Psychedelics, Depression, and the Brain: A Breakthrough Framework for Mental Health

31:54And that's the that's the lens that will look at the brain under the effects of 5-MeO. But it's a massive challenge because it's hard to find people who can stay still on 5-MEO. You can't find them. People call them Buddhas, Buddha sitters, because, you know, they go into this like enlightenment state and also are very still when they do it. The phenomenology, the psychological effects profile of 5-MEO seems a little extra, seems a little different to psychedelics, which are wild and weird enough, you know. um so how is that even possible that there could be anything more than say an lsd trim yeah so it's truly remarkable you know michael pollan called it the everest of psychedelics yeah others have called it you know whatever god molecule and this kind of thing the god molecule yeah the ultimate and then you know with the entropic brain principle pure theory here because we don't have much if any real quality human brain imaging data yet pure theory has led me to think that pure consciousness which is just as you were describing it you described it as pure experience white so not not not black not a blackout it's not that the lights went out all of the lights of, you know, a myriad suns, as Stan Grof described it.

33:26You know, this brilliant white light, like the light that's been described in near-death experiences, as you said. So that's at this other end of the spectrum, as I see it, you know, blackout down this end with very low entropy. And so if this white owl is up here, is it extremely high entropy? That's what I've suspected. And I don't know. I don't know yet because we don't have the data. In fact, there's some data that's come through that suggests some paradoxical quality to the activity that you also get some slow waves, which is weird. So maybe a bit like sleep, but then a bit or a lot like a psychedelic opening up and expansion.

34:13So I suspect that we're missing something at the entropic end. and this is a thing that people don't always realize that we're very much, we're liberated by the tools that we have like the first scientist Galileo using his telescope to see further but he could only see so far as well those telescopes have got a lot better since and we've been able to see further and further and further and so we should be aware that our tools right now can only allow us to see so far and seeing very fast brain activity ain't easy. It's easily confounded by muscle artifact, even things like people smiling, people laughing, moving around.

35:00It really messes up the data. I strongly suspect that there is a strong entropic component to the 5-MeO experience. And put it this way, that's kind of a big part of the quest that I'm on in studying 5-MeO is to test that hypothesis. And how do you... But I do see it's a bit...

35:21Dr. Mark Hyman:Well, how do you see it being used clinically in differentiating it from the use of psilocybin or MDMA? Is there... In other words, with all these psychopharmacological effects of these compounds, are there specific indications that are better or worse for different compounds? For example, ibogaine is being used for addiction, right? To break the cycle of addiction, which is really fascinating. but how do you see these sort of as a cocktail of new psychopharmacological compounds that aren't necessarily new, they've been around for thousands of years or hundreds of thousands of years being used in human societies?

35:56Dr. Mark Hyman:How do you see the indications being different? Well, I do have a dream, as others do, of like the doctor of the future having a briefcase that he opens it up and he's got some ketamine, some MDMA, some psilocybin and so on, some ibogaine, and he hears about the symptom profile and the history. And, you know, it's not that one drug will work always better than the other necessarily. So there's some subtlety to it. There's almost some artistry to it, I think. But let's take, for example, someone with a history of complex trauma now with a lot of emotional instability, difficult um history with relationships you know something in in that domain of what the dsm would call a borderline personality disorder should they have a big trip on lsd or could that be psychologically agitative could that even tip them over into a psychotic disorder if poorly managed and and it could um so i wonder whether you know lower doses and a longer regimen of say an experience every month or two or three over a 12 year period you know the the gold standard treatment for for borderline is a is a long psychotherapy you know a year or so of psychotherapy yeah dbt yeah yeah yeah quite so why not slot the psychedelic dosing into that approach rather than slam someone with 5meo let them meet god and expect it to be one and done yeah and everything's you know kushti now it does it's it's too simplistic it sounds a bit like what in you know spiritual circles some might call bypassing bypassing the work you know the hard work of actually oh god I have to go back there and and talk about how I was abused or or what have you I'd rather I'd rather not you know of course you'd rather not but um but maybe that is a big part of the roots sadly tragically that's feeding the way your life has been and and continues to be so it's hard work but we can't bypass it you know so um that would be one of the subtleties.

38:27But then there are others who are locked into this reinforced pattern of escape through hard drug abuse or alcoholism. They could benefit from a big reset, that factory settings reset. And I suspect that you can get there through, say, Ibogaine. It's a very long trip. it's a very much it sounds like i've never gone there myself but a thorough life review that might be a big recalibration for people you know um so that that's that computational perspective without divorcing it from a psychological one because people have the life review they they realize things that they've repressed or what have you things that they've um sort of you know not wanted to look at um shadow aspects of the psyche um yet maybe you can you can have that factory reset um effect also through a short-lived blast with 5meo that could be useful it's just difficult to know how long that window would stay open for and whether you've been guilty so to speak of some bypassing like you haven't really done the work you've bypassed levels of the psyche in a sense you bypass the personal you know what's happened in your lifetime and maybe even bypassed you know a kind of collective unconscious transpersonal with with archetypal beings and themes of human nature not just your own life and gone to something so transcendent that it's pure consciousness that's beautiful and you've realized that love is a fundamental and so on yet there's been some bypassing there and in time as you return to normal waking consciousness you haven't kind of massaged away those those knots that came about because of, you know, adverse life experiences.

