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

Mark Hyman, MD

Full Transcript

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Dr. Mark Hyman
This seems like a quantum jump, both the metabolic psychiatry and psychedelic psychiatry.

Dr. Robin Carhart-Harris
I do see it as like a system reset and then back to sort of default function. The idea is that we become injured by life, adversity, trauma, get reinforced in a particular way, perhaps for defensive reasons. But I think there's something to it. I don't think it's all of it, but I do think it's a shake up, a recalibration of the parameters, if you will. Robin Carhart Harris is a neuroscientist.

Dr. Mark Hyman
And leading researcher in psychedelic therapy known for his groundbreaking studies

Dr. Robin Carhart-Harris
on psilocybin and mental health.

Dr. Mark Hyman
What we're finding with these compounds is one, two, three sessions seems to do the trick.

Dr. Robin Carhart-Harris
Our first patient had been on I don't know how many antidepressants and this got her well and she's still well. So it can turn things around.

Dr. Mark Hyman
It seem like they're sort of cracking open on pathways for people to explore around getting relief from really intractable problems that create so much human suffering. Before we jump into today's episode, I wanna share a few ways you can go deeper on your health journey. While I wish I could work with everyone one on one, there just isn't enough time in the day, so I built several tools to help you take control of your health. If you're looking for guidance, education, and community, check out my private membership, the HymanHive, for live q and a's, exclusive content, and direct connection. For real time lab testing and personalized insights into your biology, visit Function Health.

You can also explore my curated doctor trusted supplements and health products at doctorhyman.com. And if you prefer to listen without any breaks, don't forget you can enjoy every episode of this podcast ad free with Hyman Plus. Just open Apple Podcasts and tap try free to start your seven day free trial. So Robin, you know, your work has been really revolutionary in the whole field of psychedelic medicine. Even saying psychedelic medicine is kind of a bit of a heresy.

And, and yet, here we are. Like, I think Michael Pollan wrote his book, How to Change Your Mind in 2018, and that set off this whole conversation in our culture around psychedelics and their impact on mental health, on performance enhancement, neuroplasticity, and the treatment of really treatment resistant conditions in medicine, like PTSD, depression, sometimes more serious conditions. And your work has really pioneered a lot of the mechanistic understanding of how these things work in the brain, which is something that a lot of people really have not focused on. They focus on does does it it work clinically, what's the benefit, but how does this actually changing your brain to actually have these impacts as something that I think no one's really taken a deep look at, except, you know, your work has really pioneered that. So I'm very excited to talk to you about this whole field because, you know, we've really failed in so many ways in psychiatry to deal with some intractable problems.

Mental health crisis is huge. Depression is, you know, the biggest source of disability and loss of quality of life years and cost to society. It causes so much unnecessary suffering and we've really had very poor modalities for treating it. And a lot of the SSRIs and antidepressant medications, psychiatric meds don't work that well. They don't work for a lot of people.

They often have side effects and they're often things you have to take for life but don't really cause true remission. They might mitigate symptoms. And here we're talking about a medicine that people are researching like you that has the potential to really interrupt this whole cycle of chronic mental illness and get people free by changing the structure and function of the brain in ways that we never have seen possible before. And it's it's interesting because these compounds have been used, you know, throughout human evolution for I don't know how many thousands or even hundreds of thousands of years when the first person came upon a psychedelic who was a hunter gatherer way back when. And and now we're, introducing these into medicine, which was haven't been quite approved for for, use as a a pharmacotherapy with the FDA, but it's coming.

It's coming soon. So what I I'd love to start out with is is asking you how how did you get into this whole field and what what pulled you into the whole field of neuroscience and psychedelics and the intersection of those two things?

Dr. Robin Carhart-Harris
Sure. Well, these days I tend to give the honest and sort of transparent answer, which is that it did start.

Dr. Mark Hyman
Because you went to a party, and you had a great experience.

Dr. Robin Carhart-Harris
There you go. Well, funnily enough, yes, I took some LSD. It was psychedelic use. It was LSD, and I was very young. I was in my teens.

I was curious. I just, you know, had heard things and wanted to know for myself. So that experience opened my mind as the cliche goes, but that is what happened. And then over the years, I was drawn to psychology and depth psychology in particular. So psychoanalysis, psychodynamic psychology, school or perspective of psychology that recognizes that the mind is more than the conscious mind, that there's an unconscious domain or realm in a sense that the mind is far deeper than we realize through the vantage of normal waking consciousness.

And so that was the discipline that I I was schooled in. During studying psychoanalysis, I discovered that psychedelics had been used in psychotherapy as tools to catalyze and deepen psychotherapy. And that was done in in the mid twentieth century, and it was a big thing for a while. You know, big names like Ethel Kennedy and Cary Grant had had this this, therapy and and seemingly had been benefited from it. And so when I found that and I had had my own psychedelic experiences, a light bulb went off, and I thought, oh my goodness.

You know? This psychoanalysis thing, I was loving it, but it felt somewhat more like an art than a science. And, being quite practically minded, I wanted some tools to to, you know, better in a sense the science of of the mind and you might say the science of psychoanalysis even. And so I thought, wow. This is an opportunity.

And through that, I reached out to people who I hoped could enable a path towards studying psychedelics, and I was lucky in reaching out to the right people. A guy called David Nutt, who some will have heard of. He's the former chief scientific adviser to the UK government on drug policy, so called drugs are. Been running something called drug science ever since. So generally a drugs expert, and he opened the door for me.

I managed to do a PhD with him. Another important person in this story is Amanda Fielding of the Beckley Foundation. She provided support, brought in funding as well for the work. So we we went down a track of doing a series of what became a series of brain imaging studies with different psychedelic drugs.

Dr. Mark Hyman
Yeah. I mean, this is really an interesting point because, you know, most most of your background was in, basically traditional psychoanalysis and also in psychopharmacology. The joke in medicine is that neurologists pay no attention to the mind and psychiatrists pay no attention to the brain. And he said like, well, why don't we look at the brain and see what's happening in here? And why are we seeing these state changes for people that have profound sort of longitudinal impacts in relieving suffering from mental illness, what's actually happening in the brain.

