Dr. Robin Carhart-Harris: The Science of Psychedelics for Mental Health

00:00:00.000 | Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life.

00:00:06.000 | I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine.

00:00:14.000 | Today, my guest is Dr. Robin Carhart-Harris.

00:00:17.000 | Dr. Carhart-Harris is a distinguished professor of neurology and psychiatry at the University of California, San Francisco.

00:00:25.000 | He's one of the leading researchers in the field of psychedelics and how they change neural circuitry in the brain.

00:00:30.000 | His laboratory is responsible for understanding, for instance, how psilocybin, also sometimes referred to as magic mushrooms,

00:00:37.000 | change neural circuitry in the brain such that new ideas and new forms of learning occur.

00:00:42.000 | His laboratory is also responsible for carrying out various clinical trials,

00:00:47.000 | which have demonstrated that appropriate dosages of psilocybin can alleviate major depression in more than 67% of people that take the drug.

00:00:55.000 | Now, this is not to say that everybody should take psilocybin, and today's discussion describes both the clinical trials

00:01:01.000 | and why treatments with psychedelics in some cases work and in some cases do not work in order to treat major depression,

00:01:07.000 | as well as discussions around psilocybin, lysergic acid diethylamide, sometimes also referred to as LSD,

00:01:14.000 | DMT, and how these change the brain and how those brain changes can relate to changes in mental health

00:01:20.000 | as it relates to depression and other psychiatric challenges,

00:01:23.000 | as well as how psychedelics are being applied in order to change neural circuitry for sake of expanding different aspects of the human mind,

00:01:30.000 | including creativity, intelligence, and much more.

00:01:33.000 | During today's discussion, Dr. Carhart-Harris teaches us about the history of the study of psychedelics,

00:01:39.000 | as well as how the legislature, that is the laws surrounding psychedelics, are evolving in the United States and elsewhere

00:01:46.000 | for the use of psychedelics to treat psychiatric challenges.

00:01:49.000 | By the end of today's discussion, you will have a thorough understanding of how psychedelics work,

00:01:53.000 | both in the short term during the actual journey or trip.

00:01:56.000 | In fact, much of my discussion today with Dr. Carhart-Harris talks about the different aspects of the psychedelic journey

00:02:02.000 | and how those relate to therapeutic outcomes.

00:02:06.000 | By the end of today's discussion, you will also understand the long-term effects of psychedelics,

00:02:09.000 | that is, how they can actually rewire the brain.

00:02:12.000 | Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford.

00:02:17.000 | It is, however, part of my desire and effort to bring zero cost to consumer information about science

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00:06:26.000 | I hope to see you there.

00:06:28.000 | And now for my discussion with Dr. Robin Carhart-Harris.

00:06:31.000 | - Dr. Carhart-Harris, welcome.

00:06:34.000 | I've been wanting to talk to you for a long time.

00:06:36.000 | I certainly have known who you are for quite a while

00:06:40.000 | because I place you in this very small

00:06:43.000 | but very special and important category of researchers

00:06:48.000 | who has been pioneering the use of psychedelics

00:06:51.000 | for the treatment of specific clinical conditions

00:06:54.000 | and really carrying the torch for essentially the entire field.

00:06:57.000 | So I want to start with a voice of gratitude

00:07:01.000 | and say thank you for doing this incredibly important work.

00:07:04.000 | Could you tell us a little bit about what psychedelics are?

00:07:07.000 | In fact, I'm curious as to how the name psychedelic ever came to be

00:07:11.000 | and what you think they potentially reveal about the workings of the brain.

00:07:17.000 | And then we'll talk about the clinical applications.

00:07:19.000 | Sure. Well, even that one is a kind of hot one

00:07:25.000 | because opinions differ on how to define psychedelic.

00:07:30.000 | But perhaps a good starting place is to start with the etymology.

00:07:34.000 | Where did the word come from?

00:07:36.000 | And it was a Brit, excommunicated,

00:07:40.000 | living in Canada, Humphrey Osmond,

00:07:45.000 | who was due to present a paper at a National Academy of Sciences meeting

00:07:52.000 | on psychotomemetics, drugs that mimic aspects of psychosis in their action.

00:08:00.000 | And certain drugs like mescaline, let's see 1956 and LSD,

00:08:05.000 | were on the bill and he felt dissatisfied

00:08:11.000 | with them being under this category of psychotomemetics

00:08:14.000 | and felt that the signature psychological effects of these compounds

00:08:19.000 | went beyond just mimicking psychotic symptoms.

00:08:22.000 | And so he wanted to find a more apt term to speak to,

00:08:27.000 | in a sense the principal component of their action.

00:08:31.000 | And he jotted down a few different possibilities,

00:08:36.000 | about a dozen or so I think,

00:08:38.000 | and one of them was psychedelic actually it started as

00:08:43.000 | and ended up being psychedelic.

00:08:45.000 | And he had a correspondence going on with another Brit,

00:08:50.000 | also living in the US, Aldous Huxley,

00:08:53.000 | where they were playing with some terms to refer to these compounds.

00:09:00.000 | And in the end Osmond won with psychedelic

00:09:04.000 | and he had this little ditty of

00:09:08.000 | "To fathom hell or soar angelic, just take a pinch of psychedelic."

00:09:14.000 | That's where he put the disclaimer in.

00:09:17.000 | And so what does that mean?

00:09:21.000 | It's two ancient Greek words, psyche means the human mind

00:09:26.000 | or if we're being actually true to the ancient Greek it means soul.

00:09:33.000 | And then the other component means to make clear or to make visible

00:09:40.000 | or to make manifest or to reveal.

00:09:43.000 | So all of those work.

00:09:45.000 | And it's a neologism, it's a made-up word

00:09:49.000 | but it does have that ancient Greek origin

00:09:53.000 | and it's speaking to this principle

00:09:57.000 | that these compounds reveal aspects of the psyche,

00:10:02.000 | of the human mind, the soul, that are ordinarily not entirely visible.

00:10:08.000 | And so that's the etymology and it's wonderfully poetic

00:10:12.000 | but I happen to think it's also very accurate.

00:10:15.000 | It's a useful term because it's sort of, you might say,

00:10:20.000 | valence non-specific.

00:10:22.000 | It doesn't say you're going to have a great time

00:10:24.000 | or that you're going to go mad.

00:10:26.000 | It's more that it reveals a psyche and it could be hellish

00:10:31.000 | but it could be heavenly.

00:10:32.000 | And so that's the etymology and also a bit of the psychology

00:10:38.000 | and sort of, you know, pointing to the phenomenology,

00:10:42.000 | the subjective experience.

00:10:44.000 | But there's also a pharmacology here

00:10:48.000 | and quite recently there was put out a consensus statement

00:10:53.000 | about psychedelics that's really referring to what we call

00:10:58.000 | classic psychedelics to say that these are all compounds

00:11:01.000 | that work on a particular receptor in the brain,

00:11:05.000 | the serotonin 2A receptor

00:11:07.000 | and that's another way that we could define these compounds.

00:11:11.000 | I said this one's a little hot

00:11:13.000 | because I'm of the view that while the pharmacology is really useful,

00:11:19.000 | how the drugs work chemically, you can't avoid the phenomenology

00:11:24.000 | and if we're true to the etymology, where the term came from,

00:11:27.000 | then we must recognize and we cannot neglect

00:11:31.000 | the subject of experience.

00:11:33.000 | - Thank you for that beautiful description

00:11:36.000 | of what brought us to today

00:11:39.000 | in terms of using the word psychedelics

00:11:41.000 | and now it's thrown around all the time.

00:11:43.000 | - Yeah, too much.

00:11:45.000 | - Yeah, too much and I'm guessing, well not guessing,

00:11:47.000 | I'm certain that it's also used to describe many compounds

00:11:50.000 | that don't touch the 5-HT2A, the serotonin 2A receptor.

00:11:56.000 | So there is a broader categorization by most people

00:12:00.000 | and it'll be interesting to see

00:12:02.000 | where all the nomenclature and naming goes.

00:12:04.000 | For the time being, I'd love for you to tell us

00:12:07.000 | a bit more about this idea that psychedelics,

00:12:10.000 | however one defines them,

00:12:12.000 | can reveal something about the mind

00:12:15.000 | that can't be revealed otherwise.

00:12:17.000 | Are you talking about the subconscious?

00:12:20.000 | I mean, psychologists and most famously Freud,

00:12:24.000 | and also Jung and also neuroscientists, I think,

00:12:26.000 | think about subconscious processing.

00:12:29.000 | I think perhaps the most salient example for me

00:12:31.000 | that's outside the realm of anything psychedelic

00:12:35.000 | would be blind sight.

00:12:37.000 | This phenomenon that you take people that are blind

00:12:39.000 | but still have some connectivity in their brain

00:12:42.000 | and you present them a board with a computer screen

00:12:46.000 | with different number of dots on each side

00:12:48.000 | and you say, how many dots are on each side of the screen?

00:12:50.000 | And they say, what do you mean?

00:12:53.000 | They're trying to guess

00:12:54.000 | and their guess rate is accurate

00:12:57.000 | far more than chance would predict.

00:13:00.000 | So they have so-called blind sight

00:13:02.000 | and people have said, well,

00:13:04.000 | this is the subconscious revealing itself.

00:13:06.000 | There's no psychedelic drug involved

00:13:08.000 | but what you're describing is a pharmacologic induced state

00:13:13.000 | that reveals something that normally,

00:13:16.000 | should we assume, is masked

00:13:18.000 | or that we are oblivious to

00:13:22.000 | even though it's expressing itself?

00:13:23.000 | What does it mean for these drugs

00:13:25.000 | to be revealing something about the workings of the mind

00:13:29.000 | that would not be obvious to us otherwise?

00:13:31.000 | Yeah, so the example of blind sight is interesting

00:13:36.000 | but it's different.

00:13:38.000 | Blind sight would be referring to non-conscious processing,

00:13:42.000 | maybe implicit processing,

00:13:44.000 | so stuff going on in the mind in perception

00:13:47.000 | in a sense that is below the threshold

00:13:49.000 | of conscious awareness.

00:13:51.000 | But yet is influencing you.

00:13:52.000 | So it's kind of related but it's different.

00:13:56.000 | So in depth psychology, psychoanalysis,

00:14:00.000 | psychodynamic psychology,

00:14:02.000 | Sigmund Freud, Carl Jung and so on,

00:14:05.000 | we talk about the unconscious

00:14:08.000 | and there it's more about the kind of blood and guts

00:14:14.000 | of the human condition, the human nature,

00:14:18.000 | both the personal unconscious

00:14:20.000 | so things that you might not want

00:14:22.000 | to necessarily be conscious of because it's painful.