40:34And sadly, whether it's your past or the nature of the sort of matrix of your current life circumstances, things will conspire to pull you back. Yeah. And we shouldn't be so naive and idealistic to think that a one-and-done model is going to be super beneficial in the long term.

40:55Dr. Mark Hyman:So essentially it's combining, and this is how it's being developed, and the FDA now in an attempt to approve MDMA therapy, is psychedelic-assisted therapy. So it's not just the psychedelic, but it's combined with therapy to help integrate or process the emotions to sort of make it stick a little bit better. And so it seems like, you know, there's different use applications for different things. Like, you know, everything from very severe mental illness and complex PTSD to, you know, treatment, reasons of depression, all the way on the other end of the spectrum to cognitive enhancement and spiritual development.

41:34Dr. Mark Hyman:So you've got this whole spectrum of use of these compounds from people who are really struggling and sick and suffering to people who just want to kind of reach a different level of awareness or consciousness or spiritual development. So I find that fascinating because there's very few things in medicine like that where you have a use case that's quite broad. Isn't it? Isn't it? It's almost the full spectrum. I guess, where is it not? And there's a question mark over schizophrenia, for example. It's not clear to me that that would be, certainly would it be easy and would it be sufficiently beneficial over risky?

42:16And it's a tough call, that one. Maybe delusional disorder.

42:20Dr. Mark Hyman:Yeah, because you've got brain disorders that are more medical. I would say schizophrenia, autism, these are encephalopathies. They're metabolic encephalopathies of the brain, and they are now being treated with mitochondrial therapies, such as ketogenic diet or mitochondrial interventions, such as supplements, like Suzanne Goh, who's been on the podcast, talked about with autism, where she sees on fMRI scans, basically an energy deficit. And we're seeing bipolar disease, schizophrenia, and severe mental illness being treated with ketogenic diets, which also do similar things such at Mayo and many other places.

42:58Dr. Mark Hyman:You know, what's interesting about things like depression or trauma or PTSD or anxiety is that they're often a combination of both structural issues that are in terms of brain, how the brain's operating, but also have sort of been developed as a result of life experiences and traumas. So they're not necessarily just purely a sort of metabolic problem. Like I don't think schizophrenia or autism is because you had trauma or had some terrible life experience. These are brain disorders that are more sort of fixed in their pathobiology. But when you've got something like depression or anxiety or PTSD, even in addiction, these are things that kind of rise out of life experience.

43:38Dr. Mark Hyman:And then the brain is changed in some way. And these psychedelics seem to unlock the brain from its rigid, stuck patterns in beliefs and allows then sort of the ability to start to process things where talk therapy or psychoanalysis maybe hasn't been effective or even drug therapy with like SSRIs and other psychiatric medication. You know, just to healthily play devil's advocate, you know, I wouldn't be too absolutist about even schizophrenia and autism in saying that there couldn't in the pathogenesis of those disorders have been certain styles of life experience that contributed. There's a thing that can happen in medicine that you'll be super aware of that you can have these explanations of convenience almost that, oh, okay, phew, it's nothing to do with parenting, say.

44:35And good, good, we can put it all on the genetics, say. But genetic explanations of mental illness over time and in recent years in particular have been found to be so fallible to lack specificity. And sure, there's a genetic contribution to autism and schizophrenia in particular. But schizophrenia, even it lacks specificity and smudges into other diagnostic categories. degrees you know most schizophrenia is a preceded by mood disorder depression anxiety so it ain't so clean-cut and that that's one thing that we've realized in in psychiatry that there's so much overlap you know it's it's like biopsychosocial problems requiring biopsychosocial solutions and you even in the domain of say schizophrenia if we go to bio uh we might we might not necessarily be treating then the whole of the picture it's so hard of course you know classically to to come at schizophrenia with psychological intervention but but people are doing that in sophisticated interesting novel ways through things like avatar therapy you know where through computer animation you can create an avatar an image an animated image of of the voice the persecutory voice tormenting voice and and then work in dialogue to to sort of um change your relationship with this persecuting voice yeah almost to make peace with it so that it it starts to quieten down so there could be clever ways to combine you know biopsychosocial and treating even things that on the face of it look especially one way so multimodal treatments you can't just do one approach.

46:29Dr. Mark Hyman:I think that's fascinating. You're probably right about that. You know, what's so fascinating to me, though, is this incredible revolution we're seeing in psychiatry from two different angles. One is this whole metabolic theory of psychiatry that has to do with brain energy deficits that lead to various psychiatric states that are often related to our highly processed, high-sugar, starch diet. It causes basically a metabolic dysfunction, just like diabetes. And we're seeing this in everything from Alzheimer's, but also in common mental illnesses like schizophrenia, bipolar disease, even depression.

47:08Dr. Mark Hyman:And at the same time, we're seeing this like a psychedelic revolution, which is sort of another angle of approaching it. So you've got like psychedelics, and you've got dietary interventions and mitochondrial interventions, both sort of emerging as a sort of a paradigm shift in psychiatry. So it seems like we're at an inflection point in psychiatry where, all the old ideas of mental illness are sort of falling away, and we're now having to think differently about how to approach these problems, which, like I said at the beginning, are among the most sort of prevalent and disabling conditions that humanity suffers from today, and for which we have really lousy treatments.