And I think that's kind of a revolutionary idea because really nobody's really looked at the function structure of the brain and how it's impacting mental health. And, you know, like, what are the biomarkers of of psychiatric illness? We don't really have them. We have this classification system, which is a DSM five or diagnostic and statistical manual number five that categorizes people based on their symptoms and to groups of diagnoses like depression or anxiety or bipolar or schizophrenia, and there's subcategories of each one. It gets very granular, but it doesn't tell you anything about the mechanism or what's happening in the brain or the cause.

And and, you know, I think what's fascinating to me about psychedelic medicine is that you're beginning to look at the brain. And and your your work starts to look at functional MRI imaging, EEGs, changes in in brain states. And I think I'd love to sort of talk to you about how do you think about these things in the context of mental health and in terms of the psychedelic experience and the intersection of psychedelic drugs or medicines and these physiological measurable changes in the brain and then the consequential benefits that people see, of depression or PTSD or suffering. I'd love to unpack that a little bit for us because it's it's something that

Dr. Robin Carhart-Harris
Of course. Yeah. Well, part of why I've been looking forward to this conversation is that I I suspect we might align to some extent on our perspectives here because, yeah, I have that background in-depth psychology, so that's all sort of mind stuff. Dare I say it, soul stuff. You know, psyche Yeah.

Translate most literally as soul. So it's the whole of of the mind. And, yet, I also was schooled in in basic neuroscience and and neuropsychopharmacology. So I tend to see this thing that we're looking at as having two faces, like the two sides of a coin. I also quite like the analogy from physics of wave particle duality that something can exist in in two ways based on an observer.

Really, it's it's us coming in and taking a look at it and then, you know, say a a wave collapses to a particle and we see it as particle because of us coming in and measuring it. It's a little bit like that, I think, with mind and brain. We could look at the mind side and take a good look and write many books about it and and stroke our beards and so on. Or we can look through the metaphorical telescope of brain imaging and look at this biological phenomenon and its dynamics. And the two are entangled, you know, again, a sort of a term from physics, quantum physics.

And I I think there's there's something to that view, and and that's that's how I go about my work. It's like a a Libra, like a scale with a equal balance of of the mind and soul stuff and the biology. And I've come to the view as I I know others have too that perhaps our our failings over the decades and longer in mental health care has come about through being too locked into a particular prism or perspective. For example, you know, for a good fifty years plus, biocentrism has dominated psychiatry. We have heads of of the, you know, major funding bodies saying, these aren't, you know, mind disorders.

They're brain disorders.

Dr. Mark Hyman
Mhmm.

Dr. Robin Carhart-Harris
And it's almost like a dictat. You know? You're you're sort of being told to think of it that way, but is it the truth? You know? Or or would it be healthy to think of these disorders as as existing and expressing, yes, in the biological domain, but also the psychological and the social, and dare I say it, the spiritual too.

Could we think of causation along those tracks as well? Could we get insight from one particular tract while acknowledging that the other the other tracks or tracks, they don't then go into nonexistence. They're always entangled. You know? So think, for example, about a placebo.

You have a you might have a psychological response to a placebo, say it's given for pain, and you experience some pain relief. And then we know in in neuroscience that that process has a biological counterpart even though the mechanism on the face of it looks psychological. So these things are always entangled. I think there's something healthy about, you know, holding these things in balance and and not getting too locked into any particular perspective.

Dr. Mark Hyman
Yeah. I mean, it's it's fascinating because, you know, when you think about the history of these compounds throughout human evolution, they've been usually delivered in the context of a spiritual framework. So whether it's

Dr. Robin Carhart-Harris
Yeah.

Dr. Mark Hyman
Medicine men, you know, with peyote in in Native American tradition or the shamans of South America with Ayahuasca or, you know, the Yaqui Indians with maybe toad medicine or different things that that they've done. So I think there's a really interesting kind of context with these evolved from, which is to create a spiritual experience that allows you to evolve as a human being. And what I I find really fascinating is, I'm sure you know this book by, Daniel Goldman and and, Richard Davidson called Altered States where they took lifetime meditators, you know, guys who've been in a cave in Tibet for forty years meditating for tens of thousands of hours. They brought him to The United States. They put him in functional MRI machines, and they saw that their their function in their brain was different, that that that their things like the default mode network were suppressed, which is this area of the brain that identifies yourself as the ego separate, different.

Then it's depressed. It makes you feel connected with everything, one with everything. And, and it's very similar to what happens with psychedelics. And this is a lot of what your work has found is that these kinds of brain correlates of spiritual experiences are there. And and it's kind of like a shortcut to kind of instead of spending forty years in a cave meditating, you kinda get to have a glimpse of what it's like to see reality in a different way.

And you you have this really interesting theory, this entropic theory of of of the brain and how these psychedelic medicines disorganize our thinking that's often rigid or fixed that keeps us in our perspective and our suffering and our particular worldview. And it kind of breaks that open and allows you to have a different view of things. So so would you talk more about some of the the things that happen in the brain as a result of of these these psychedelic treatments?

Dr. Robin Carhart-Harris
You know, it was funny comparing notes with the the Buddhist, so to speak. Yeah. Seeing so many parallels. It's something that often comes up in the psychedelic domain that that there are parallels with, say, Buddhist insights and methods, of course, meditation being a classic one. And and, yes, talking to neuroscientists doing work on the neuroscience of meditation and seeing similar things, dips in default mode network activity, for example, as people get out of their self, their ego tunnel, and and into something broader.

So that was cool to see that, you know, that in our blobs on brains, the images that we get from our fMRI scanning and such like, we were seeing the same thing, you know, these blue blobs in in regions of the default mode network and so on. Over time, you know, that perspective personally, I would say matured into this entropic brain hypothesis. I'd I'd be more daring and call it an entropic brain principle now, because it seems so well supported. It's a principle that describes the neural correlates of phenomenal consciousness, what it is like to be in any state of being, a state of consciousness. At one far end, the the end of low entropy, the lights go out.

