamut of psychiatric disorders. Not schizophrenia to, my knowledge are being looked at, so there's so much ground ground, you know, Groundswell of activity. And I think these small investigator LED studies typically, they're small because trials are expensive are going to be reporting positive results. I know what we're seeing and it will be, you know, for let's see now.
At least four trials or with really positive results in very difficult to treat disorders and that's just us. And I know there's so much elsewhere, diction disorders as well. You know, my Johnson's work, obviously, Michael Bogan shoots, so all this compelling Groundswell, it's really something and yet, you know, the system to really make a big breakthrough in terms of Licensing is, of course slow and it's sort that can frustrate people, but it
It has to.
It has to be done properly
else. We revert back to what happened in the 70s, where there was a lot of interest in psychedelics, it's kind of interesting to me, there was a close juxtaposition of meditation and kind of Behavioral approaches to US, self-directed state change and psychedelics meditation, kind of made it through the hatch. I mean there were some years where it was considered kind of counterculture. Whoo.
Ooh Magic Carpet, weirdo stuff by Western science. But now I'm in their tens of thousands. Tens of thousands is not an overstatement of quality studies exploring. How meditation can provide advantages for the mind. And even for mental health and psychedelics are now catching up, but they used to be close cousins in the, in the cultural framework. But the problem was, I think psychedelics were viewed as
Making people crazy and University professors lost their jobs for having discussions. Like the one that you and I are having right now and some people went to jail but mostly mostly people either left academic institutions or lost their jobs. Whereas now these are some of the these studies of the sort that you are doing and that are taking place at Stanford and Hopkins and elsewhere are some of the greatest magnetic pole for philanthropy for universities donors are very
Interested in supporting these sorts of studies because they and their family members and people they know suffer from Psychiatric illness for which the current big farm approaches, simply have not worked. So, it's sort of interesting to me that what once was seen as kind of poison is now being viewed as a potential therapeutic. It's not just interesting. I think it's hopefully it speaks to the
The evolution of the human species. People seem to be coming more open-minded about becoming more open-minded, that's good. Yeah, and yet
Yeah, it's there's so much that's happening so fast and as you know, there are elements of its complex. If eyeing the space. There's there is critique there's been some bad practice in psychedelic therapy. Boundary Crossing issues that have caused some scandals. That's too bad, isn't it?
Yeah, well, you know, I think to the gene therapy, right? It just takes one, bad incident, gene therapy was on a fast track, three decades ago and
Then what? Sadly child died in a gene therapy trial and it's like, shut down gene therapy, practically for half a decade, and then it slowly started ratcheting up again. Bree gene therapy, broadly defined. And now we're in the age of, you know, potential directed gene therapy using crispr, and things of that sort, which makes people some people cringe and other people very excited. You know, if you have Huntington's in your family, crispr is like the most exciting technology ever because you could potentially eliminate it from your family line.
Forward course. So I just really hope that we can be balanced as this all plays out because it could go similar way, given the stigma, given the history that people be very Twitchy with, with some isolated incidents and, you know, over-generalized them, perhaps in a sense it's shining a light on them, I think is important that that has happened recently.
Is important because it really drills home. How important it is that this work be done, right? And and what the necessary safeguards and and standards should be. Yeah, and it won't be, it won't be an easy Road for words but but let's hope you know, we got to hope that it succeeds because current treatments your people talk about the Mental Health crisis, and
To your point earlier about anorexia rates. It's not always actually the case. When you look at the epidemiology, when you look at the data that you see a big inflection in, you know, diagnosis or cases of psychiatric illness, I would say it's more that the treatments haven't moved they have really progressed and got any better since the 1950s more or less and and new drugs have been more of the same. So there haven't been any paradigm.
It's and that's why I get a little impassioned. When I talk about psychedelic therapy and that point, that this is something different. It's not, you know, a drug everyday. It that system is not cutting it, you know, do we really want to keep on with that system? Sure, you know, not, everyone will want to trip and that will terrify some people so much that they'll just want to be on their Lexapro or or a non psychedelic.
Urkel whatever. And of course it should be allowed to have those options, of course, and the more options the better, but I think there is Great Value in, really understanding what psychedelic therapy is. And and I think when you do you realize that it is a major Paradigm challenge or many levels and and the fact that it's different might be its greatest appeal at the moment. I think.
Well, I am certainly grateful for your passion for the potential for psychedelics to be added to the array of potential treatments. And I really also appreciate how much you put it in there. Alongside the other treatments maybe even combination with other treatments as opposed to saying. This is the thing that's going to cure everything and yet the passion that you have for this potential Paradigm Shift, the one that really appears to be happening at the level of clinical data. Now
Is so important. So I want to extend it voice of gratitude for that and for the work that you're doing, I mean, I've been outside of this field, but as a neuroscientist, I've been paying careful attention to it, really? For the last five seven years or so. And it's abundantly clear that it is a small group of individuals who are really thinking in terms of how the system works now, and what needs to be done in order to change the system.
The better like yourself that are really the driving force behind this new movement, or paradigm shift that without question is going to lead to improvements in mental health and physical health outcomes. So I just want to say thank you for that. Also, thank you so much for joining us today to share this immense knowledge set about the history of psychedelics. What they are, what they aren't their clinical applications as seen in your
Laboratory and other Laboratories, I'm sure people already noticed this but you're incredibly generous in terms of attribution and and also in your caution about explaining how some of the results in particular on anorexia. Fibromyalgia are perhaps preliminary, but very exciting, they're not published yet anyway. We wouldn't call them preliminary and also for touching on mechanism, that is not just about people feel better, but pointed to some potential underlying mechanisms in terms of connectivity changes and on and on,
And so thank you so much for your time today. Thank you for the work that you're doing and thank you for the work. That is sure to continue. We will provide links to studies in your laboratory links to your laboratory, so people can learn more and support in the ways that they deem appropriate for them. But just thank you. Thank you. Thank you. Such important work. You're doing Robin.
Thank you. Angie is Peanut
pleasure, thank you for joining me today for my discussion with dr. Robin, Carhart Harris. I hope you found it to be as
- about the science and clinical uses of psychedelics as I did if you'd like to learn more about dr. Carhart Harris's. Research or support that research or inquire into being a research subject. In one of his laboratory,
studies, please see the links
in the show notes. Captions in addition, please see the links to his Twitter account and other social media accounts. Also in the show, no captions. Also in the show notes, captions, you'll find a link to dr. Carhart Harris's Twitter account where he regularly posts about new advances in the field of psychedelic science. If you
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