47:47Dr. Mark Hyman:So to me, it's a very exciting time. I wrote a book, I don't know if you know Robin, about 15 plus years ago, called The Ultra Mind Solution, about how to fix your broken brain by fixing your body first. In other words, there was the mind-body effect, but there was also the body-mind effect. So if you had microbiome issues or immune issues or inflammation or mitochondrial dysfunction, these can all manifest as psychiatric problems or as problems of attention or memory. I just think we're just at this exciting moment. What I kind of want to sort of ask a little bit more about is some of the clinical applications of these things.

48:25Dr. Mark Hyman:And you've done some interventional trials, for example, a psilocybin and depression. It was published in JAMA and also Lancet. And you've really shown how these treatments can be very effective when often traditional psychiatric medicine can't and have long-lasting effects. So I'd love you to talk about sort of how you think about these things being applied at scale in the population in terms of psychiatric medicine. I guess mechanistic approaches has led me along. You know, that's the greatest mystery, I feel the phenomenology of everything, mental health, psychedelic experiences that has been so well characterized, that's been done to death, you might say, whereas the black box that we're still in the dark about and are only sort of feeling sort of certain shapes now and getting some handle on things.

49:18is the biology of it all really. And just like, you know, say germ theory and how that revolutionized medicine and longevity and so on. Once we better understand mechanisms, it's so empowering. I don't think the penny drops for people so easily around mechanisms. You know, I've heard people in the psychedelic space say, oh, we know it works, or we just need to show the man, you know, the regulators that it works because we know it works and i kind of get that but it's very naive and and it's very preaching to the choir because there's a world out there that doesn't get this and is actually very suspicious of it so to to demonstrate how it works is very important and powerful on an epistemic level on understanding this this thing but also on a practical level because only by understanding how it works do you shed light on the actual nature of the problem that you're now solving and how to solve it better.

50:25So it's a very powerful perspective once you realize its importance. Yeah, so I do very much like that. You can go in either direction, top-down, mind-to-body or bottom-up, body to mind and and the power of being open to both and harnessing both could very much be the

50:54Dr. Mark Hyman:the way of the future so so in terms of the applications you know in your work around you know different mental health issues you know the way i i see these and maybe i'm just sort of naive about it is they seem to work better for things like depression anxiety trauma um but maybe not so well for things like you know personality disorders or do they work in bipolar situations and i i'm curious about what what the best applications for these are i think your intuition intuition's right um the only caveat is that but those things are also easier to treat with other treatments, sure, they're not that good.

51:31So SSRIs is the path we could, the thing we could unpack here. You know, though, I had a strong feeling we did a trial, as you said, with the treatment resistant depression, that was the first depression trial of this current era, this psychedelic, psychedelic renaissance, as people describe it, that really, you know, got a got a snowball going and we did that small trial it ended up being 20 people and saw really promising results but we also learned a hell of a lot about the challenges so some people it was a beautiful recovery you know they look like a different person afterwards and i've i stayed in touch with a few of them and they're still well they've never relapsed and this is gosh this is 10 years on yeah one of them our first patient lovely lady sort of taken on a world of burden, social worker, living in London and, you know, just tough life circumstances and so on, and had developed depression very early on into middle-aged.

52:36And she had been on, I don't know how many antidepressants, but, you know, so many, let's say seven. Some people have tried 14 in that trial. And this got her well, and she's still well. I caught up with her recently. It's beautiful. So it can turn things around. But those are the best cases. But in that trial, we also saw more complex, complicated cases. And I think when those people came along, there was more going on than just a depression. There always is. But there was complex trauma histories. There were other diagnoses that could come in like autism, spectrum disorder and bipolar, well, rather borderline personality disorder so i think your intuition's right that it's harder to treat that complexity but the caveat being it's harder to treat full stop so can psychedelics be effective but done in a different way you know in those those early trials and still in a lot of trials it it's it's almost a one and done approach meaning it's only one or two treatment sessions and the strong One impression I've got and others too is that that's not enough for the complexity and actually a broader, and that's why I brought up borderline earlier, you know, a broader therapeutic period of time is required to really, you know, work on those complexities that are in these people.

54:02Dr. Mark Hyman:So more treatments and maybe higher doses or different doses? Yeah, more treatments, not necessarily higher doses. I don't think we need to go to more drug for that complexity necessarily. I wouldn't rule it out either. But funnily enough, a longer, a more generous amount of psychotherapy. I know that's expensive and almost a luxury in the modern healthcare system. But they're very unstable. And the complexity for me says there's psychological complexity. This ain't going to be easy. yeah, let's not be too naive and idealistic that we could turn it around with a quick fix. So that's basically what I mean with those more complex cases.

54:47But I still think psychedelics could be helpful. There's just some more finesses required in that treatment.

54:54Dr. Mark Hyman:I mean, personality disorders are interesting because they're the thing when I was in medical school, you were taught that these are just intractable and they don't change. The joke was that if you have an anxiety or sort of neurotic disorder, you drive yourself crazy and think the rest of the world is fine. But with a personality disorder, you think you're fine and you drive everybody else crazy. And so there's little insight. And so it's hard. Those are treatment-resistant problems. And yet they're pretty prevalent. And the question, what are the origin of these? Are they trauma? Can they be treated with some of these compounds?