Sort of literally, there's nothing there. You're knocked out with an anesthetic. You're in deep sleep. You've suffered a brain injury. You're in a coma.

There's no content. And if you look at ongoing brain activity, it's very uneventful. It's very predictable. It's very low entropy. And if you are lucky enough to say, you know, come out of a disorder of consciousness or you wake up from your deep sleep or you recover from your anesthetic, the entropy comes back and brain activity is much more rangeful, much more diverse, much less predictable, and that corresponds to this increase in entropy.

So we knew that for a few years, but what psychedelic research did was to show that you can dial that entropy even higher. And, that was another light bulb moment for me. We first saw it around 2017. We published on it with LSD, psilocybin, and also ketamine in a psychedelic like dosage, saw brain entropy dial up under all of those compounds. And with it, people's conscious experience, the subjective experience was deeper, richer, more diverse, more changeable.

So for me, that was like a moment, a a kind of moment of, oh, there's a mapping here. There's a mapping, and it's a really simple one, you know, between, in a sense, more bits, and I say that intentionally, more bits going on in brain, more bits in conscious experience. And and that that's the gist of the entropic brain principle.

Dr. Mark Hyman
Interesting. So if you're, you know, if you're looking at these states, you know, as sort of a more more freedom and flexibility in a sense in brain function in the way entropic means disorganized or coming apart. Right? And and and yet there's a freedom in that that allows you to get liberated from these rigid structured patterns of thinking and feeling and emoting that are that are often at the root of a lot of the mental illness suffering that people have. So at the other end of the spectrum is is mental illness and that that actually is often less less entropy and and less flexibility and less ability to sort of see things in a different way.

I mean, so so is what you're saying that these these compounds actually allow you to see the same life you're having but through a different lens.

Dr. Robin Carhart-Harris
There's something that I think is direct and very functional, like computational that is the drug, you know, causing this scrambling like effect. And when I was saying, yes, you know, comparing notes with the the meditation researchers and seeing the same blue blobs in the same regions of the brain and meditation in the psychedelic state got us excited, but then things matured on into the syntropic brain principle. There, the maturation in a sense was a realization that it's a change in the quality and the quantity, but the quality of activity with the psychedelic in the direction of this entropic spectrum, higher entropy, and you could sort of glibly describe that as a scrambling scrambling up. And so, sure, it looks like a drop of activity in the default mode network, for example, or another region, but it's actually a dysregulation. So it's a subtle difference, but these days, I do like to to say it because it's more accurate that it's not that we shut off the default mode network.

That's a popular, in a sense, myth that people like. And you can get away with it, but it's not really true. You know? You're not turning it off. You're scrambling it up.

And in scrambling it up and and I say it that way because it's still very active. It's just the activity is irregular now. It was it was regular in normal waking consciousness, and that that regularity of rhythms in the brain is really what characterizes the structure and functioning of of normal waking consciousness, and that structure is breaking down under the psychedelic. So, yes, it gives us it gives us freedom because in normal waking consciousness, there are constraints.

Dr. Mark Hyman
Mhmm.

Dr. Robin Carhart-Harris
And much of what normal waking consciousness is and the way the brain is governing it involves constraint, involves a kind of data compression. It's like chunking. You know? Chunking information into broad chunks, like the gist of things, like seeing the the whole of a forest rather than individual trees. We do that all the time.

It's kinda gestalt, you know, seeing the the whole rather than the individual parts. We're doing that all the time. We're doing it right now with the language that that we're using, you know, metaphor and so on, just chunking stuff up, this data data compression. And the entropic brain effect is a data decompression. All those bits now, you know, that literally relate to the increase in entropy are being sort of unpacked from this otherwise sort of zipped up, you know, style of functioning in normal waking consciousness.

So it's like, you know, an unzipping of what's all this information? And and that does breed freedom freedom of mind. And a really exciting development that I've realized only in in recent years is that I I strongly suspect that there's a formal relationship between entropy, brain entropy, brain and mind entropy, I would say, and brain and mind plasticity. Mhmm. Plasticity, people should know, isn't necessarily neuroplasticity.

We tend to think of it that way. Neuroplasticity has a great seductive appeal. It's a great brand in a sense. Oh, psychedelics promote neuroplasticity. They've gotta be good.

Right. You know? That's really the way it goes. But people should know that psychedelic promote plasticity. Let's lop off the neuro for a bit.

What does plasticity mean? It means the property the property of changeability or malleability, the ability to be shaped or molded. So that's a very basic thing. That could apply to all sorts of things.

Dr. Mark Hyman
And why is that good

Dr. Robin Carhart-Harris
in biology?

Dr. Mark Hyman
And why is that good in mental illness?

Dr. Robin Carhart-Harris
Because we get stuck. Just as you were alluding to, we get stuck in reinforced ways of feeling, thinking, behaving, and that characterizes not all of mental illness, but most of it. It's the principal component of mental illness getting stuck in these reinforced ways of being. Why do we do it? That's another question.

I strongly suspect we do it because it's defensive, because it's a way to get by. Rather than swimming in a horrible state of suffering all the time, at least we've got our whatever, you know, crack pipe or escape into delusion or, you know, caloric control that gives me a sense of controlling my body and my feelings and anorexia. You know? So much of mental illness, I believe, and I think others suspect it too, is this is this reinforcement is getting stuck in ruts. I call it canalization, which funnily enough, formerly is the inverse of plasticity.

Plasticity is changeability, canalization formally means an inability to change.

Dr. Mark Hyman
Well, that's fascinating because if, you know, what what's really remarkable to me with these compounds that are being used, whether it's MDMA or psilocybin or LSD or ibogaine, is normally in medicine, you have a chronic condition like depression or PTSD. You need to take chronic medications. And what we're finding with these compounds is, you know, one, two, three sessions seems to do the trick. And it doesn't quite make sense because how does the effect last, right? It's not like the drug is still in your system or the compound is still in your system.

How do you see these persistent benefits with only episodic short term use rather than pharmacological solutions to psychiatric illness, which are chronic lifelong mitigations?