00:14:26.000 | So that's the repression aspect,

00:14:29.000 | pushing it out of conscious awareness.

00:14:31.000 | Repressed memories in particular?

00:14:33.000 | Yeah, like traumatic memories,

00:14:35.000 | difficult relationships.

00:14:38.000 | It could be complex trauma,

00:14:40.000 | not necessarily just a specific index trauma

00:14:44.000 | but a series of trauma.

00:14:46.000 | And then you have the collective unconscious

00:14:49.000 | which was really Carl Jung's contribution

00:14:51.000 | to say that there's a transpersonal quality

00:14:57.000 | to the unconscious.

00:14:59.000 | There's aspects about humans,

00:15:01.000 | not just this individual human.

00:15:04.000 | There's aspects to our minds,

00:15:07.000 | our psyches that are not fully available

00:15:10.000 | to conscious awareness

00:15:12.000 | but can come up in certain states.

00:15:16.000 | You know, psychoanalysis went crazy for dreaming

00:15:19.000 | as their royal road to a knowledge of the unconscious.

00:15:22.000 | That was Freud.

00:15:24.000 | But we now know with psychedelics

00:15:28.000 | and this was what drew me into the area

00:15:31.000 | was discovering literature

00:15:33.000 | that was speaking to this particular action,

00:15:36.000 | the psychedelic action,

00:15:38.000 | and was saying that when these drugs

00:15:43.000 | like chilis-D, psilocybin, found in magic mushrooms,

00:15:47.000 | when they're used in psychotherapy,

00:15:51.000 | material comes up that maybe may have been repressed

00:15:57.000 | that is of therapeutic value

00:16:02.000 | and awareness and insight of this material

00:16:05.000 | seems to catalyze the therapeutic process

00:16:08.000 | with strong emotional release,

00:16:10.000 | these cathartic experiences.

00:16:12.000 | And insights, you know,

00:16:15.000 | whether they're insights that are personal

00:16:18.000 | or whether they're transpersonal.

00:16:21.000 | But for me this is really

00:16:24.000 | where the meat of it is with psychedelics

00:16:28.000 | and classic psychedelics in particular,

00:16:30.000 | the likes of compounds like LSD and psilocybin.

00:16:35.000 | I would say that if it wasn't for this action

00:16:38.000 | by classic psychedelics,

00:16:41.000 | we wouldn't be so interested in psychedelics.

00:16:44.000 | I think if we only had compounds

00:16:46.000 | like ketamine, MDMA, cannabis,

00:16:49.000 | that could be said, broadly speaking,

00:16:52.000 | to be psychedelic-like,

00:16:54.000 | I don't think it necessarily would have captured

00:16:57.000 | the world's attention as psychedelics are right now.

00:17:01.000 | I actually think there's a major gap to fill

00:17:05.000 | is this principle action of the classic psychedelics.

00:17:10.000 | What does this mean that I'm referring to?

00:17:12.000 | Psyche revealing, what is that?

00:17:15.000 | And I suppose where I'm going with this is

00:17:19.000 | what is that in terms of the biology as well?

00:17:22.000 | What's going on in the brain and the body

00:17:24.000 | when people become aware of things

00:17:27.000 | that previously they weren't fully aware of?

00:17:30.000 | - I'd like to talk about some of the clinical trials

00:17:34.000 | that you've been involved with.

00:17:36.000 | In particular, looking at psilocybin,

00:17:39.000 | as you mentioned,

00:17:40.000 | the principal hallucinatory psychedelic agent

00:17:44.000 | in magic mushrooms.

00:17:46.000 | I'd like to start with a kind of nuts and bolts question

00:17:49.000 | just so that everyone's on the same page.

00:17:52.000 | I've read the papers that you've published

00:17:56.000 | and that others have published in this area,

00:17:58.000 | and typically the dosages used in these trials

00:18:01.000 | are 25 milligrams of psilocybin,

00:18:05.000 | and we talk about one recent trial in particular

00:18:08.000 | that compared 25 to 10 milligrams

00:18:10.000 | to more frequent use of very small amounts,

00:18:13.000 | one milligram over three weeks, for instance.

00:18:16.000 | However, when people talk about magic mushrooms,

00:18:21.000 | they often talk about gram doses of the mushroom

00:18:24.000 | because I'm assuming that they contain

00:18:27.000 | milligram dosages of psilocybin.

00:18:30.000 | Here we're not encouraging use of any kind.

00:18:33.000 | These are clinical trials,

00:18:36.000 | but there's a clarity of understanding

00:18:38.000 | what is the conversion typically?

00:18:40.000 | Like one gram of magic mushrooms

00:18:43.000 | will contain how many milligrams of psilocybin on average?

00:18:48.000 | Because what I'm trying to do here

00:18:50.000 | is calibrate people to this idea

00:18:52.000 | of microdosing versus macrodosing,

00:18:55.000 | and that's fairly straightforward to do

00:18:57.000 | with respect to the clinical trials,

00:18:59.000 | but then in a lot of the lay discussion around this,

00:19:02.000 | you hear about heroic doses versus microdoses,

00:19:05.000 | and so I think there's a lot of confusion.

00:19:07.000 | So if you would, educate us on this idea

00:19:11.000 | of what's a microdose

00:19:13.000 | and perhaps also how many milligrams of psilocybin

00:19:18.000 | are contained in a gram of "magic mushrooms."

00:19:22.000 | Sure. Well, a microdose is,

00:19:25.000 | neither of these are that simple,

00:19:27.000 | but they're fun, it's a fun challenge.

00:19:30.000 | But microdose, one definition is that

00:19:34.000 | it's a dose of typically a classic psychedelic

00:19:37.000 | like LSD or psilocybin

00:19:40.000 | that has sub-perceptible psychedelic effects.

00:19:46.000 | It doesn't put you into a noticeable altered state

00:19:50.000 | of consciousness that feels like you're tripping.

00:19:53.000 | And if that was LSD,

00:19:57.000 | it looks as though the threshold is around about,

00:20:02.000 | let's see, 10, 11, 12 micrograms.

00:20:05.000 | Micrograms.

00:20:07.000 | I want to be very clear here, micrograms.

00:20:09.000 | So 10 micrograms of LSD,

00:20:13.000 | are you saying will not induce visual hallucinations

00:20:16.000 | in most people?

00:20:18.000 | That's threshold level.

00:20:20.000 | That's about the level that some people

00:20:23.000 | who are sensitive could feel it.

00:20:26.000 | But if you were to talk to the microdosing gurus,

00:20:31.000 | they might say that that's kind of the ballpark

00:20:33.000 | for an LSD dose that you would consider a microdose

00:20:38.000 | and then you would take sort of semi-regularly.

00:20:41.000 | It's typically something like one day on, one day off

00:20:45.000 | or one day on, two days off, this kind of thing.

00:20:48.000 | There's different protocols.

00:20:50.000 | And yeah, so some like Jim Faderman,

00:20:55.000 | one of the popularizers of microdosing.

00:21:00.000 | I think would say that a true microdose

00:21:03.000 | should be sub-perceptible.

00:21:05.000 | You shouldn't feel it.

00:21:07.000 | Yet the assumption is it's going to change you in some way

00:21:11.000 | on a kind of trait level, more than a state level.

00:21:15.000 | Maybe behaviorally.

00:21:17.000 | And the typical story goes it will improve well-being

00:21:22.000 | and maybe, maybe it could improve certain aspects

00:21:27.000 | of cognition, say related to creative thinking.

00:21:30.000 | I emphasize that maybe there,

00:21:33.000 | because that's another angle with microdosing.

00:21:35.000 | We're kind of waiting for some compelling evidence.

00:21:39.000 | As things stand right now,

00:21:41.000 | I'd say we lack that compelling evidence.

00:21:44.000 | There's some suggestive stuff,

00:21:46.000 | but often the study designs aren't that strong.

00:21:49.000 | It's really hard to do a study with microdosing

00:21:52.000 | because you need to have permission

00:21:56.000 | to give people a microdose that, for practical reasons,

00:22:00.000 | they would go home with.

00:22:03.000 | And otherwise, you're requiring them to be in the lab,

00:22:09.000 | say three times a week for X number of weeks

00:22:13.000 | to meet the criteria of a course of microdosing,

00:22:17.000 | which might be two or three times a week for, say, a month.

00:22:23.000 | And that's a hard thing to do in a lab study.

00:22:26.000 | It's expensive.

00:22:28.000 | You'd need to do that against a suitable control,

00:22:32.000 | so a placebo control.

00:22:34.000 | And there is a study that's been done in New Zealand

00:22:38.000 | that has some interesting preliminary data

00:22:41.000 | that did, I think, kind of did the design right.

00:22:45.000 | But it hasn't been published yet.

00:22:50.000 | We've seen some positive findings presented

00:22:53.000 | around improvements in mood,

00:22:55.000 | but it's a bit early to get too excited about that.

00:22:59.000 | Needs to go through peer review and all that.

00:23:02.000 | But as things stand, the evidence is pretty thin,

00:23:07.000 | and we have to be honest about that.

00:23:10.000 | We did quite a creative study with my colleagues at Imperial,

00:23:16.000 | the guy leading that, Balash Shigeti, Hungarian chap,

00:23:20.000 | did a really creative design, very much his brainchild.

00:23:24.000 | He instructed people to do their own blinding,

00:23:28.000 | their own placebo-controlled blinding

00:23:31.000 | of their own microdosing.

00:23:33.000 | So this was a classic citizen science study,

00:23:36.000 | like do-it-yourself science,

00:23:38.000 | where they would get their LSD tabs and chop them up,

00:23:41.000 | put them into gel capsules, opaque,

00:23:45.000 | have other capsules that are the placebos

00:23:47.000 | that they just close, empty capsule.

00:23:49.000 | And then there was a whole barcode scan technique

00:23:53.000 | so that you kind of shuffle them up, you know,

00:23:56.000 | but they've got the barcode in, the QR code,

00:23:59.000 | so you can break the code later on,

00:24:02.000 | but once you've shuffled them up,

00:24:04.000 | you no longer know which ones have the microdose in

00:24:07.000 | and which ones are empty.

00:24:09.000 | - Was this LSD? - This was LSD.

00:24:11.000 | He also tried it with mushrooms,

00:24:14.000 | and what he did with the mushrooms was

00:24:15.000 | people would burp sometimes, they'd belch,

00:24:17.000 | and then they'd have this mushroom taste.

00:24:19.000 | So then he instructed people

00:24:21.000 | to get some non-psychoactive mushroom material to put in.

00:24:26.000 | - So it's really-- - Not an easy study.