55:31Dr. Mark Hyman:I don't know if anybody's looking at that. But I think it's an interesting area where there's narcissistic personality or borderline. They are looking at it. I'll bring in something that I haven't so far and it's important, which is, and we've alluded to it, which is, yes, this is psychedelic assisted therapy. So this isn't just giving a drug. This is providing some kind of psychological supportive container. And we have these components set, setting. Set is your mindset, your expectations, your psychology that you bring to the experience. listen And then setting is the environment, all the environmental factors.

56:08Back in the 60s, I believe it was, a psychologist, Betty Eisner, brought in a third component, which she called matrix, the psychosocial matrix. So setting you might think of as the environment in which you have the experience, the trip. There's music listening. You have ideally two people looking after you in that setting. And things are decorated in a particular way. And there might be a sort of ritual ceremonial-esque feel even in the trials, you know. And I think that's okay. And that's how it's been done for generations. I don't think we should worry too much about that. That might be part of how we can learn from tradition to benefit, you know, progression in the future.

56:58But that's setting. And so the matrix is is sort of the complex psychosocial, you know, life circumstances, you know, it takes some homeless person, it's going to be hard to, to get one and done success with psychedelic therapy when they have to go back to, you know, the tenderloin in San Francisco, right back to the streets. yeah if you're homeless yeah that's that's naive thinking isn't it so yeah i mean there's this other component around what could be done um even if it's sort of a triaging like okay so could we not do this because the matrix is so bad that feels really tragic or is there a way of doing some kind of group work where there's and now it's getting idealistic but is there a way to work on that very negative matrix too in these treatments.

57:50Dr. Mark Hyman:Yeah, I think Paul Farmer calls that structural violence, the social, political, and economic conditions that drive disease, right? So if you're living on the homeless district in San Francisco and the Tenderloin, which you're talking about, it's hard to kind of go think about having a psychedelic experience and then going back and living on the street and being okay. And that's it, you know, that's what this biopsychosocial model gives us is a fuller, it's a more comprehensive look at the problem and um it's because for many i i believe if we're honest and accurate there's a realization that that's because all of this stuff matters and contributes and and and it would be too naive and simplistic to think it could be just all biology say um and that'll solve the problem you know and maybe what's dominated psychiatry since the 50s 60s 70s has been you know the drug revolution in psychiatry and chronic medication whether that's with antidepressants or mood stabilizers it's a way of treating that is about mollifying symptom severity taking the edge off my feeling was that psychedelic therapy is radically different yeah it's this more holistic treatment approach that recognizes the different ways that the illness expresses and and is caused and and therefore will treat it as such you know so treating all the the different elements recognizing all the different elements the biopsychosocial spiritual but ss rise is different it ain't that typically it's doctor prescribes you your esotelopram and your your lexacro and off you go with your prescription to um cvs or what have you and you pick it up and that's the system and well that was quick that was easy and that's my treatment for depression and then you go back home and okay it's taking the edge off life feels a little easier but um I have no sex life now or um life's also a little depleted somehow I'm not really feeling it so much when I listen to this music or what have you so you know actually a psychiatrist colleague of mine who was open about his own depression and medication for it said that he said oh i'm a classic responder to ssri's um but for me i'd have to live uh three years to get one well you know it's like life the dog's experience yeah yeah yeah he's he's open to psychedelic therapy as well um but uh it's interesting so these are different approaches They're different models that work in different ways, and one is one of symptom mollification through a biocentric approach developed, inspired mostly by animal research.

1:00:39Dr. Mark Hyman:But it doesn't really work that well. I mean, when you look at the response rates to SSRIs across depression, it's pretty shitty. I mean, they do work for some people, but for the majority, it's marginal. Barely 50%. Yeah. Yeah, barely 50 % response. And then the response that you get, is it really a good and full response? Are you really living again? Are you really flourishing? I don't know. I don't know. And then the other side effects. So psychedelics, you know, it's a different approach. It requires a bit of courage, actually, you know, or a lot of courage. It's like, oh, you know, we're going to have to go to some dark stuff, potentially.

1:01:20Yeah. That ain't easy. and all this weird, you know, for a naive person who doesn't know psychedelics, this all sounds horribly scary, like, oh, God, I got to go through some kind of hell. When it's told right, which I often like to do, I don't want to dress it up that this is, you know, a one way ticket to meeting God and spiritual enlightenment. Sure, that can happen. But sometimes it can be really hellish, it can be horrible for people and judgments impaired and if people aren't being looked after that could be dangerous for them so there's very much a way to do this and a way to hold it and let's be honest about human nature and the psyche that when you release the unconscious it ain't all light you know yeah it's just as much shadow as light but it seems when you're

1:02:10Dr. Mark Hyman:in those experiences you're much able better able to hold the darkness in other words whatever you're reliving or experiencing, your brain is in this state where you're able to tolerate reliving or experiencing or thinking about it in ways that can release some of that trauma. To be honest, Mark, I'd say it depends. It depends. If you're held well by the certain setting, then yes. It's like - You can have a bad trip too, right? You can look at anything. Yeah, you can look at your abuser and they manifest as a devil figure. you can do that because i'm holding you and you can almost make peace well let's say make peace with this thing that has tormented you for the rest of your life and that's that's the beauty that's the magic but if that happens and you're out at burning man and all of a sudden you're having an experience like that i mean it could go well you know but it might not yeah and so So it's very intentional the way we do this work.