Dr. Robin Carhart-Harris
Well, I know it's a very computational way to put it, but I I do see it as like a system reset, you know, and then back to sort of default function. And so the idea is that through the, you know, slings and arrows of outrageous fortune, we become injured by life, adversity, trauma, get reinforced in a particular way, perhaps for defensive reasons, likely for defensive reasons. And so it's not the the default function anymore. You know? This system looks atypical.

And to wider society, this looks atypical. You know? Alcoholism or hard drug abuse or starving oneself in anorexia. That that doesn't look normal. That doesn't look healthy.

So what do you do with that? And it seems very simplistic, very computational, but I think there's something to it. I don't think it's all of it, but I do think it's a it's a shakeup. It it's a it's a system reset, a recalibration of the parameters if you want.

Dr. Mark Hyman
I mean, is it is it the insights that people have while they're on them, or is it something about the compounds and how they affect the structure and function of the brain?

Dr. Robin Carhart-Harris
It's both because the insights and the quality of the experience seem to matter. So if we go by data and evidence, which we should, then the trip itself seems to matter. Some people have been debating that recently, but we should be data led. It sometimes surprises me that they're more willing to look at mouse data than human data, but human data says the experience matters. I think they do that because they're mouse researchers, they can't hear about the experience of the of the mouse.

But that's the limitation. You know? But in in our species, in the species that we're trying to treat, we have that, you know, privilege, and and people report on their experiences. They they rate them. They rate different dimensions of their experiences, and we find that that a couple of dimensions I'll highlight.

One, yes, it's psychological insight, very strong predictor of therapeutic outcomes downstream. The other one is emotional release. It's strong emotion. What what is that? What's that look like?

Well, often it looks like people crying. Yeah. It's a cathartic a cathartic release. And maybe people can join the dots there and think about depth psychology, and catharsis was a strong aspect of of depth psychology and thinking about how psychoanalysis as a psychotherapeutic modality can work. There there's repression, and then there's a it could be a in psychoanalysis in the talking cure process that can if you're lucky over the years, there can be a strong release of emotion, and and that can be therapeutic, and that was noticed by Freud and others.

But with psychedelics, you know, that ability to release pent up repressed feeling emotion is is very much catalyzed. It's really a key part of the secret sauce there. So, yeah, sure, I I characterize things in this very computational way, a system reset, but that's not all of it. You know? People aren't offline.

It's not like ECT. It's not like shock therapy. It's not like you just, you know, scramble people up that way. The scrambling up has an experience to it and a very rich experience, and you're online. You know?

You're you're in this waking dream. Mhmm. And so you can remember it. You can tell it back. And and what is that?

What does that look like? Well, if you look at all the different dimensions, emotional release, psychological insight, and also a spiritual component as well is really, you know, the core factors that seem to be seem to be the vehicles that that carry people towards therapeutic outcome.

Dr. Mark Hyman
Well, that that sort of interesting way of reframing, you know, medicine, which is very mechanistic. Right? You're talking about, yes, there are mechanisms and things we're seeing in the structure and function of the brain. We're seeing this sort of disorganization that allows you to be free from rigid patterns of thought and feeling and emotion and kind of reset the brain into its original factory settings. But you're also talking about a deeper, kind of more mushy area, which is sort of the soul consciousness spiritual experiences, which these tend to invoke.

And, you know, I think, you know, one of the things that you're studying is is five MEO DMT, which is dimethyltryptamine, is a compound that's found in nature in the Sonoran Desert toad. It's very short lived. And I've done it once. It was quite remarkable. And I I imagine you've done it as well.

And it was unlike anything I've ever experienced, but it was very short experience, but you you had this sense of pure just pure experience with no no thing in it. It was just pure light and white and blissful and almost like you were dead, but you're alive. It was almost like when you hear those stories of people having these blissful experiences of, you know, going through that white tunnel as they die and then having this sort of a blissful peaceful experience. I mean, that is sort of what it is. And I know when you're born and when you die, you have a release of DMT in your brain that is normally there in small amounts.

So I I I'm I'm curious about this particular compound and how how you see it differently or similarly to things like psilocybin or MDMA and what you're finding with this particular compound, which I think you're using in different studies now.

Dr. Robin Carhart-Harris
Well, I'd love to. We've got a a grant application in with NIMH, so fingers crossed there. And it would be a brain imaging study combining EEG and fMRI. So looking at brain waves with the kind of swimming cap EEG device, electrical activity oscillating across time. And with fMRI, we get a very granular, fine grained spatial resolution.

So those in combination are very complementary, and and that's the that's the lens that will look at, the brain under the effects of five MeO. But it's a massive challenge because it's hard to find people who can stay still on five MEO. You can't find them. People call them Buddhas, Buddha sitters because it's you know, it's they they go into this, like, enlightenment state and, obviously, are very still when they do it. The phenomenology, the psychological effects profile of five MEO seems a little extra, seems a little different to psychedelics which are wild and weird enough.

You know? So how is that even possible that that there could be anything more than, say, an LSD trip? Yeah. So it's truly remarkable. You know, Michael Pollan called it the Everest of psychedelics.

Yeah. Others have called it, you know, whatever.

Dr. Mark Hyman
The god molecule.

Dr. Robin Carhart-Harris
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 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 Groff described Yeah. 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 of the spectrum, I as I see it. You know? Blackout down this end with very low entropy. And so if this white tau 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 a bit like sleep, but then a bit or a lot like a psychedelic opening up and expansion. So I suspect that we're missing something at the entropic end, and 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, you know, the first scientist, Galileo, using his telescope to see further. Mhmm.

But he could only see so far as well. You know? Those telescopes have got a lot better since.

Dr. Mark Hyman
Yeah.

Dr. Robin Carhart-Harris
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 and seeing very fast brain activity ain't easy. You know? It's it's easily confounded by, like, muscle artifact, even things like people smiling, people laughing, moving around. It it really messes up the data.

I strongly suspect that there is a strong entropic component to the five MEO experience. And put it this way, that's kind of a a big part of the quest that I'm on in studying five MEO is to test that hypothesis.