00:24:28.000 | - Not an easy study.

00:24:30.000 | And it was, I love that kind of science,

00:24:33.000 | you know, real creative, first mover kind of science.

00:24:37.000 | And the results were fascinating

00:24:39.000 | because the short story is that the microdosing

00:24:43.000 | didn't compellingly beat the placebo.

00:24:46.000 | - It did not. - It didn't.

00:24:48.000 | And he controlled, because he asked,

00:24:51.000 | he controlled for expectancy.

00:24:54.000 | So people's positive expectancy,

00:24:56.000 | which is in a sense the vehicle

00:24:58.000 | that carries the placebo response,

00:25:00.000 | it's why you have a placebo,

00:25:02.000 | is that positive expectancy can drive

00:25:04.000 | a therapeutic effect to, you know, a large extent.

00:25:08.000 | So he measured that pre-trial

00:25:11.000 | and then used it to kind of correct for the response.

00:25:14.000 | And how did it work?

00:25:16.000 | Those who got a placebo

00:25:18.000 | but thought they got a microdose

00:25:21.000 | did as well as those who thought they got a microdose

00:25:25.000 | and did get a microdose.

00:25:27.000 | So it was the bigger effect,

00:25:29.000 | the majority of the effect was in thinking

00:25:32.000 | that you got a microdose.

00:25:34.000 | So in a sense it was a victory

00:25:36.000 | for the power of the placebo response.

00:25:40.000 | And it's created all sorts of controversy.

00:25:41.000 | People don't want to believe it,

00:25:43.000 | you know, that kind of thing.

00:25:45.000 | But that's the beauty of science, isn't it?

00:25:47.000 | That science is not about what you want to believe.

00:25:50.000 | That right there is the beauty of science, really.

00:25:53.000 | - I love that experiment.

00:25:55.000 | Kudos to them.

00:25:57.000 | I'm not going to attempt to say his last name correctly.

00:26:01.000 | - I tried, yeah.

00:26:03.000 | I probably made a mess of it.

00:26:05.000 | - No, no, I think you got it.

00:26:08.000 | You were involved in a clinical trial

00:26:10.000 | that was published last year

00:26:12.000 | comparing 25 milligrams of psilocybin

00:26:16.000 | to 10 milligrams of psilocybin

00:26:18.000 | to a drug called escitalopram.

00:26:24.000 | - Yeah, Lexapro, yeah.

00:26:26.000 | - And this one milligram over three week dosage.

00:26:31.000 | I'm wanting to discuss the results of that study a bit

00:26:36.000 | and some of the other trials that you've done

00:26:38.000 | involving psilocybin for depression,

00:26:40.000 | the treatment of depression.

00:26:42.000 | Could we calibrate ourselves?

00:26:44.000 | 25 milligrams of psilocybin,

00:26:46.000 | is that what wouldn't,

00:26:48.000 | it's going to be a perceptible dose, presumably.

00:26:50.000 | Hallucinations and all that.

00:26:52.000 | And is that what one would find in,

00:26:54.000 | I'm guessing here, if I'm accurate,

00:26:56.000 | this does not mean that I have experience here,

00:26:58.000 | but two grams of mushrooms?

00:27:01.000 | - More than that, we think, yeah.

00:27:03.000 | Sorry, I missed that one.

00:27:05.000 | Went off on a tangent.

00:27:06.000 | But yeah, 25 milligrams of psilocybin would be,

00:27:10.000 | we don't know and it's important that I say that

00:27:13.000 | because I wouldn't want people to hear my answer here

00:27:16.000 | and then use it to calibrate their own dosing of mushrooms

00:27:20.000 | and get it way off.

00:27:22.000 | So it's guesswork and I would love to see someone

00:27:24.000 | do a proper study on it

00:27:26.000 | and look at the psilocybin content

00:27:33.000 | in a given mass of psilocybin mushrooms, magic mushrooms.

00:27:38.000 | But to my knowledge, that hasn't really been done.

00:27:42.000 | Someone like Paul Stamets would give a better answer here,

00:27:47.000 | but I think the percentage within the mushroom mass

00:27:51.000 | of psilocybin in the mushroom mass

00:27:54.000 | and psilocin, which is the metabolite of psilocybin,

00:27:59.000 | in the 1%, a little bit higher maybe, range.

00:28:04.000 | - Okay, so one gram, 1,000 milligrams of magic mushroom

00:28:09.000 | would contain about 10 milligrams of psilocybin.

00:28:14.000 | Is that right?

00:28:15.000 | - Broadly speaking, yeah.

00:28:16.000 | - Okay, great.

00:28:17.000 | That helps calibrate.

00:28:18.000 | And I think, again, just allows the layperson

00:28:21.000 | to understand a bit more of where we're headed

00:28:24.000 | with these psilocybin trials and the results.

00:28:28.000 | We don't have to restrict our discussion

00:28:29.000 | to just that one clinical trial,

00:28:31.000 | but if we include that one

00:28:33.000 | and compare it to some of the other trials that you've done,

00:28:35.000 | I mean, your laboratory is seeing phenomenal,

00:28:39.000 | in my opinion, phenomenal results

00:28:41.000 | in the treatment of otherwise intractable depression,

00:28:45.000 | major depression, which so many people suffer from,

00:28:49.000 | from two, I suppose they're two sessions

00:28:56.000 | using psilocybin in these ranges of 10 to 25 milligrams.

00:28:59.000 | Do I have that correct?

00:29:01.000 | - Yes.

00:29:02.000 | - Okay, could we talk a little bit

00:29:03.000 | about what people typically experience

00:29:06.000 | during those sessions

00:29:08.000 | that allows this phenomenal transformation

00:29:11.000 | of mood and state and trait as well?

00:29:15.000 | And I'm especially interested in whether or not

00:29:19.000 | is the experience during those sessions

00:29:23.000 | that is the trigger that's necessary

00:29:26.000 | for the transformation from a depressed

00:29:28.000 | to a non-depressed state?

00:29:30.000 | Because the impulse is to think it is,

00:29:32.000 | that what one thinks and sees and hallucinates

00:29:35.000 | and hears is so vital.

00:29:37.000 | But of course, these drugs can create neuroplasticity changes

00:29:41.000 | in our neural wiring, presumably for long periods of time.

00:29:44.000 | So what are your thoughts on the experience itself?

00:29:48.000 | And maybe for those who have not done these compounds before,

00:29:52.000 | you can explain a little bit about what's typical for people

00:29:54.000 | and what you think is leading to that incredible

00:29:57.000 | positive and pervasive change in mood, state, and trait.

00:30:01.000 | - I would say that it's more than impulse

00:30:04.000 | that is leading us to think that the experience is important.

00:30:08.000 | It's really data and converging evidence now.

00:30:12.000 | So independent teams, independent studies

00:30:18.000 | are converging on the magnitude of certain kinds of experience.

00:30:23.000 | Rated, yes, with subjective rating scales

00:30:26.000 | is predicting therapeutic outcomes

00:30:29.000 | pretty strongly and very reliably.

00:30:33.000 | And so that's guiding us.

00:30:36.000 | Now, could you say, well, maybe those experiences

00:30:38.000 | are some kind of epiphenomenon of, say,

00:30:41.000 | a central brain action?

00:30:43.000 | Well, absolutely, but then all experience

00:30:47.000 | is an epiphenomenon by that principle.

00:30:48.000 | And yet we care about it, you know?

00:30:50.000 | And it matters to us and in our human relations with each other.

00:30:55.000 | So I think it does matter to a human being

00:30:58.000 | when they're in, say, a psilocybin therapy session

00:31:01.000 | and as the drug effects begin to come on

00:31:04.000 | and the body starts to feel a little strange and tingly

00:31:09.000 | and there's some initial anxiety.

00:31:16.000 | And then in their mind's eye,

00:31:18.000 | they start to notice patterns and maybe colors

00:31:22.000 | and then maybe those patterns deepen and they're dynamic

00:31:26.000 | and they have this fascinating organic quality.

00:31:29.000 | Are the patients in your studies typically using an eye mask?

00:31:34.000 | So they're in the eye mask, so eyes closed.

00:31:37.000 | That's why you said mind's eye as opposed to

00:31:39.000 | looking out into the clinical setting.

00:31:41.000 | Yes, and that's one of the major differences

00:31:44.000 | between psychedelic therapy versus taking a psychedelic,

00:31:46.000 | is you shut your eyes, you know?

00:31:48.000 | And it's a world away from taking a psychedelic,

00:31:52.000 | yeah, a rave or something, you know?

00:31:55.000 | In a sense, good luck with that.

00:31:57.000 | But in psychedelic therapy, yeah, it's, you know,

00:32:02.000 | settled conditions, there's music playing

00:32:06.000 | and what I'm describing here is very much the default.

00:32:10.000 | There's actually, you know, very little variability

00:32:14.000 | between the different sites that have done this work

00:32:16.000 | on these conditions.

00:32:18.000 | Typically it's two people, ideally mental health professionals,

00:32:24.000 | at least one who's a psychiatrist or a clinical psychologist

00:32:28.000 | or some other kind of psychotherapist or psychiatric nurse.

00:32:32.000 | But ideally two who meet those criteria

00:32:37.000 | with a individual who's ingested the drug

00:32:40.000 | and music playing throughout,

00:32:43.000 | a kind of runway into taking the drug and then throughout,

00:32:46.000 | so there's continuity.

00:32:48.000 | Music with lyrics or without lyrics?

00:32:50.000 | Without lyrics to begin with

00:32:52.000 | and the music typically is spacious to begin with

00:32:57.000 | and then builds and becomes atmospheric.

00:33:05.000 | There might be, I don't know, some tribal drums

00:33:07.000 | in the distance or something as it develops

00:33:11.000 | or like the sound of a bird in the distance,

00:33:14.000 | you know, a bird's call.

00:33:16.000 | And then as it gets into more stronger drug effects,

00:33:22.000 | the music starts to coax emotion

00:33:29.000 | and very intentionally, you know, strings,

00:33:33.000 | for example, would come in and it would be an interesting experiment

00:33:39.000 | and one that we'd love to do, actually,

00:33:42.000 | to see whether if you were to pull that out,

00:33:45.000 | whether the psychedelic experience would be as emotionally intense

00:33:50.000 | as it is in psychedelic therapy

00:33:53.000 | when you have music there as a default.

00:33:55.000 | And across the board, people should find this remarkable

00:33:58.000 | because it kind of is.

00:34:01.000 | All of the published studies that are now, you know,

00:34:03.000 | having such an impact on psychiatry and beyond

00:34:07.000 | have music there as a staple component

00:34:11.000 | and we just take it as assumption that it needs to be.