1:03:14And hopefully people are hearing and realizing that it's really a world away from going off to CVS and getting your Lexapro prescription. And the mechanism is different as well. The Lexapro release serotonin, sort of bathe the brain in more serotonin, which helps you get by. It takes the edge off stress. It's like incubating against stress and those slings and arrows. But what psychedelics do is actually a more direct stimulation of a certain aspect of the serotonin system, promoting plasticity. It's definitely psychological plasticity and probably neuroplasticity, too. And saying it that way might be a little enlightening for people because they might think, oh, the neuroplasticity thing, that's a done deal, right?

1:04:05well in mice but human evidence of neuroplasticity it ain't really there yet you know we're working

1:04:16Dr. Mark Hyman:on it we'll have some brain imaging markers of it quite soon yeah but the whole story is based on work in in little mice brains and and not much else to be honest well that's the bit of your work you know using functional MRIs for those who don't know what they are they're they're not just looking at the structure of your brain, they're looking at the function in a dynamic way where you're looking at different metabolic pathways, different neurotransmitter functions, inflammation, lots of things you can detect that you wouldn't see just looking at a structural image. It's fixed. And that's where you're seeing a dynamic picture of brain function.

1:04:51Dr. Mark Hyman:And I think some of the data is showing that some of these compounds like psilocybin increase various trophic factors for the brain like BDNF or brain-derived neurotrophic factor that helps to sort of increase brain connections and sort of neuroplasticity. So I think there's some of that data that looks pretty promising. And I think Paul Stamets is talking about its use in things like Alzheimer's and Parkinson's, where there's sort of a decreased connectivity in the brain and helping enhance that connectivity. I just want to be careful to manage expectations is all, because most of, as you say, most of the data in humans is fMRI.

1:05:25It's functional. It's brain activity, not structure. we've yet to see really clearly i've got a paper under review it's been under review for about two and a half years it's ridiculous really held up in the review process who knows what was going on there but at least it's it's available in pre-print people can look it up on bioarchive leon's l-y-o-n-s et al is and there we show through diffusion tensor imaging looking at the white matter tracks of the brain that there are some changes after a single dose of psilocybin so let's see if that replicates of course but it's a super exciting finding prefrontal tracks changed so we we shall see the bdnf yeah you can pick it up peripherally in the blood and and see it go up um so there's a lot of indirect stuff could it treat alzheimer's parkinson's well There's a trial at UCSF looking at psilocybin for Parkinson's.

1:06:26It's just been published, actually. Ellen Bradley, Josh Woolley, and colleagues. Really good work, really promising. It was a simple design, open label, so there's no placebo control. So we need to be careful at this stage about extrapolating too much. They did see improvements even in motor symptoms. But like I said, let's be careful because placebos are - Spoken like a true scientist.

1:06:51Dr. Mark Hyman:and all the caveats yeah yeah it's still such a new field so we're still learning about all the applications and the different properties that has and alzheimer's yeah alzheimer's you know people will there's been a little bit of work people can't remember their trip they can't remember the experience and so it hasn't worked that well so far yeah yeah it's kind of tragic but maybe there's a way to treat alzheimer's earlier on that's more preventative and prophylactic yeah so um never say never and it's it's certainly sufficiently promising enough that we should be doing that work and and you know a lot of the things i've seen on that too has been around microdosing what's your perspective on microdosing these compounds versus therapeutic dosing it's a great theory and in principle i can get it that a little dose of a psychedelic could give you some of the benefit like lubrication you know loosening the cogs giving you a bit of that freedom a bit of that plasticity that ability to change whether it's neuroplasticity or not at least plasticity the ability to change um uh without necessarily you know the heaven and hell blood and guts of a full-on psychedelic trip um and maybe if you do that you know a few times a week and twin it with good lifestyle and and and i don't know spiritual practice or some psychotherapy that could be that could catalyze those other things and it could be very good for you so i love the theory um and i think it could be i think there's probably something to it and the caveat here that i've got to do because because i have to be evidence-led is that the evidence today is a little underwhelming for microdosing and part of the issue is that the trials have been um limited really they there haven't been many and when they've been done um they haven't often dosed for long enough in my view i'm not sure that they've um necessarily had the right yeah protocols of twinning the microdosing with something i still believe that there's a synergy just like there is with higher doses psychedelic assisted therapy there's there's a synergy between the drug and the way it's taken and the context in which it's taken and i think it would be a little surprising to think that you can bypass that even with these lower doses i still think context matters so that's been missing from the trials the placebo effect as we say it's it's a potent thing so it's hard to beat placebo in these trials when they're not long enough so i tend to think in time it will probably come through and it will be a thing i don't think it's as easy to demonstrate its its efficacy um a lot of people are using it just for sort of performance enhancement and you know just creativity and yeah that's interesting so yeah like getting out of their head so to speak you know what one application a novel one is like a golfer imagine a golfer you know all this this these lessons that they've had oh i've got to do this with my swing i can't do that and all this on you know i can't do this and all these doubts uh and the yips over a putt you know all this heady stuff yeah well if you could get get all of that crap away yeah and and get into the body and get into a more like easy breezy flow state then uh so that's a that's a novel application for improving golf or tennis i like that wow well just make sure you keep the dose low i want to make sure we cover you know some of the concerns about risk because i think you know there's this great heady sort of renaissance going on now where there's a lot of promise a lot of hope for a lot of treatment resistant conditions as we talked about depression and you know more severe things like PTSD or complex PTSD.