Dr. Mark Hyman
And then how do you

Dr. Robin Carhart-Harris
But I do see it's a bit

Dr. Mark Hyman
Well, how do how do you see it being used clinically in in in differentiating it from the use of psilocybin or MDMA? Is there there is that in other words, with all these psycho pharmacological 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. How how do you see these sort of as a cocktail of of of new psycho pharmacological compounds that aren't necessarily new. They've been around for of years or hundreds of thousands of years being used in in human human societies.

How do how do you, you know, see the indications being different?

Dr. Robin Carhart-Harris
Well, do have a dream as 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 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 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 agitated? Could that even tip them over into a psychotic disorder if poorly managed? And and it could. So I wonder whether, you know, lower doses and a longer regimen of, say, an experience every month or two or three over a twelve 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.

Dr. Mark Hyman
Yeah. DBT.

Dr. Robin Carhart-Harris
Yeah. Yeah. Yeah. Quite. So why not slot the psychedelic dosing into that approach rather than slam someone with five MEO?

Let them meet God and expect it to be one and done. Yeah. And everything's, you know, cushty now. It does it's it's too simplistic. It sounds a bit like what in, you know, spiritual circles, some might call bypassing.

Mhmm. 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 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 that would be one of the subtleties. But then there are others who are, you know, locked into this reinforced pattern of escape through hard drug abuse or alcoholism, they could benefit from from a big reset, you know, that factory settings reset.

And I 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 a thorough life review. That might be a big recalibration for people. You know?

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 sort of, you know, not wanted to look at, shadow aspects of the psyche. Yeah. Maybe you can you can have that factory reset effect also through a short lived blast with five MEO. 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 of some bypassing. Like, you haven't really done the work. You 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.

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

Dr. Mark Hyman
So essentially, it's combining, and this is how it's being in the FDA now, in an attempt to improve MDMA therapy is psychedelic assisted therapy. So it's 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, you know, cognitive enhancement and spiritual, you know, sort of development. Right?

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 wanna kind of reach a a different level of awareness or consciousness or spiritual development. So I I find that fascinating because there's very few things in medicine like that where you you have a, you know, a a use case that's quite broad.

Dr. Robin Carhart-Harris
Isn't it? Isn't it? It's almost the full spectrum. I 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 wouldn't be easy and and would it be sufficiently, you know, beneficial over over risky. And and it's it's a tough call, that one.

Dr. Mark Hyman
Well, it's

Dr. Robin Carhart-Harris
Maybe delusional disorder.

Dr. Mark Hyman
Yeah. Because, you know, you've got you've got brain disorders that that are, you know, more medical. I would say schizophrenia, autism, these are encephalopathies. They're metabolic encephalopathies of the brain, and and they they are now being treated with mitochondrial therapies such as ketogenic diet or mitochondrial interventions such as supplements. Like Susan Go, 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, also do similar things such as Mayo and many other places. You know, what's interesting about things like depression or trauma or PTSD or anxiety is that they're 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 trauma. So they're not necessarily just purely a sort of metabolic problem. Like, don't think schizophrenia or autism is because you had trauma or had some terrible life experience. These are these are brain disorders that are more sort of fixed in their in their in their pathobiology.

But but you've got something like depression or anxiety or PTSD. Even addiction, these are things that kind of rise out of life experience and then the brain has changed in some way. And these psychedelics seem to unlock the brain from its rigid, stuck patterns in beliefs and allows them to have the ability to start to process things where talk therapy or psychoanalysis maybe hasn't been effective. Or even drug therapy with SSRIs and other psychiatric medication.

Dr. Robin Carhart-Harris
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 that there 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. You know?

And good. Good. You know, we can put it all on the genetics, say. But genetic explanations of of mental illness of over time and in recent years in particular have been found to be so fallible Yeah. To to lack specificity.

And, sure, there's there's a genetic contribution to autism and schizophrenia in particular, but for schizophrenia, even it lacks specificity and smudges into other diagnostic categories. You know, most schizophrenias are 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 even in the domain of, say, schizophrenia, if we go to bio, we might we might not necessarily be 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 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 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.

Dr. Mark Hyman
Multimodal treatments. We can't just do one approach. I think that's fascinating. You're probably right about that. You know, what's 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 or 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. And at the same time we're seeing this psych the psychedelic revolution, which is, sort of another angle of approaching it. So you've got like psychedelics and you've got, you know, dietary interventions and mitochondrial interventions both sort of emerging as a sort of a paradigm shift in psychiatry.

So it seems like we're in an inflection point in psychiatry where all the old ideas of, you know, mental illness are sort of falling away and we're we're now having to think differently about how to approach these problems which, you know, like I said at the beginning, are among the the most sort of prevalent and disabling conditions that humanity suffers from today and for which we have really lousy treatments. Yeah. To me it's just a very exciting time. I I wrote a book, don't if you know Robin, about fifteen plus years ago called The Ultramind Solution about how to fix your broken brain by fixing your body first. In other words, that there was the mind body effect, but there was also the body mind effect.

So if you had Yeah. Microbiome issues or immune issues or inflammation or mitochondrial dysfunction or these can all manifest as psychiatric problems or as problems of of, attention or memory. I just think we're in this exciting moment. What I what I kind of, wanted to ask a little bit more about is is some of the clinical applications of these things. And you've done some interventional trials, for example, psilocybin and depression 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.

Dr. Robin Carhart-Harris
I guess, mechanistic approach 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 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 is the biology of it all really. And just like, you know, say, germ theory and how that revolutionized medicine and 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 Yeah. The regulators that it works because we know it works. Yeah.

And I kinda 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. To so to to demonstrate how it works is very important and powerful on a epistemic level on understanding this this thing, but also on a practical level because only by understanding, you know, how it works do you shed light on the actual nature of the problem that that you're now solving and how to solve it better. You know? So it's a very powerful perspective once once once you realize its importance. Yeah.

So I I do very much like that. You know, you can you can go in either direction, top down, mind to body, or or bottom up, body to mind. And and the power of being open to both and harnessing both could very much be the the way of the future.