00:34:15.000 | I tend to share that assumption

00:34:17.000 | but it's remarkable that it hasn't been tested properly

00:34:20.000 | but it's there.

00:34:22.000 | And, you know, if you were to run with that

00:34:24.000 | and if you were, you know, had a kind of critical agenda,

00:34:29.000 | well, this is music therapy, you know.

00:34:31.000 | Why are you making all this fuss about psychedelics?

00:34:34.000 | It's music that's there in all of these trials

00:34:37.000 | with all these fantastic findings.

00:34:39.000 | So there is something to that, you know,

00:34:41.000 | and this will team me up probably to talk about psychedelic therapy

00:34:47.000 | being a combination treatment.

00:34:49.000 | We have a hyphen between the two

00:34:51.000 | because I share the hypothesis,

00:34:57.000 | the assumption that should be tested better,

00:34:59.000 | that there is a positive interaction between the two,

00:35:02.000 | that there's a synergy between the two.

00:35:04.000 | - That's why it's psychedelic therapy with a hyphen,

00:35:07.000 | just like Carhartt-Heron.

00:35:09.000 | I'd like to take a quick break

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00:36:24.000 | This is extremely useful to hear

00:36:27.000 | because I think most people think,

00:36:29.000 | okay, psychedelic, whether or not

00:36:31.000 | they have experience with psychedelics or not,

00:36:33.000 | get some visual hallucinations,

00:36:35.000 | some auditory hallucinations, some synesthesia,

00:36:37.000 | some visual auditory blending,

00:36:39.000 | somatic sensation, you know, rubbing a surface

00:36:41.000 | and being able to elicit the sounds

00:36:44.000 | in one's mind, of course, et cetera.

00:36:50.000 | But so seldom do we actually hear about

00:36:51.000 | the specifics of these clinical trials

00:36:54.000 | in a way that, for instance, points to music

00:36:56.000 | as one of the perhaps key variables.

00:36:58.000 | Now, you mentioned that as people enter

00:37:01.000 | these psychedelic states that there's

00:37:04.000 | a little bit of initial anxiety.

00:37:06.000 | About a year and a half ago,

00:37:09.000 | I had a discussion with Dr. Matthew Johnson

00:37:11.000 | who's running some psilocybin trials

00:37:13.000 | at Johns Hopkins, as you know.

00:37:15.000 | And he mentioned the critical importance,

00:37:19.000 | at least in his mind, to this idea

00:37:20.000 | of the patient "letting go" or allowing

00:37:24.000 | the experience to take them someplace mentally

00:37:28.000 | as opposed to trying to constrain

00:37:32.000 | their sensory and cognitive experience.

00:37:35.000 | I'm curious what your reflections

00:37:39.000 | are on that idea and why it might

00:37:41.000 | be so valuable clinically.

00:37:45.000 | And this ties back to this,

00:37:49.000 | earlier discussion we were having

00:37:50.000 | about the unconscious or about psychedelics

00:37:52.000 | revealing something that's there all the time

00:37:54.000 | but that we don't have access to.

00:37:57.000 | And again, I'm struggling to find

00:38:00.000 | the right language for this because

00:38:02.000 | we don't really have a neural mechanism

00:38:04.000 | like top-down inhibition or something

00:38:06.000 | like that to explain how this, you know,

00:38:08.000 | unconscious might be uncorked

00:38:11.000 | in the psychedelic experience.

00:38:13.000 | But to make it quite simple and direct,

00:38:15.000 | how important do you think it really is

00:38:18.000 | for the patient to feel like they are

00:38:19.000 | "letting go" and what in the world

00:38:22.000 | is letting go in biological terms?

00:38:25.000 | Yeah, yeah. Well, I think we'll get there

00:38:27.000 | in terms of having the neural correlates

00:38:30.000 | of the mind revealing itself to itself,

00:38:32.000 | you know, the emergence of the unconscious

00:38:37.000 | into consciousness or unconscious material

00:38:42.000 | into conscious awareness.

00:38:46.000 | It's a wonderful challenge.

00:38:47.000 | It's a huge challenge,

00:38:49.000 | but it's a challenge to embrace.

00:38:51.000 | And letting go very much is, again,

00:38:53.000 | a staple component of how the different teams

00:38:57.000 | do this work in terms of encouraging

00:39:01.000 | a willingness to let go.

00:39:04.000 | And when we started out doing our depression work

00:39:07.000 | and did that first trial,

00:39:10.000 | it was the first trial of a psychedelic illness

00:39:15.000 | in formerly diagnosed depression, you know,

00:39:16.000 | where that was the target population,

00:39:22.000 | a depressed population.

00:39:24.000 | It was the first modern study to do that.

00:39:26.000 | And we visited Hopkins, our friends there,

00:39:28.000 | and were mentored on how to do the guiding,

00:39:34.000 | Bill Richards, Mary Cosimano.

00:39:40.000 | They were just so brilliant.

00:39:44.000 | And, you know, wise in their guidance to us

00:39:45.000 | as to how to do the guiding in our trial.

00:39:51.000 | And so this phrase of trust, let go, be open,

00:39:55.000 | you'll hear a lot.

00:39:59.000 | I don't know who fairly it should be attributed to,

00:40:01.000 | but I would attribute it to Bill, Bill Richards.

00:40:05.000 | Yeah, everything's borrowed.

00:40:10.000 | You probably get it.

00:40:12.000 | You probably got it from someone else,

00:40:13.000 | but it's such a key principle.

00:40:15.000 | And it's almost like a mantra

00:40:17.000 | that you're trying to instill in people trust,

00:40:19.000 | let go, be open.

00:40:22.000 | And those different components

00:40:25.000 | where the trust is about therapeutic rapport,

00:40:27.000 | that again, you know, this goes beyond just intuition now.

00:40:30.000 | We've formally measured therapeutic rapport.

00:40:34.000 | We do it even with just a single item,

00:40:37.000 | a visual analog scale item,

00:40:41.000 | the subjective rating scale item.

00:40:42.000 | On the morning of dosing,

00:40:45.000 | and we find that it's a significant predictor

00:40:47.000 | of the quality of the experience

00:40:51.000 | that you have under the drug

00:40:53.000 | in the psychedelic therapy,

00:40:55.000 | and then the therapeutic outcomes

00:40:57.000 | X weeks or months later.

00:40:59.000 | So very powerful kind of chain

00:41:02.000 | of sort of predictive components there.

00:41:05.000 | But trust, essentially important.

00:41:10.000 | And again, not just intuition,

00:41:11.000 | but the data pointing to that.

00:41:13.000 | Let go.

00:41:15.000 | There's a readiness to surrender,

00:41:17.000 | to let go, to not resist.

00:41:20.000 | And we do measure that too

00:41:23.000 | and see that it's predictive of response.

00:41:25.000 | And then the being open

00:41:28.000 | is about a willingness to go there,

00:41:30.000 | to confront, to be inquisitive.

00:41:35.000 | Something that's easier said

00:41:39.000 | than done can be terrifying.

00:41:40.000 | When you're dealing

00:41:43.000 | with a very vulnerable population,

00:41:45.000 | it's probably more the rule

00:41:48.000 | than the exception that they're carrying

00:41:51.000 | some significant adversity,

00:41:53.000 | life adversity or frank trauma

00:41:55.000 | that they've suffered.

00:41:58.000 | And so that message of be open,

00:42:00.000 | be willing to confront

00:42:03.000 | and to go there is really powerful.

00:42:08.000 | And that's how it plays out.

00:42:09.000 | And often there is struggle.

00:42:12.000 | There's something going on

00:42:14.000 | that is I don't want to be feeling this,

00:42:16.000 | make it stop.

00:42:18.000 | That can be nightmarish at times,

00:42:20.000 | but it's very, very strong.

00:42:22.000 | And with these big doses that we give,

00:42:24.000 | it's very strong.

00:42:26.000 | And actually a student

00:42:29.000 | that I've worked with,

00:42:32.000 | I think now doing a PhD,

00:42:37.000 | Ari Brauer is working

00:42:38.000 | on a fantastic project

00:42:40.000 | characterizing the different phases

00:42:42.000 | of the psychedelic experience

00:42:44.000 | where the early phase is dominated

00:42:46.000 | by negative emotions

00:42:48.000 | and negatively valenced feelings

00:42:51.000 | of anxiety and struggle.

00:42:55.000 | And then it's a different story

00:42:57.000 | in the latter half.

00:42:59.000 | - Could I ask about that?

00:43:01.000 | First of all, I think that's fascinating

00:43:03.000 | and important to analyze

00:43:06.000 | and again, I'm delighted here

00:43:07.000 | because people typically hear

00:43:09.000 | about a psychedelic journey,

00:43:11.000 | but we never really hear

00:43:13.000 | about the kind of stereotypic components

00:43:15.000 | of the beginning, middle and end

00:43:17.000 | of that journey.

00:43:19.000 | We know that there's a peak

00:43:21.000 | and that there's a kind

00:43:23.000 | of a parachuting down and et cetera.

00:43:25.000 | But when you say that typically

00:43:27.000 | there's an anxiety,

00:43:29.000 | maybe some negative valence

00:43:31.000 | in the early stage,

00:43:33.000 | do you mean about the sensations

00:43:35.000 | that people are remembering?

00:43:36.000 | Likewise for the positive phase

00:43:38.000 | of the psychedelic journey or trip,

00:43:40.000 | are people, do they still call it a trip?

00:43:42.000 | - Yeah. - All right.

00:43:44.000 | I guess we'll use trip

00:43:46.000 | for the psychedelic trip.

00:43:48.000 | Are people feeling positive

00:43:50.000 | about the experience like,

00:43:52.000 | ah, like there's been some sort

00:43:54.000 | of breakthrough or they're

00:43:56.000 | in a calmer state or is it

00:43:58.000 | that they tend to be focusing

00:44:00.000 | on prior events that were positive?

00:44:02.000 | So in other words,

00:44:04.000 | we're reading through

00:44:05.000 | of some concept that comes

00:44:07.000 | to mind for people,

00:44:09.000 | maybe about an earlier trauma

00:44:11.000 | or maybe about a sense of self

00:44:13.000 | or a sense of other forgiveness.

00:44:15.000 | It could be any of these things,

00:44:17.000 | but what do we know about

00:44:19.000 | the kind of finer details of all that?

00:44:21.000 | - I would say the initial struggle

00:44:23.000 | is more against the general

00:44:25.000 | drug effects than pinning it

00:44:27.000 | on something specific.