1:10:50Dr. Mark Hyman:And yet there are risks and there are concerns about, you know, who this could be applied to, what are the dangers? Are there people who should be worried about it? Because I imagine a lot of people listening have somebody they know or themselves who've struggled with mental illness and they're thinking, well, how could this apply? And should I explore this? And, you know, what are the sort of caveats you'd have around its application in terms of the risk profile? Yeah. You know, even when we're doing this conversation and I've emphasized context and setting setting and this is psychedelic assisted therapy and and not just the drug you know you'd be surprised how many people go away from a conversation like this and think i just need to get myself a load of mushroom and it will treat my depression and uh and then they have a hellish time or they do it without someone looking after them and they injure themselves and sadly those tragedies have happened and they happen and um and they often happen to young people as well so it's a real thing the risk is real impaired judgment is a major one you're tripping balls and you're tripping on your own i don't know you injure yourself you think you can fly that people think that's an urban myth it's not entirely you know there have been a number of cases of people either falling or jumping from height or thinking they can swim and going into the sea, thinking they can breathe underwater, you know, this impaired judgment, it's a real thing.

1:12:15You know, it might sound like always having to say this because he's a professional scientist. But no, I truly believe it. Like you need to trip under guidance, especially if you're a young person or someone naive to psychedelics, you've really got to have that sober sitter and do it the proper way. Otherwise, the risks are a real thing. I mean, you don't literally transcend this bag of bones and go off to some uh you know that that thing's still there it's just yeah yeah profoundly altered uh brain function and mind function yeah impaired judgment is a major risk um also psychological vulnerability psychiatric vulnerability yeah could you make things worse i have a lot of people heard about you could make things worse Yeah, it could be, you know, the fancy term iatrogenesis that you are doing harm.

1:13:08You're actually, rather than improving health, you're worsening it. And that can happen because you're opening a can of worms. You know, someone does have a recollection of some awful trauma that they've experienced that they've buried down. And they don't have the right professional trained person to help them through that. and then so things go wrong and they've been really destabilized it might not be as black and white as that they might just have had a really big trip and now just don't know what's real anymore and they start to doubt reality like that that was an airline pilot to try to you know down the the the aircraft because he'd had a big mushroom trip recently and was doubting reality wow so that kind of dissociation derealization that's scary i don't want my pilot it's scary as hell you know and so let's get real about psychedelic this is a it's a thing and so it needs to be held and the right kind of education needs to come in around the integration process the landing um sort of relevant in that context uh you know to ground people on terra firma and and get get bring them back to earth after they've they feel like they've transcended this earth and gone to some you know celestial other realm um they still got to pick up the kids from school you know and and do the dishes and so on when you think about how these

1:14:38Dr. Mark Hyman:compounds have been used throughout human history they're always been in the context of the right set and setting you know and usually in some kind of initiation rites or in some type of therapeutic sense for dealing with soul illness or dealing with various conditions, but you don't ever see this being used sort of recreationally, like in these traditional cultures. You know, they have, you know, very, very rigid, in some ways, structures for experiencing these things, whether it's ayahuasca or, you know, traditional shamans with psilocybin or peyote. There's rituals that go along with this that provide the context, that provide a framework, that provide a sort of cultural and social support to kind of have this crazy wild experiences that people are having.

1:15:23Dr. Mark Hyman:But to me, I think, you know, we can get that right. I think, you know, it's going to take some work, but it seems like that's an important caveat here is that, you know, if you're thinking about this, make sure you're going to do it in the right way with the right person who's had experience. And right now it's not legal. So, you know, it's underground, but there's a whole underground movement of this and therapists who are doing this kind of waiting for it to become legalized. It's massive. Yeah, what are you most excited about next in your research around psychedelics? What do you think is the next frontier?

1:15:55Dr. Mark Hyman:Where are you focused? What's happening in the field that you want to preview for us? Well, there's so much, it's hard to pick one thing. I could go to, you know, adolescent mood disorder, depression, we want to do a trial there. I strongly suspect that we could do better than SSRIs for young people and wonder whether psilocybin therapy could be that better if done well. It's one thing, the 5-MeO work, pushing the frontiers of consciousness science. We're doing a set and setting study to test the assumed synergy between drug and set and setting. So set and setting should really matter under drug versus under placebo.

1:16:36So we're doing that work. And another study that we're doing, which we're close to completing, is a deep dive into the psychedelic experience with a sort of machine learning approach, an AI-esque approach. AI machine learning rests on depth of data. That's the parlor trick in a sense. The seeming incredible intelligence, impressive intelligence is because of a ridiculous amount of training. It rests on the data, deep, big, big data.