Dr. Mark Hyman
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. I said, though, they they seem to work better for things like depression, anxiety, trauma, but maybe not so well for things like, you know, personality disorders or do they work in bipolar situations. And I'm curious about what what the best applications for these are.

Dr. Robin Carhart-Harris
I think your intuition's right. The only caveat is that that those things are also easier to treat with other treatments. Sure, they're not that good. So SSRIs is is the the path we could the thing we could unpack here. You know, though, I had a strong feeling.

We we did a trial, as you said, with 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.

Dr. Mark Hyman
Mhmm.

Dr. Robin Carhart-Harris
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 ten 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 and, you know, just tough life circumstances and so on and had developed depression very early on into middle aged, and 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 in that trial. And this got her well, 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 the depression. There always is, but but there was, you know, 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 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 that are that are in these people.

Dr. Mark Hyman
So so more more treatments and maybe higher doses or different doses?

Dr. Robin Carhart-Harris
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, longer a longer and more generous amount of psychotherapy.

I know that's expensive and and almost a luxury in in the modern health care system, but that they're very unstable. And and the complexity for me says there's psychological complexity. This ain't gonna be easy. Yeah. Don't 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 with those more complex cases. But I still think psychedelics could be helpful. There's just some more finesse is required in that treatment.

Dr. Mark Hyman
I mean, personality disorders are interesting because they're they're you know, they're the thing when I was in medical school, you you were taught that these are just intractable and they they don't change. And the joke was that, you know, if you have a, you know, 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 it's hard. These are those are treatment resistant problems.

And yet they're pretty prevalent. And I the question, know, what are the origin of these? Are they trauma? Can they be can they be treated with some of these compounds? I don't know if anybody's looking at that, but I think it's interesting area where this narcissistic personality

Dr. Robin Carhart-Harris
is borderline. I'll bring in something that I haven't so far, and it's important, which is 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

Dr. Mark Hyman
Mhmm.

Dr. Robin Carhart-Harris
Setting. Set is your mindset, your expectations, your psychology that you bring to the experience. And then setting is the environment, all the environmental factors. Back in the sixties, I believe it was a psychologist, Betty Eisner brought in a third component, which she called mate 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 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. But that setting and so the matrix is is sort of the complex psychosocial, you know, life circumstances. You know? It takes some a homeless person, it's gonna 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 or,

Dr. Mark Hyman
you know Right.

Dr. Robin Carhart-Harris
Back to the streets.

Dr. Mark Hyman
Yeah. If you're homeless.

Dr. Robin Carhart-Harris
Yeah. That's that's naive thinking, isn't it? So, yeah, I mean, there's this other component around what could be done. We even if it's sort of a triaging, like, okay. So could we not do this because their matrix is so bad?

That's 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 that very negative matrix too in these treatments.

Dr. Mark Hyman
Yeah. 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 in the Tenderloin, which you're talking about, it's hard to kinda go think about having a psychedelic experience and then going back and living on the street and being okay.

Dr. Robin Carhart-Harris
And that's it, you know, that's that's what this biopsychosocial model gives us is a fuller, it's a more comprehensive look at the problem. And 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.

Dr. Mark Hyman
And and

Dr. Robin Carhart-Harris
and it would be too naive and simplistic to think it could be just all biology, say. Yeah. And that'll solve the problem. You know? And maybe what's dominated psychiatry since the fifties, sixties, seventies has been, you know, the drug revolution in psychiatry and chronic medication, whether that's with antidepressants 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 SSRIs is different. It it it ain't that. Typically, it's doctor prescribes you your escitalopram and your your Lexapro, and off you go with your prescription to CVS or what have you, and 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.

Dr. Mark Hyman
And

Dr. Robin Carhart-Harris
then you go back home and, okay, it's taking the edge off. Life feels a little easier, but I have no sex life now or 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, 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 SSRIs. But for me, I'd have to live three years to get one.

Well, you know, it's like life

Dr. Mark Hyman
experience. Yeah.

Dr. Robin Carhart-Harris
Yeah. And he's he's open to psychedelic therapy as well, but it's interesting. So these are different approaches. They're different models that work in different ways, and one is a a one of symptom modification through a biocentric approach developed, inspired mostly by animal research.

Dr. 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 it's pretty pretty shitty. I mean, they really they do work for some people, but but for the majority, it's

Dr. Robin Carhart-Harris
it's marginal. Percent. Yeah. Yeah. Yeah.

Barely fifty percent response. And then the 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 gonna have to go to some dark stuff potentially.

Yeah. 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 gotta go through some kind of hell. When it's told right, which I often like to do, I don't wanna 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 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.

Dr. Mark Hyman
But it seems when you're in those experiences, you're much able better able to hold the darkness. In other words, whatever you're reliving or experiencing, your your brain is in this state where you're able to tolerate reliving or experiencing or thinking about it in ways that, you know, can release some of that trauma.

Dr. Robin Carhart-Harris
To be honest, Mark, I'd say it depends. It depends. If you're held well by the certain setting, then then yes. Yeah. It's like

Dr. Mark Hyman
You can have a bad trip too.

Dr. Robin Carhart-Harris
Right? Look at anything. Right. Yeah. You can look at your abuser, and and they manifest as a devil figure.

Mhmm. You can do that because I'm holding you. Mhmm. And 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 this it's very intentional the way we do this work. And, hopefully, are hearing and realizing that it's really a world away from going off to CVS and getting your 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 Mhmm. 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 and putting 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? Well, in mice.

Dr. Mark Hyman
Mhmm.

Dr. Robin Carhart-Harris
But human evidence of neuroplasticity, it ain't really there yet. Know, we're working 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.

Dr. Mark Hyman
Well, a 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. Lot lots of things you can detect that you wouldn't see on just looking at a structural image. It's fixed.

And and that's where you're Yeah. You're seeing a dynamic picture of brain function. And and and I think, know, some of the the data 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 and sort of neuroplasticity. So I think there's some of that data that looks pretty promising. And I I think Paul Stamets is talking about its use in things like Alzheimer's and Parkinson's where there's sort of a a decreased connectivity in the brain and in helping enhance that connectivity.