00:44:29.000 | It's more that normal waking

00:44:32.000 | and consciousness, we have a sense,

00:44:34.000 | generally speaking, if we're well

00:44:36.000 | or well enough, a sense

00:44:38.000 | of assuredness about what's what.

00:44:40.000 | There's a table here and so on.

00:44:42.000 | And we have that assuredness

00:44:45.000 | to an extent about ourselves as well.

00:44:48.000 | It might be illusory, but we have it.

00:44:50.000 | And what the drug's doing is

00:44:52.000 | it's breaking down all of that

00:44:54.000 | and it's scary as hell.

00:44:56.000 | And if it's a big dose,

00:44:58.000 | it's just like human nature

00:45:01.000 | to rage against that a bit

00:45:02.000 | and a bit like dying.

00:45:05.000 | I don't want this.

00:45:07.000 | It feels like I could be dying.

00:45:09.000 | - I might lose my mind.

00:45:11.000 | - Yeah, that too. - And never come back.

00:45:13.000 | - Those two are the classics is,

00:45:15.000 | oh, but I might know

00:45:17.000 | that I've taken a psychedelic

00:45:19.000 | and I might even know

00:45:21.000 | a bit about psychedelics,

00:45:23.000 | but I still fear that I'm gonna go mad.

00:45:25.000 | Or that I know they,

00:45:27.000 | generally speaking,

00:45:30.000 | these drugs don't have

00:45:31.000 | a high fertility risk.

00:45:34.000 | I still think I'm gonna die.

00:45:42.000 | And it's just, it's very palpable

00:45:45.000 | and that comes up.

00:45:47.000 | So yeah, that's,

00:45:49.000 | I mean, those are the core fears

00:45:51.000 | that those two,

00:45:53.000 | and very reliably that comes up.

00:45:55.000 | And it's really like a basic drug action.

00:45:57.000 | It's dose dependent,

00:45:59.000 | but it's a basic drug action

00:46:00.000 | that is forcing something

00:46:02.000 | about the nature of the mind

00:46:04.000 | and the way it's made up

00:46:06.000 | that makes it feel that way.

00:46:08.000 | Oh, but it feels like I'm losing my mind

00:46:10.000 | or it feels like I could lose my mind

00:46:12.000 | or that I could go insane

00:46:14.000 | or that maybe I'm dying here

00:46:17.000 | and this is bad.

00:46:19.000 | Yeah.

00:46:21.000 | - You've talked many times before

00:46:23.000 | and have done really wonderful work

00:46:25.000 | looking at the changes

00:46:28.000 | in communication between different brain areas

00:46:30.000 | while people are under the influence of psychedelics.

00:46:33.000 | And I think the gestalt of those data,

00:46:35.000 | correct me if I'm wrong,

00:46:37.000 | is that compared to the non-psychedelic state

00:46:39.000 | that under psychedelic influence,

00:46:41.000 | there is far more,

00:46:43.000 | let's just call it interconnectivity

00:46:45.000 | or communication between brain areas

00:46:48.000 | that typically aren't communicating,

00:46:50.000 | which probably is not surprising to people

00:46:52.000 | given the subjective effects of these drugs.

00:46:55.000 | What is the evidence

00:46:57.000 | that after the psychedelic journey is over

00:46:59.000 | that some or perhaps all of that enhanced communication

00:47:04.000 | across brain areas is maintained?

00:47:06.000 | And if so, what role do you feel that could play

00:47:09.000 | in these incredible positive therapeutic outcomes?

00:47:13.000 | - Yeah.

00:47:15.000 | So we've had some recent findings in that direction

00:47:19.000 | where yes, it's true.

00:47:21.000 | And the picture that says a thousand words

00:47:26.000 | that some people might be familiar with

00:47:28.000 | are these two circles,

00:47:30.000 | a project that we did in collaboration

00:47:33.000 | with some researchers

00:47:35.000 | where ordinarily the communication

00:47:37.000 | is going on within systems.

00:47:40.000 | Like other regions of the visual system

00:47:44.000 | will be speaking mostly within the visual system.

00:47:48.000 | There'll be a kind of cliquishness

00:47:50.000 | or a modularity to the quality

00:47:53.000 | of the communication in the brain.

00:47:55.000 | And then the cool finding with psilocybin

00:47:58.000 | was the first paper is that the communication,

00:48:03.000 | yes, it sort of transcends these modules

00:48:05.000 | and becomes much more intermodular,

00:48:08.000 | crossing different modalities.

00:48:11.000 | And that effect correlated with the magnitude

00:48:14.000 | of the subjective effects,

00:48:16.000 | and then we replicated it with LSD

00:48:18.000 | using different methods.

00:48:20.000 | And a new paper will come out soon

00:48:23.000 | where DMT showing a similar effect.

00:48:25.000 | It's a bit of a debate

00:48:27.000 | about what regions are most implicated,

00:48:29.000 | but the general effect of an increase

00:48:31.000 | in global functional connectivity

00:48:33.000 | is what we call it,

00:48:35.000 | or global communication in the brain.

00:48:37.000 | - And this is while under the influence

00:48:39.000 | of these drugs. - This is under the influence.

00:48:41.000 | - So putting people into a brain scanner

00:48:43.000 | while they are under the influence of the drug.

00:48:45.000 | Is that right? - Yes, yes.

00:48:47.000 | - That itself must be quite an experience

00:48:49.000 | given that these scanners are small tubes.

00:48:52.000 | You've got a bite bar in your mouth.

00:48:53.000 | That's quite a study.

00:48:56.000 | - You don't always have a bite bar,

00:48:58.000 | at least with the psychedelics,

00:49:00.000 | but yeah, you've got to keep your head still

00:49:02.000 | and you have the loud MR scanner noise going.

00:49:06.000 | But because it's regular,

00:49:09.000 | there aren't too many surprises.

00:49:11.000 | So it's actually surprisingly tolerable.

00:49:15.000 | - And you're in a hospital setting,

00:49:17.000 | so you're not worried about what would happen

00:49:19.000 | if you had a cardiac event or something.

00:49:21.000 | - Most people generally tolerate that setting quite well,

00:49:24.000 | surprisingly well.

00:49:26.000 | But yeah, we do all that,

00:49:28.000 | and yes, we do see that opening up

00:49:31.000 | of the communication across systems in the brain.

00:49:35.000 | And it does speak to kind of intuition

00:49:38.000 | about the subjective experience

00:49:40.000 | that different modalities might be blending with each other.

00:49:45.000 | - Sorry for interrupting, but I have to ask,

00:49:49.000 | have you thought that the activation of the serotonin 2A receptor

00:49:52.000 | is what's responsible for the increased communication

00:49:55.000 | between brain areas that under normal circumstances

00:49:58.000 | would not be communicated?

00:50:00.000 | - Yes, so there's a few reasons why some modeling work,

00:50:03.000 | computational modeling work that first identifies

00:50:06.000 | where the 2A receptor is

00:50:08.000 | and then looks at models its basic effects

00:50:11.000 | on neural activity will recapitulate the,

00:50:18.000 | or recreate the effect that we see

00:50:21.000 | actually in the data with the scanning.

00:50:24.000 | So doing the computational modeling,

00:50:27.000 | you can see the same effect by knowing

00:50:29.000 | where the key receptors are

00:50:33.000 | and then making them do a certain thing

00:50:35.000 | that we know psychedelics do.

00:50:37.000 | - I can imagine two possibilities,

00:50:39.000 | and I think it's important to distinguish between these two.

00:50:42.000 | One possibility is that the activation

00:50:46.000 | of this serotonin 2A receptor leads to increased connectivity

00:50:49.000 | and thereby auditory and visual hallucinations emerge,

00:50:54.000 | changed patterns of thinking emerge, et cetera.

00:50:57.000 | That's sort of the obvious interpretation,

00:50:59.000 | but the scientist in me has to ask,

00:51:02.000 | is it possible that all of that increased connectivity

00:51:07.000 | is occurring and yet that is a distinct phenomenon

00:51:11.000 | layered on top of some other effect

00:51:14.000 | like drugs impacting access to the unconscious, hallucinations.

00:51:19.000 | In other words, is it the increased connectivity

00:51:22.000 | that's leading to the subjective experience

00:51:24.000 | or are those two things happening in parallel?

00:51:26.000 | - Well, they happen in parallel and they map to each other,

00:51:29.000 | but the question of causality, what causes what,

00:51:33.000 | is the tricky thing where I would suggest

00:51:39.000 | that the causality is circular,

00:51:43.000 | that they influence each other,

00:51:44.000 | and this gets a bit philosophical,

00:51:47.000 | but it kind of matters because otherwise,

00:51:50.000 | there's a trap that it's easy to fall into

00:51:54.000 | where you're thinking that it's all about the brain action

00:51:58.000 | causing the subjective experience,

00:52:00.000 | and that's typically what we do in cognitive neuroscience.

00:52:03.000 | It's kind of like the sort of first port of call

00:52:07.000 | kind of materialist approach,

00:52:11.000 | but one can be a materialist essentially,

00:52:13.000 | but still appreciate that circular causality

00:52:16.000 | that mind also interacts with brain,

00:52:19.000 | and it's so hard to pick the two apart

00:52:22.000 | and there is a kind of essential dualism

00:52:24.000 | where subjective experience is a thing in and of itself,

00:52:28.000 | but that's not to divorce it from what's going on

00:52:31.000 | on the biological level.

00:52:33.000 | - The reason I ask is because as I understand it,

00:52:37.000 | nowadays there's a bit of a movement

00:52:40.000 | within the scientific community that studies psychedelics

00:52:43.000 | to develop drugs that can essentially cure

00:52:48.000 | or alleviate many of the symptoms of depression or trauma

00:52:51.000 | that are built off our understanding

00:52:54.000 | of how psychedelics like psilocybin,

00:52:56.000 | and here I'll throw MDMA in there,

00:52:58.000 | although classically not a psychedelic.

00:53:00.000 | It kind of gets lumped in.

00:53:02.000 | We can get back to that later,

00:53:04.000 | but that do not produce hallucinations

00:53:08.000 | or massive changes in subjective experience.

00:53:10.000 | Actually, I think this is what initially

00:53:12.000 | got us into conversation on Twitter

00:53:14.000 | is I had learned about this paper

00:53:16.000 | published out of a group at UC Davis

00:53:18.000 | that essentially modifying psychedelics

00:53:20.000 | so that they have potential therapeutic application

00:53:23.000 | for the treatment of depression,

00:53:25.000 | but zero hallucinogenic properties.

00:53:29.000 | And I thought, wow, this is going to be

00:53:31.000 | a very controversial thing in the world, right?