1:17:12Dr. Mark Hyman:And how are you using that in psychedelic research? theoretically you could you could draw from deep data from other states and then see how the psychedelic matches into that what we've tried to do which is sort of ridiculously ambitious in a sense is to get the deep data ourselves by giving people psychedelics four times and scanning their brains for a total of 15 hours in this study i mean yeah 12 of which are while tripping wow so most of it isn't and so we're we're getting the data to do the training and the data actually derives from the psychedelic you know keep it simple stupid kind of approach okay so it is really ambitious because we're trying to essentially predict the nature of someone's trip from their brain activity if i break it down that's kind of what it is it's sort of you know mind reading where the mind reading is reading what you're tripping so in the future we might be able to do that in a in quite an interesting way sort of even predicting some of the minutiae of of the content of the trip say a dmt trip but at this point we're just trying to predict whether and how intensely someone's having any psychological insight whether they're feeling good or bad and uh whether they're resisting the experience or letting go to the experience so Is that through AI you're looking at that?

1:18:41Yeah, it's the basic mechanism of AI, which is through collecting the deep data to then train an algorithm to predict based on what it knows about a mapping between this in the brain, this in experience. If we see this in the brain, we can predict this in experience. That's the trick. It's called decoding. It's been done for a while in human neuroscience. People have used that approach. People like Jack Gallant at UC Berkeley have used that approach to predict what people are viewing in terms of movie watching, what people are listening to in terms of audio scripts. Others have done things like what people are dreaming, which is amazing, what people are imagining.

1:19:34um so there's some really cool applications of that approach and our way of coming at this is trying to predict what people are tripping albeit in this very rudimentary way to begin with and and

1:19:46Dr. Mark Hyman:you think that'll give you insights about who to use this on how it works sort of how to apply it more broadly you know it's a bit like the entropic brain principle what i'm realizing is that you could use this biomarker and this might sound very biocentric here but like let's not you know diminish the importance of biology it's still bottom line and it gives us power really the biology power to to manipulate that in a positive way we may well find that there is a sweet spot of brain entropy that people need to be at for them to be sufficiently plastic to change their abnormal unhealthy habits of their beliefs, for example.

1:20:34And so based on some readout, seeing the level of entropy, we could dial or even titrate dosage to hit that sweet spot. And so with the machine learning approach, we might see we can extend on that principle and see, for example, if I see this thing in the brain like less prefrontal cortex engagement, I can feel pretty good that this person is letting go to the experience. They're not pushing back and resisting the experience. Ideally, I mean, we're not there yet, but I could see something like that in real time or some proxy of it, some other indirect measure of it. And therefore, you know, without talking critically, I think this is the key thing that I'm not explaining yet, but without intervening and talking to the individual and disrupting their trip, I can have that information and then tailor my treatment based on that special information that I'm getting.

1:21:43Dr. Mark Hyman:It's like personalizing the therapy based on what's happening in the brain and how they're responding to the treatment. And that's fascinating. Yeah. You could do that ahead of time. You know, you could pick your drug like we were talking about with a briefcase of options, but you could also do it more directly in real time, you know, tailoring things based on what you're seeing without necessarily checking in. I mean, you can check in, too, and talk to them, but people often can't talk when they're under the influence, and they also can't easily articulate what's going on. No, it's profound. I mean, I remember being 18 and eating a load of mushrooms and just like reality never looked the same.

1:22:22Dr. Mark Hyman:It really reset a lot of things in my way of looking at the world, experiencing the world, and made me realize that the kind of the rigid ways that I was experiencing life was only one filter and that I put on basically a new set of glasses and could see the world in a different way. And it just changed how I interacted with my own experience personally. psychologically, spiritually, how I saw myself in the world, how I saw the world. And I sort of, you know, there's so much hope and promise for these compounds that have been around forever. Some of them are new. Obviously, like MDMA that's developed by Merck as a drug.

1:23:01Dr. Mark Hyman:I'm sort of wondering, from your perspective and the lens you're seeing the future, you know, five years from now, where do you think this field is going to be? Do you think this is going to become more part of standard psychiatric treatments because there's so much there's so much suffering and pain and there's so little hope for so many of these people is you know are we going to get to a place where we actually have effective treatments and they can be applied widely across the population yes um you know it's a balance of hope qualified by not um by managing expectation and not falling into a trap of like a toxic positivity like yeah it's gonna happen it's gonna be fantastic and it's gonna happen and it's gonna be complicated but like on on balance it's gonna be good and it's gonna be an improvement but they'll still be sadly there'll be tragedies there'll be bad practice and so we need to get that right and mitigate those those risks so i I do think it will happen five years.

1:24:04Psilocybin assisted therapy or psilocybin therapy will be a licensed medicine for depression. I'm pretty confident about that. MDMA might have got through for veteran PTSD, for example. Within five years, I'd feel pretty confident psilocybin will be through on a federal level as a licensed medicine. And then on a state level, you have something like the cannabis legal cannabis model where certain states are legalizing. At the moment, we have in Oregon and also Colorado's opening up adult assisted magic mushroom experiences, essentially. And I think it's close to 10 ,000 people, if not more, have gone through that.

1:24:52It's a big data set. It is, isn't it? and they're not collecting enough data. Hopefully we're going to try and change that. We're doing a survey. So watch this space on that and others too. But yeah, people could check out my lab website to see that because I should be advertising it because it depends on that. You know, we need to put it out there so that people do that. We need to collect those data. You know, it's a public health reason why we need to collect those data. know whether this is safe enough and beneficial.