Dr. Robin Carhart-Harris
I just wanna be careful to manage expectations is all Because most of, as you say, most of the data in humans is fMRI. It'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 preprint.

People can look it up on bio archive. Lyons, l y o n s, et al. And it there we show through diffusion tensor imaging, looking at the white matter tracts 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 tracts changed.

So we we shall see the BDNF. Yeah. You can pick it up peripherally in the blood and and see it go up. So there's a lot of indirect stuff. Could it treat Alzheimer's, Parkinson's?

Well, there's a trial at at UCSF looking at psilocybin for Parkinson's. It'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. Yeah. 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

Dr. Mark Hyman
is Spoken like a true scientist. Like, all the caveats. Not really. Yeah. Yeah.

Yeah. It's still such a new field, so we're still learning about all the applications and the different properties that

Dr. Robin Carhart-Harris
has And and Alzheimer's, yeah, Alzheimer's, you know, people will there's been a little bit of work. People can't remember their trips. They can't remember the experience, and so it hasn't worked that well so far.

Dr. Mark Hyman
Mhmm.

Dr. Robin Carhart-Harris
Yeah. Yeah. It's kinda tragic, but maybe there's a way to treat Alzheimer's earlier on that's more preventative and prophylactic. Yeah. So never say never, and it it's it's certainly sufficiently promising enough that we should be doing that work.

Dr. Mark Hyman
And and, you know, a lot of the things I've seen on that too have been around microdosing. What's your perspective on microdosing these compounds versus therapeutic dosing?

Dr. Robin Carhart-Harris
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 a 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 without necessarily, you know, the heaven and hell, blood and guts of a full on psychedelic trip. 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, and I think it could be I think there's probably something to it. And the caveat here that I gotta 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 limited, really. They there haven't been many. And when they've been done, they haven't often dosed for long enough. In my view, I'm not sure that they've 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 I think it would be a little surprising to think that you can bypass that even with these lower doses. I 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 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.

Dr. Mark Hyman
Yeah. A lot of people are using it just for sort of performance enhancement and, you know, just creativity and Yeah. And that's interesting. So

Dr. Robin Carhart-Harris
Yeah. Like, getting out of their head, so to speak. You know, 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 gotta 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, and the yips over a part, you know, all this heady stuff. Yeah. Well, if you could get get all of that crap away

Dr. Mark Hyman
Yep.

Dr. Robin Carhart-Harris
And and get into the body and get into a more, like, easy, breezy flow state, then it's a that's That's a

Dr. Mark Hyman
a novel application for improving golf or tennis. Isn't that like that? There you go. Wow. Well Just

Dr. Robin Carhart-Harris
make sure you keep the dose low.

Dr. Mark Hyman
I wanna 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 complex PTSD. And yet, there there are risks, and there are 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 struggle 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?

Dr. Robin Carhart-Harris
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 a 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 mushrooms, and it will treat my depression. And and then they have a hellish time. Yeah. Or they do it without someone looking after them, they injure themselves.

And, sadly, those tragedies have happened, and they happen. And 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. You know, it might sound like, oh, he's 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 gotta have that sober sitter and do it the proper way. Otherwise, the the risks are a real thing. I mean, you don't literally transcend this bag of bones and and go off to some, you know, that that thing's still there. It's just, yeah, profoundly altered brain function and mind function.

Yeah. Impaired judgment is a major risk. Also, psychological vulnerability, psychiatric vulnerability.

Dr. Mark Hyman
Yeah. Could you make things worse? I think a lot of people heard about

Dr. Robin Carhart-Harris
You could make things worse. Yeah. It could be, you know, the fancy term I iatrogenesis that you you are doing harm. You're you'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.

Dr. Mark Hyman
Mhmm.

Dr. Robin Carhart-Harris
And they start to doubt reality like that that as 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.

Dr. Mark Hyman
Wow.

Dr. Robin Carhart-Harris
So that kind of dissociation, derealization

Dr. Mark Hyman
That's scary. I don't want my pilot It's

Dr. Robin Carhart-Harris
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. Relevant in that context to, 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.

They still gotta pick up the kids from school, you know, and and do the dishes and so

Dr. Mark Hyman
on. When you think about how these 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 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.

But I to me to me, I think, you know, we can get that right. I think, you know, it it's gonna take some work, but it seems like that's an important caveat here, is that if you're thinking about this, make sure you're gonna do it in the right the right way with the right person who's had experience. So 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.

Dr. Robin Carhart-Harris
It's massive.

Dr. Mark Hyman
Yeah. What what are you what are you most excited about next in your research around psychedelics? What what do you think is the next frontier? Where where are you focused? What what's happening in the field that that you wanna preview for us?

Dr. Robin Carhart-Harris
Well, there's so much. It's hard to pick one thing. I could go to, you know, adolescent mood disorder, depression. We wanna do a trial there. I strongly suspect that we could do better than SSRIs for young people.

Mhmm. I wonder whether psilocybin therapy could be that better if done well. It's one thing. The five 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, so 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 sort of machine learning approach, an approach. Yeah. AI machine learning rests on depth of data. That's 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.

Dr. Mark Hyman
And how are you using that in in psychedelic research?

Dr. Robin Carhart-Harris
Theoretically, you could you could draw from deep data from other states and 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 fifteen hours

Dr. Mark Hyman
Mhmm. In

Dr. Robin Carhart-Harris
this study. I mean, yeah, 12 of which are while tripping.

Dr. Mark Hyman
Wow.

Dr. Robin Carhart-Harris
So most of it is under 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 whether they're resisting the experience or letting go to the experience. And so

Dr. Mark Hyman
Is that through through AI you're looking at that? Through

Dr. Robin Carhart-Harris
Yeah. It's 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 it's called decoding.

It's been done for a while in human neuroscience. People have used that approach. People like Jack Galantz 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. So there's some really cool applications of that approach, and and our way of coming at this is trying to predict what people are tripping, albeit in this very rudimentary way to begin with.