00:53:34.000 | Because the history of psychedelics, as you pointed out,

00:53:37.000 | is being one of people accessing different modes of thinking,

00:53:39.000 | feeling, seeing things, letting go, trust, et cetera,

00:53:43.000 | a therapeutic relationship.

00:53:45.000 | And here we have, I don't want to say pharma

00:53:48.000 | because it's not really pharma,

00:53:50.000 | but we have laboratories who are trying

00:53:52.000 | to tease apart the activation of receptors

00:53:55.000 | independent of all that subjective experience

00:53:57.000 | in order to essentially treat the same conditions.

00:54:00.000 | I'd love for you to comment on this,

00:54:02.000 | where you think it might be going

00:54:05.000 | and whether or not you think that's the right

00:54:07.000 | or the wrong approach, if it has any validity at all.

00:54:10.000 | - It is pharma, it's just smaller pharma,

00:54:13.000 | sort of startup pharma.

00:54:15.000 | - Okay, so because pharma would like to have drugs

00:54:17.000 | that can cure depression, but don't make people hallucinate.

00:54:19.000 | Is that correct? - Oh, they would.

00:54:21.000 | And patients might, and the system would love it

00:54:24.000 | because the system is used to it.

00:54:26.000 | It's medicine. - Right.

00:54:28.000 | And it doesn't give this mental imagery

00:54:31.000 | of the summer of love in San Francisco

00:54:34.000 | or of kaleidoscope eyes, right?

00:54:37.000 | It's more, you could imagine the more,

00:54:41.000 | I have to be careful with my wording here,

00:54:43.000 | those who would not be inclined toward that

00:54:47.000 | might embrace a therapeutic that is strictly effective

00:54:51.000 | at treating depression with no hallucinations.

00:54:53.000 | - Yeah, and it doesn't look like an individual

00:54:57.000 | lying on a sofa, crying their eyes out.

00:55:03.000 | - Yeah. - About the life

00:55:04.000 | that they've lived and that deep catharsis

00:55:08.000 | being life transforming.

00:55:10.000 | They're very different from that model.

00:55:13.000 | I'm skeptical of it for a few reasons.

00:55:17.000 | And one is that I can't see the logic.

00:55:23.000 | I can't see the pieces fit in a way that's compelling.

00:55:31.000 | And I'm also skeptical 'cause I think

00:55:33.000 | it could easily be wishful thinking

00:55:36.000 | because of that point that patients would like it

00:55:40.000 | and the system would like it.

00:55:42.000 | And I just, you gotta bear that in mind as well.

00:55:47.000 | So wouldn't it be convenient if it were true

00:55:52.000 | and you could get the therapeutic action

00:55:54.000 | without the psychedelic effects?

00:55:56.000 | - Well, in a way, that's a little bit

00:55:59.000 | what microdosing seems to be designed to do.

00:56:01.000 | Like you said, take dosages that are below

00:56:03.000 | that perceptual or awareness of some effect threshold

00:56:08.000 | over a longer period of time in an attempt

00:56:10.000 | to ping the circuits or alter the circuits

00:56:14.000 | but not hallucinate, not have a catharsis.

00:56:17.000 | - So if microdosing can do that and it's sub-perceptible,

00:56:22.000 | then microdosing isn't a psychedelic action

00:56:25.000 | because where's the psychedelic action?

00:56:28.000 | When psychedelic, when defined means psyche revealing,

00:56:31.000 | you're not getting that effect.

00:56:33.000 | You might be getting the pharmacology.

00:56:35.000 | You might be getting some direct serotonin

00:56:37.000 | to a receptor agonism that could be driving

00:56:40.000 | a therapeutic response but you can get that

00:56:43.000 | with SSRIs as well.

00:56:45.000 | And so my point is, what's new?

00:56:48.000 | Okay, maybe it's a bit new and people are now developing

00:56:52.000 | direct two-way agonists rather than indirect

00:56:57.000 | through a serotonin releaser like the selective

00:56:59.000 | serotonin reuptake inhibitors.

00:57:01.000 | The SSRIs like Lexapro.

00:57:03.000 | - Are there any SSRIs that selectively agonize,

00:57:08.000 | which folks by the way means activate in a good way.

00:57:12.000 | Agony sounds terrible to those in foreign might think

00:57:15.000 | that mean that disrupt but that can activate

00:57:18.000 | the serotonin two-way receptor.

00:57:20.000 | Are there any drugs that will do that

00:57:22.000 | that are not psychedelic?

00:57:24.000 | I'm not aware of any but then again,

00:57:26.000 | I'm not a psychopharmacologist.

00:57:27.000 | - There are, I mean are there any that are licensed

00:57:30.000 | and used as medicines in psychiatry?

00:57:33.000 | I actually had this debate recently on social media

00:57:38.000 | and I couldn't see a compelling example.

00:57:42.000 | I saw two-way agonists that were used for other things.

00:57:45.000 | You have a compound like Lisseride used in treating

00:57:49.000 | Parkinson's but actually it's more of a dopamine agonist.

00:57:53.000 | - Right, so they're always hitting other things, right?

00:57:55.000 | - Yeah, yeah.

00:57:56.000 | - They're always tapping other neurotransmitters.

00:57:58.000 | - Or they're being used for other things.

00:58:00.000 | So is there a selective serotonin

00:58:02.000 | two-way receptor stimulator, an agonist,

00:58:04.000 | that isn't psychedelic, that is therapeutic in psychiatry

00:58:09.000 | and the answer firmly is no.

00:58:11.000 | I haven't seen it yet.

00:58:13.000 | Will they develop one?

00:58:15.000 | Well, for patient's sake, I hope so

00:58:17.000 | because it would be great.

00:58:19.000 | Let's wait and see.

00:58:21.000 | If they do, I doubt it will be psychedelic

00:58:24.000 | or have much to do with psychedelic therapy

00:58:26.000 | and it would be much more like the system we're used to

00:58:31.000 | of chronic pharmacotherapy, take your drug every day.

00:58:35.000 | Let's hope they find it and it works for patient's sake

00:58:40.000 | but as things stand right now, I'm a little skeptical.

00:58:44.000 | Now, some of the findings that are being seen

00:58:47.000 | that are really exciting, fantastic work being done

00:58:52.000 | showing things like increases in the communication components

00:58:57.000 | of neurons, dendritic growth, spine growth,

00:59:03.000 | synaptic spine growth.

00:59:05.000 | - Yeah, by the way, folks, just I'll interrupt

00:59:07.000 | not necessarily spine, the bone, not the cerebral column

00:59:12.000 | but spines are these little tiny twigs with bulbs

00:59:16.000 | on the end of neurons that allow for communication points

00:59:21.000 | in neurons.

00:59:22.000 | So neuroplasticity is often associated with growth

00:59:23.000 | of dendrites and spines and so forth

00:59:25.000 | which is what Robin's referring to.

00:59:27.000 | That reminds me and I just want to make sure

00:59:29.000 | that we close the hatch on the earlier answer

00:59:31.000 | because I interrupted you.

00:59:33.000 | Is the increased connectivity or communication

00:59:37.000 | between brain areas that's observed

00:59:39.000 | while people are under the influence of the psychedelic

00:59:42.000 | also observed later after the effects of the drug wear off?

00:59:46.000 | And then I'll just throw in another question there

00:59:50.000 | on the topic now, to what extent do we think

00:59:52.000 | that neuroplasticity, structural changes in neurons,

00:59:55.000 | functional changes in neurons are responsible for that

00:59:59.000 | and how long does that last?

01:00:01.000 | Let's say I come into your clinic.

01:00:03.000 | I'm a subject in your experiment.

01:00:05.000 | I'd come in in the morning.

01:00:07.000 | I'd do my psychedelic journey five or six hours later.

01:00:10.000 | I'm parachuting back to reality as we call it

01:00:13.000 | and then I go home, increase connectivity lasts for how long

01:00:19.000 | and how long are the structural brain changes occurring?

01:00:22.000 | Well, you're asking fantastic questions

01:00:24.000 | and partly because we don't have the answer yet

01:00:27.000 | but we do have some data and so we have looked at,

01:00:32.000 | first of all, in a sense the functional plasticity

01:00:35.000 | or what we assume it to be

01:00:37.000 | or at least the functional changes,

01:00:39.000 | the increase in communication across systems,

01:00:42.000 | that increase in global connectivity,

01:00:45.000 | functional connectivity.

01:00:48.000 | Do we see it after the trip?

01:00:49.000 | We know we see it during the trip,

01:00:51.000 | pretty well replicated,

01:00:53.000 | correlating with intense drug effects.

01:00:55.000 | Do we see it after the trip?

01:00:57.000 | Well, the answer is we've seen it

01:00:59.000 | in two different depression cohorts,

01:01:02.000 | psilocybin therapy for depression.

01:01:04.000 | In one study where we looked the next day,

01:01:06.000 | we saw it, a kind of residual effect

01:01:13.000 | similar to what you see acutely being seen the next day

01:01:17.000 | and then in a subsequent study,

01:01:18.000 | we saw it also three weeks later.

01:01:22.000 | So we've seen it in two independent data sets,

01:01:25.000 | this decrease in modularity is how we measure it.

01:01:29.000 | It's the same thing essentially.

01:01:31.000 | Broadly speaking, it's the same thing,

01:01:33.000 | an increase in global connectivity,

01:01:36.000 | functional connectivity and actually unpublished,

01:01:39.000 | we've seen it in healthy volunteers

01:01:41.000 | on a correlational level,

01:01:43.000 | not on an absolute change level

01:01:46.000 | but if you look at its relationship

01:01:48.000 | to a mental health outcome,

01:01:50.000 | and this is an important thing to stress

01:01:52.000 | with the depression work,

01:01:54.000 | we saw a relationship between the magnitude of that change,

01:01:57.000 | the decrease in modularity

01:01:59.000 | or increase in global connectivity

01:02:01.000 | and the improvement in symptom severity.

01:02:04.000 | So interesting.

01:02:06.000 | And just to state it a different way,

01:02:08.000 | so what Robin's referring to is when you say modularity,

01:02:11.000 | as neuroscientists we think of

01:02:13.000 | the different modular networks of the brain

01:02:15.000 | that the eye talks to a region of the thalamus

01:02:18.000 | involved in vision which talks to the visual cortex

01:02:20.000 | which eventually converges with auditory information of course

01:02:25.000 | but there's a separation or modularity of function.

01:02:29.000 | This increased connectivity is cross-modular

01:02:32.000 | during the trip but afterwards as well

01:02:34.000 | and you're saying that that correlates very strongly

01:02:37.000 | with the strength of the therapeutic outcome for depression.