1:25:27Dr. Mark Hyman:Well, this is really helpful. Mental health has been such a problem throughout human history and we've had really very crappy treatments and we have different theories but it seems like a quantum jump. Both the metabolic psychiatry field, nutritional psychiatry and psychedelic psychiatry seem like they're cracking open our old ideas and providing new pathways for people to explore around getting relief from really intractable problems that create so much human suffering i think so i'd be interested how what you think of this sort of comparison but you know germ theory when when did that come around 18 something or other middle of the 19th century and and then it was only really after that that lifespan i know there are a few factors you know better dissemination of knowledge but lifespan And longevity is going up quite reliably.

1:26:18And so, you know, medicine couldn't treat sickness well enough for a long time because it didn't understand it well enough, didn't understand its mechanism. Now into the 21st century, a quarter of the way in, we're still not treating mental illness well enough, arguably because we don't understand how it's caused well enough. But I feel confident that that's going to change within this century, and it's probably going to change quite soon.

1:26:47Dr. Mark Hyman:Yeah, it's an exciting moment. I remember being in medical school and residency and spending a month in a psychiatric hospital, not as a patient, but as a student. And I was just so distraught at the failure, just sort of the abject failure of our current model and how much we were just sort of drugging, literally drugging people into stupors to manage their psychiatric illness without real relief or benefit. And to me, this is such a hopeful time, and your work has been such a key catalyst in this, especially understanding the mechanistic changes happening in the brain, and understanding there's something there there, I know, as opposed to just some squishies, have a great trip and have a psychedelic experience and see God, and then your life's different.

1:27:38Dr. Mark Hyman:But you're actually trying to understand what's happening in the brain, and that's gonna teach us a lot about how we need to think about these compounds and how we can apply them across the different mental health challenges and how we need to think about, you know, integrating this into psychiatric care, into our mental health model, which really, you know, it's so, you know, it's so far from this right now in practice, right? And yet, you know, things accelerate pretty quickly. So, you know, nobody was washing their hands in medicine and before surgery until suddenly they did after 50 years of people saying, hey, this is a good idea.

1:28:13Dr. Mark Hyman:So I think we're maybe in that moment. And it's very encouraging to me because when I wrote my book on sort of the brain and both mental illness and both attention and memory disorders, I was, sort of my joke was I called myself the accidental psychiatrist because I was seeing that there were pathways to treat mental illness that I wasn't learning about in medical school or in my training that were real. And it was almost accidentally that I found these things. And sort of like you hear the story about the Ibogaine discovery. It was sort of an accident. There was an addict. It was a narcotic addict who took it and his cravings went away.

1:28:49Dr. Mark Hyman:So it was like those kinds of experiences are quite changing, you know, change the culture. They change our practice. So I think, I just want to thank you for your work and all you do. You know, we still have a lot to learn and that's clear from how you told the story. It's like we're basically at the beginning of this journey, but hopefully it's going to unlock a lot of insights that help relieve human suffering because at the end of the day, that's what it's all about. I know people can learn more about your work. Then go to your website, carhartharrislab.com and follow you on social media and different places.

1:29:24Dr. Mark Hyman:We'll put all the links in the show notes to follow Robin and track his work. And I continue to kind of follow what you're doing and very, very excited about next steps and where we're going with all this. But I love the idea of five years from now being approved therapy for various kinds of mental health disorders that really are treatment resistant. Well, I'd be surprised if I got that wrong. So let's see. But thanks, Mark. It's been a real pleasure. Really good to talk to you. I was looking forward to it and really enjoyed doing it with you. No, thanks, Robin. Hope I see you in person sometime soon and go follow your work and everybody keep track of this because this is a field that's going to, I think, make a huge impact in suffering and humanity, which, you know, there's very few things that come along like this, I think, that hold the promise that this does to really crack open an ossified field that has not really done very well for humanity.

1:30:17Dr. Mark Hyman:So, thank you. Thank you. Thank you. My fingers are crossed. If you love this podcast, please share it with someone else you think would also enjoy it. You can find me on all social media channels at Dr. Mark Hyman. Please reach out. I'd love to hear your comments and questions. Don't forget to rate, review and subscribe to The Dr. Hyman Show wherever you get your podcasts. And don't forget to check out my YouTube channel at Dr. Mark Hyman for video versions of this podcast and more. Thank you so much again for tuning in. We'll see you next time on The Dr. Hyman Show. This podcast is separate from my clinical practice at the Ultra Wellness Center, my work at Cleveland Clinic, and Function Health, where I am Chief Medical Officer.

1:30:53Dr. Mark Hyman:This podcast represents my opinions and my guests' opinions. Neither myself nor the podcast endorses the views or statements of my guests. This podcast is for educational purposes only and is not a substitute for professional care by a doctor or other qualified medical professional. This podcast is provided with the understanding that it does not constitute medical or other professional advice or services. If you're looking for help in your journey, please seek out a qualified medical practitioner. And if you're looking for a functional medicine practitioner, visit my clinic, the Ultra Wellness Center at ultrawellnesscenter.com and request to become a patient.

1:31:26Dr. Mark Hyman:It's important to have someone in your corner who is a trained, licensed healthcare practitioner and can help you make changes, especially when it comes to your health. This podcast is free as part of my mission to bring practical ways of improving health to the public. So I'd like to express gratitude to sponsors that made today's podcast possible. Thanks so much again for listening.