Dr. Mark Hyman
And and you think that'll give you insights about who to use this on, how it works, sort of how to apply it more broadly?

Dr. Robin Carhart-Harris
You know, it's 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 let let's not, you know, diminish the importance of biology. It's still bottom line. And it gives us power, really, the the biology, power to to manipulate that in a positive way, we may well find that there is this sweet spot of brain entropy that people need to be at for them to be sufficiently plastic to change their abnormal, unhealthy habits, their beliefs, for example. And so based on some readouts, seeing the level of entropy, we could dial or even, you know, titrate dosage

Dr. Mark Hyman
Uh-huh.

Dr. Robin Carhart-Harris
To hit that sweet spot. And so with the machine learning approach, we might see we we can extend on that principle and and see, for example, you know, 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, like, proxy of it, some other indirect measure of it. And therefore, you know, without talking critically, I think this is the 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

Dr. Mark Hyman
Mhmm.

Dr. Robin Carhart-Harris
And then tailor my treatment based on that that special information that I'm getting.

Dr. Mark Hyman
Almost like personalizing the therapy based on what's happening in the brain and how they're responding to the treatment, and that's fascinating.

Dr. Robin Carhart-Harris
Yeah. You could do that ahead of time. You know, you could pick your drug like we were talking about with a briefcase of of options, but you could also do it more directly in real time Mhmm. You know, tailoring things based on what you're seeing without without necessarily checking in. I mean, you can check-in too and talk to them, but that people often can't talk when they're they're under the influence.

And they also can't, yeah, they can't easily articulate what what's going.

Dr. Mark Hyman
No. It's it's profound. I I mean, you know, I remember being 18 and eating a load of mushrooms and just, like, reality never looked the same. You know, it really reset a lot of things in my way of looking at the world, experiencing the world, and made me realize that the the kind of the rigid ways that I was experiencing life was only one filter. And then I put in basically a new set of glasses and could see the world in a different way, and it just 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, yeah, I I sort of, you know, there's so much hope and promise for these these compounds that have been around forever. Some of them are new. Obviously, I got MDMA that's developed by Merck as a drug. I I'm sort of wondering from your perspective and the lens you're seeing the future, you know, five years from now. Where where do you think this feels gonna be?

Do you do you think this is gonna become more part of standard psyche 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 it you know, are are we gonna get to a place where we actually have effective treatments and they can be applied widely across the population?

Dr. Robin Carhart-Harris
Yes. You know, it's a balance of hope, qualified by not, by managing expectation and and not falling into a trap of, 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 and mitigate those those risks. So I do think it will happen five years.

Psilocybin 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. In within five years, I'd feel pretty confident psilocybin will be through on a federal level as a licensed medicine. And 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 Yeah. Adult assisted magic mushroom experiences, essentially. And I think it's close to 10,000 people, if not more, have gone through that.

Dr. Mark Hyman
It's a big dataset.

Dr. Robin Carhart-Harris
Dare I say. It is, isn't it? And they're not collecting enough data. But, hopefully, we're we're gonna 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 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. We need to know whether this is safe enough and beneficial.

Dr. Mark Hyman
Well, this is really helpful. I mean, it's you know, because mental health has been such a problem throughout human history, and and we've had really very crappy treatments, and we have different theories. But it seems like a a quantum jump. Both the the metabolic psychiatry field, nutritional psychiatry, and psychedelic psychiatry seem like they're sort of 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.

Dr. Robin Carhart-Harris
I think so. I'd be interested how you 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 nineteenth 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 life span, longevity is is going up quite reliably.

And 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 mechanisms. Now into the twenty first century, a quarter of the way in, we're still not treating mental illness well enough Yeah. Arguably because we don't understand how it's caused well enough. But I feel confident that that's gonna change within this century, and it's probably gonna change quite soon.

Dr. Mark Hyman
Yeah. It's it's a it's a it's an exciting moment. I I remember being in medical school and I was at residency and spending a month in a psychiatric hospital, not not as a patient but as a student. And I was just so distraught at the failure, the sort of 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 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, you know, some squishies, you know, have a great trip and have a psychedelic experience and see God and then your life's different. But you're actually trying to understand what's what's happening in the brain and and that's gonna teach us a lot about how we need to to think about these 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 which really, you know, it's it's so you know, it's so far from this right now in practice. Right? And yet, you we're know, things accelerate pretty quickly. So, you know, nobody was washing their hands in medicine and before surgery until suddenly they did after fifty years of people saying, hey, this is a good idea.

So I think Mhmm. I think we're maybe in that moment. And it's it's very encouraging to me because when I wrote my book on on sort of the brain and and both mental illness and both attention and memory disorders, I I was So 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 training that were real. And then it was almost accidentally that I found these things. And sort of like the you hear the story about the Ibogaine discovery, it was sort of accident.

There was an addict, it was a narcotic addict who took it and Yeah. His cravings went away. So it was like those kinds of experiences are are quite change you know, change the culture, they change our practice. So I I think I just wanna thank you for your work and and all you do. I we, you know, we we we still have a lot to learn and that's clear from you how you told the story is like we're we're basically at the beginning of this journey.

But hopefully it's gonna 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 carcarhartharrislab.com and follow you on social media at different different places. We'll put all the links in the in the show notes to follow Robin and track his work. And and I continue to kind of follow what you're doing and very, excited about next steps and where we're going with all this. But I love the idea of five years from now being this approved therapy for various kinds of mental health disorders that really are treatment resistant.

Dr. Robin Carhart-Harris
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 and really enjoyed doing it with you.

Dr. Mark Hyman
No. Thanks, Robin. Hope I see you in person sometime soon and can follow your work and I'm gonna keep track of this because this is this is a field that's gonna I think make a huge impact in in suffering and humanity which, you know, there's there's very few things that come along like this. I think that that hold the promise that this does to really crack open a an ossified field that has not really done very well for humanity. Mhmm.

So thank you.

Dr. Robin Carhart-Harris
Thank you. Thank you. My fingers are crossed.

Dr. Mark Hyman
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