01:02:40.000 | I mean the logical extension of that

01:02:44.000 | is that extreme modularity of brain function

01:02:46.000 | is depressive in some way.

01:02:49.000 | Now we don't want to go too far

01:02:51.000 | but what does that mean that increasing cross-talk

01:02:54.000 | between different modules of the brain

01:02:57.000 | is so strongly correlated with a positive therapeutic outcome?

01:03:02.000 | We don't know other than that as a relationship.

01:03:05.000 | I mean this is the thing

01:03:07.000 | and we need to be a little careful

01:03:09.000 | not to run with it too far.

01:03:11.000 | I mean there's some things that it suggests

01:03:14.000 | I think it suggests a more flexible mode of brain functioning

01:03:21.000 | if you're not getting stuck in modules

01:03:24.000 | or the modules aren't excessively cut off from each other

01:03:29.000 | but you see different things with different presentations

01:03:33.000 | if you were to look at cognition

01:03:35.000 | sharper cognition is actually associated with more modularity

01:03:41.000 | so it's a rule that's a little slippery

01:03:43.000 | and we need to be careful with it.

01:03:45.000 | I just again I'll forgive me for interrupting

01:03:48.000 | but I think I have friends who are

01:03:50.000 | I would say are on the spectrum

01:03:52.000 | who are very linear in their thinking

01:03:56.000 | and extremely intelligent in the kind of classic sense

01:04:00.000 | of being able to ratchet through hard problems

01:04:03.000 | to arrive at a solution

01:04:05.000 | and then I have friends who are

01:04:07.000 | let's just call them what they are

01:04:10.000 | on the outside of science

01:04:11.000 | that are very expansive

01:04:13.000 | they see connections between many different things

01:04:16.000 | but sometimes you have to

01:04:18.000 | not all of them but you have to catch their ideas

01:04:20.000 | with a butterfly net and oftentimes

01:04:22.000 | what they're saying doesn't

01:04:24.000 | sometimes just doesn't make any sense.

01:04:26.000 | Now they also produce incredible creative works

01:04:28.000 | but to have a conversation with them

01:04:30.000 | is anything but a linear experience.

01:04:32.000 | They're not random thought generators

01:04:34.000 | but there's a non-linearity or randomness

01:04:39.000 | or processing that's distinct from these other folks

01:04:41.000 | that I'm describing as on the spectrum

01:04:43.000 | and of course it's a spectrum

01:04:45.000 | there's a whole range in between.

01:04:47.000 | It sounds to me like there is some therapeutic value

01:04:50.000 | to being able to move along this continuum

01:04:52.000 | from the more linear to the non-linear.

01:04:55.000 | Is that correct?

01:04:57.000 | - Yeah it's resonating what you're saying

01:04:59.000 | it's speaking to my intuition

01:05:01.000 | that you could be very passy

01:05:06.000 | passing things up, chopping things up

01:05:08.000 | like an analytical scientist.

01:05:09.000 | - A splitter. - Like I'm doing.

01:05:11.000 | - A splitter as we say in science

01:05:13.000 | you're either a lumper or a splitter.

01:05:15.000 | - Or the way I'm being very particular

01:05:17.000 | about when to call something psychedelic

01:05:21.000 | that kind of passy analytical way

01:05:23.000 | of thinking you might associate

01:05:25.000 | with a more modular system.

01:05:27.000 | Whereas the system that's more globally

01:05:31.000 | interconnected and open

01:05:33.000 | might be more flexible and creative

01:05:37.000 | and divergent in the associations and so on.

01:05:39.000 | So yes that's speaking to my intuition

01:05:41.000 | to how you're describing it.

01:05:43.000 | And I imagine if you take severe psychopathology

01:05:46.000 | severe mental illness like a depression

01:05:50.000 | I've always thought that there's something intuitive

01:05:52.000 | about the term itself

01:05:54.000 | like a depression in a landscape.

01:05:56.000 | You know which is a whole.

01:05:58.000 | - Physical depression. - A physical depression

01:06:00.000 | that it's easy to fall into

01:06:02.000 | and if you do it's hard to get out of.

01:06:04.000 | - So almost if I understand what you're saying

01:06:06.000 | correctly almost like getting stuck

01:06:07.000 | at one location on this continuum

01:06:10.000 | because most people don't reside

01:06:12.000 | at one extreme or the other full time

01:06:14.000 | and kind of migrate back and forth

01:06:17.000 | between expansive states and more linear states.

01:06:19.000 | - Like you do with low mood.

01:06:22.000 | If you're healthy and inverted commas

01:06:24.000 | you can feel your low mood, your disappointment

01:06:26.000 | but you can spring back.

01:06:28.000 | But someone with--

01:06:30.000 | - You know you can spring back.

01:06:32.000 | Whereas the suicidal depressive person

01:06:35.000 | or a suicidally depressed person

01:06:36.000 | somehow at least in my understanding

01:06:40.000 | there's something about the extreme depressive states

01:06:43.000 | and extreme anxiety states,

01:06:47.000 | something my laboratory's a bit more familiar with anxiety,

01:06:49.000 | which alters the perception of time

01:06:51.000 | such that people feel like that negative state

01:06:54.000 | is going to go on forever

01:06:59.000 | or that if it goes away

01:07:03.000 | that it's going to return at random.

01:07:06.000 | Kind of a vulnerability to the time domain.

01:07:08.000 | - Yeah, yeah that's it.

01:07:10.000 | And it's so tragic but that cognitive bias

01:07:12.000 | in depression that everything's hopeless

01:07:15.000 | and that there is no light at the end of the tunnel.

01:07:18.000 | Yeah so if you were to get stuck in that rut

01:07:21.000 | and have that bias then you're cut off

01:07:24.000 | from other things, other sensory modalities

01:07:32.000 | or modules, you know, cut off from the world,

01:07:33.000 | cut off from other people, stuck in your inner rut.

01:07:36.000 | And so yes, I think we're sharing this intuition

01:07:39.000 | that a decrease in modularity

01:07:43.000 | or an opening up of the system, the brain

01:07:45.000 | could relate to an opening up of the mind

01:07:48.000 | that is kind of enduring

01:07:51.000 | after the psychedelic dosing session.

01:07:53.000 | And yeah, and the third replication

01:07:57.000 | was to see in healthies an improvement in well-being

01:08:01.000 | because they're healthy, we don't look at depression.

01:08:02.000 | - So these are people that are healthy

01:08:05.000 | walking into the trial. - Yeah.

01:08:07.000 | - Take psilocybin twice.

01:08:09.000 | - Well, actually they do

01:08:11.000 | but the first dose is one milligram

01:08:13.000 | which they don't feel, it's a placebo dose.

01:08:15.000 | - What a quote, micro dose.

01:08:18.000 | - Yeah, we stick EG on their heads

01:08:20.000 | to measure their brain waves.

01:08:22.000 | During each dose and one milligram you see no change.

01:08:24.000 | So we, I think--

01:08:30.000 | - No, I'm just kidding.

01:08:31.000 | I've been working against the micro doses.

01:08:33.000 | I've always just been a little bit skeptical

01:08:35.000 | based on my conversations with the scientists

01:08:37.000 | actually doing the work with psychedelics.

01:08:39.000 | It seems like the answer keeps coming back.

01:08:43.000 | Do one or two, maybe three macro doses

01:08:47.000 | in a controlled safe setting.

01:08:53.000 | - Well, that's compelling.

01:08:55.000 | The evidence for that is compelling

01:08:57.000 | and that's what's making all the difference right now

01:08:59.000 | and micro-dosing is just appealing.

01:09:00.000 | But again, science isn't about what we want to believe.

01:09:02.000 | It's about what's actually coming through

01:09:07.000 | and what seems to hold up to testing.

01:09:10.000 | - I'd like to just take a brief break

01:09:14.000 | and thank one of our sponsors, which is Element.

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01:09:19.000 | that has everything you need and nothing you don't.

01:09:21.000 | That means plenty of salt, sodium, magnesium and potassium,

01:09:23.000 | the so-called electrolytes and no sugar.

01:09:28.000 | Now, salt, magnesium and potassium are critical

01:09:29.000 | to the function of all the cells in your body,

01:09:32.000 | in particular to the function of your nerve cells,

01:09:34.000 | also called neurons.

01:09:36.000 | And we now know that even slight reductions

01:09:38.000 | in electrolyte concentrations or dehydration of the body

01:09:40.000 | can lead to deficits in cognitive and physical performance.

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01:09:47.000 | of 1000 milligrams, that's one gram of sodium,

01:09:50.000 | 200 milligrams of potassium and 60 milligrams of magnesium.

01:09:53.000 | I typically drink Element first thing in the morning

01:09:57.000 | when I wake up in order to hydrate my body

01:09:58.000 | and make sure I have enough electrolytes.

01:10:00.000 | And while I do any kind of physical training

01:10:02.000 | and after physical training as well,

01:10:04.000 | especially if I've been sweating a lot

01:10:06.000 | and certainly I drink Element in my water

01:10:08.000 | when I'm in the sauna and after going in the sauna

01:10:10.000 | because that causes quite a lot of sweating.

01:10:13.000 | If you'd like to try Element,

01:10:15.000 | you can go to drink element, that's lmnt.com/huberman

01:10:17.000 | to claim a free Element sample pack with your purchase.

01:10:20.000 | Again, that's drink element lmnt.com/huberman.

01:10:26.000 | - Would you say that's right,

01:10:27.000 | the one or two or three sessions

01:10:29.000 | and how far apart are those typically spaced in time?

01:10:31.000 | - Yeah, typically one, two, three weeks across the sites

01:10:34.000 | is the way people are doing

01:10:39.000 | the psychedelic therapy dicing sessions.

01:10:41.000 | Two sessions, Hopkins, Imperial, NYU,

01:10:43.000 | that's been a kind of default too.

01:10:49.000 | We actually use three in a current anorexia trial,

01:10:55.000 | the cybin therapy for anorexia.

01:10:56.000 | Two patients left to see after 19

01:10:58.000 | who've gone through the trial,

01:11:03.000 | very exciting results there.

01:11:05.000 | - You're seeing alleviation

01:11:08.000 | of the obsessive thought about food

01:11:10.000 | and a willingness to consume healthier amounts of food.

01:11:12.000 | - Yeah, even improved weight at the long follow-up.

01:11:15.000 | - So critical.

01:11:19.000 | We did an episode on eating disorders

01:11:21.000 | and I learned that anorexia nervosa

01:11:24.000 | which by the way, folks,

01:11:25.000 | the rates of are not increasing.

01:11:27.000 | It's been pretty stable through time

01:11:29.000 | despite what's said about social media and et cetera.

01:11:31.000 | But anorexia nervosa being the most deadly

01:11:35.000 | of all psychiatric illnesses,

01:11:39.000 | which is a big statement because manic depression,

01:11:41.000 | so-called bipolar depression

01:11:45.000 | has a 20 to 30 times the typical suicide rate.

01:11:47.000 | Basically many anorexic,

01:11:52.000 | people with anorexia I think is how it's now,

01:11:53.000 | is what one says, not anorexics,

01:11:56.000 | but people with anorexia often die.

01:11:58.000 | Many of them die.

01:12:01.000 | - Yeah, so tragic.

01:12:03.000 | So often young people as well

01:12:05.000 | and similarly with suicide in terms of premature death.

01:12:07.000 | So the tragedy with psychiatry is so strong

01:12:11.000 | and so it's so rewarding to be doing that trial

01:12:15.000 | and to be seeing good results.

01:12:19.000 | I have to check myself a little bit

01:12:21.000 | that I am reporting on it in this really promissory way

01:12:22.000 | and the trial isn't yet publicly released and published

01:12:27.000 | so it's still ongoing as well.

01:12:32.000 | - But that was three sessions.

01:12:34.000 | - It is three sessions and I can't say what the dosage is

01:12:36.000 | because we still have, there is a blinding component

01:12:39.000 | but there are three dosing sessions

01:12:43.000 | and let's see now, I think they're two weeks apart.

01:12:50.000 | And we do the follow-up, yes.

01:12:51.000 | - I'd like to close out this description

01:12:57.000 | of the journey and the trip by extending past the day

01:13:02.000 | when people actually take the drug

01:13:05.000 | into this what I've heard described

01:13:07.000 | as the integration phase.

01:13:10.000 | You have to reintegrate, right?

01:13:12.000 | All this increased connectivity during the session,

01:13:14.000 | hallucinations, insights, anxiety, letting go,

01:13:19.000 | maybe revelation, maybe epiphany, okay, great.

01:13:20.000 | At what point is that consolidated?

01:13:24.000 | Meaning are these patients or subjects

01:13:27.000 | in studies having daily conversation with their therapist?

01:13:31.000 | Are they journaling every day?

01:13:35.000 | And I want to keep in mind that most people

01:13:37.000 | are not going to be part of a clinical trial

01:13:40.000 | and of course here we're not suggesting

01:13:42.000 | what people do or not do but let's just put it this way.

01:13:47.000 | How are people to use psychedelics?

01:13:49.000 | What is the way that people can maximize

01:13:52.000 | on the neuroplasticity and the brain changes

01:13:55.000 | in a positive way in the days and weeks afterwards?

01:13:58.000 | In other words, how long does this

01:14:01.000 | so-called integration last?

01:14:03.000 | And how far can we take this?

01:14:05.000 | I could imagine that how often one chooses

01:14:09.000 | to think about the insights could also have an impact.

01:14:16.000 | Because clearly people went to raves,

01:14:17.000 | clearly people did psychedelics in the 60s.

01:14:19.000 | We don't know if, clearly people do psychedelics now,

01:14:21.000 | but we don't have data on those people.

01:14:25.000 | You have access to the understanding

01:14:27.000 | of how they're spending their time

01:14:29.000 | and the therapeutic outcomes,

01:14:31.000 | which we haven't gotten to the numbers yet,

01:14:33.000 | but again are incredibly impressive.

01:14:35.000 | You know, in upwards of, as I understand it,

01:14:37.000 | 60% or more people getting relief from depression.

01:14:39.000 | - Yeah, 70, yeah.

01:14:42.000 | - 70%, incredible, especially when compared

01:14:45.000 | to the typical antidepressant treatments and so on.

01:14:46.000 | So what is this business of integration?

01:14:51.000 | How is it done properly?

01:14:54.000 | - Yeah, yeah, gosh.

01:14:56.000 | Well, how long does it last as well?

01:14:58.000 | A lifetime, you know, life is a journey.

01:15:01.000 | Like a trip is a journey.

01:15:05.000 | And there's always work to do.

01:15:08.000 | You know, as Jack Kornfield says

01:15:10.000 | after the ecstasy, the laundry.

01:15:14.000 | - I love that.

01:15:15.000 | - Yeah, there'll be other good ones as well.

01:15:17.000 | I forget them.

01:15:19.000 | But yeah, so the work's ongoing.

01:15:21.000 | Yeah, but this gives you a foot up.

01:15:26.000 | It enables people to do the work more easily.

01:15:30.000 | And that's true of the classic psychedelics.

01:15:35.000 | It's also true, very true of MDMA therapy

01:15:37.000 | for post-traumatic stress disorder.

01:15:40.000 | It's really giving you a leg up,

01:15:43.000 | making it easier to do very, very difficult work,

01:15:44.000 | going back to a trauma, trying to digest it,

01:15:47.000 | process it, integrate it.

01:15:50.000 | So it's such an essential component

01:15:54.000 | of the treatment model.

01:15:57.000 | But one has to be realistic as well.

01:16:00.000 | You know, by saying, oh, integration lasts a lifetime,

01:16:03.000 | well, people delivering a service

01:16:06.000 | can't be there for a lifetime.

01:16:09.000 | So what's the answer?

01:16:11.000 | And people are wrestling with that issue right now.

01:16:12.000 | And I think one of the solutions might be

01:16:18.000 | that it's in a sense on you to a point, you know.

01:16:20.000 | The therapeutic team can treat you to a point

01:16:25.000 | and then it becomes what you might call practice

01:16:29.000 | in a similar way that meditation is a practice.

01:16:32.000 | It's something that you have to keep up.

01:16:36.000 | And if it's something that you have to keep up,

01:16:40.000 | and if it slips, then things could slip.

01:16:41.000 | And that's the way it is.

01:16:45.000 | Or you have another psychedelic treatment, you know.

01:16:48.000 | So people have even used this term of practice

01:16:53.000 | in relation to psychedelics,

01:16:55.000 | where there's a psychedelic practice,

01:16:57.000 | like there's a meditation practice.

01:16:59.000 | But I'm using meditation intentionally here

01:17:03.000 | because they actually think that meditation

01:17:08.000 | and they think that meditative practice,

01:17:09.000 | spiritual practice, elements of spiritual practice

01:17:15.000 | could be a very important complement

01:17:18.000 | to psychedelic therapy.

01:17:21.000 | And I think it's probably doing something similar

01:17:25.000 | in terms of promoting an ability to sit with.

01:17:28.000 | A former colleague of mine said it quite well

01:17:34.000 | in relation to psychedelic therapy

01:17:37.000 | versus chronic pharmacotherapy,

01:17:38.000 | or like SSRIs being on them all the time.

01:17:40.000 | So psychedelic therapy allows you to sit with

01:17:42.000 | rather than sit on.

01:17:45.000 | And I thought that's quite good.

01:17:47.000 | Yeah, so you know, the meditation, the mindfulness,

01:17:49.000 | the ability to, yes, be presence-centered,

01:17:54.000 | but also presence-centered and accepting.

01:17:58.000 | So if things come up, you can watch and process

01:18:01.000 | and then let go.

01:18:06.000 | That holy grail of mindfulness.

01:18:07.000 | Awareness without reactivity.

01:18:13.000 | I grew up in the Bay Area

01:18:16.000 | and you'd hear this language, right?

01:18:18.000 | And I'm not being disparaging of this.

01:18:20.000 | I have friends that are on the board of Esalen

01:18:22.000 | and work down there, you know,

01:18:24.000 | and I've gone there and it's, you know,

01:18:26.000 | and yet you hear these terms, right?

01:18:28.000 | Be responsive, not reactive,

01:18:30.000 | which to a neuroscientist is like greats on me,

01:18:35.000 | which just means I have issues.

01:18:36.000 | But, and surely I do.

01:18:38.000 | But, you know, it's like, what does that mean, right?

01:18:40.000 | It's sort of saying like, oh, to be the observer

01:18:42.000 | but not be drawn into the experience.

01:18:44.000 | You know, and again,

01:18:46.000 | I don't want to be overly reductionist,

01:18:48.000 | but what I find so compelling about the emerging data,

01:18:50.000 | because it really is data on psychedelics

01:18:54.000 | as treatments for depression and trauma,

01:18:57.000 | namely psilocybin and MDMA,

01:18:59.000 | is that it really seems to allow people this space

01:19:04.000 | that is so commonly thrown around, you know,

01:19:05.000 | giving space between stimulus and reaction.

01:19:08.000 | I mean, Victor Frankl talked about this,

01:19:10.000 | but you know, I've been reading a wonderful book

01:19:12.000 | called "The Prince of Medicine"

01:19:14.000 | that dates back to the origins of medicine,

01:19:16.000 | very dense book.

01:19:18.000 | People have been talking about this stuff

01:19:20.000 | and thinking about this stuff for thousands of years.

01:19:22.000 | Psychedelics seem to give people access

01:19:24.000 | to that better version of self,

01:19:26.000 | which is remarkable.

01:19:28.000 | What's also remarkable,

01:19:30.000 | it's perhaps worth pointing out,

01:19:33.000 | I've been comfortable having this conversation.

01:19:34.000 | I would have been afraid to lose my job.

01:19:36.000 | Stanford Magazine this week

01:19:38.000 | just published an entire issue about psychedelics

01:19:40.000 | with how ketamine works, MDMA, psilocybin,

01:19:42.000 | with the appropriate cautionary notes in there,

01:19:44.000 | but clearly times are changing.

01:19:46.000 | Speaking of which,

01:19:50.000 | I know you're doing a trial on first-time use of psychedelics.

01:19:53.000 | What inspired that and what are you observing?

01:19:58.000 | And as you tell us that,

01:20:02.000 | please give us a few of the key contours.

01:20:03.000 | What's the dose?

01:20:07.000 | How old are these subjects?

01:20:09.000 | I'm assuming it's men and women.

01:20:11.000 | Are they suffering from depression or not?

01:20:13.000 | What's the landscape of that study?

01:20:15.000 | And I realize this is still early days of the study

01:20:17.000 | or maybe it's close to completion.

01:20:19.000 | It's not yet published, however, correct?

01:20:21.000 | No, it's not published.

01:20:23.000 | It's not submitted.

01:20:25.000 | It is completed.

01:20:27.000 | So this was another one of our COVID studies in a sense,

01:20:29.000 | meaning COVID hit and we had to finish the study.

01:20:32.000 | And it was hard to finish the study because of COVID.

01:20:33.000 | That was true about psilocybin therapy

01:20:35.000 | versus escitalopram, Lexapro trial,

01:20:37.000 | which is published, New England Journal of Medicine.

01:20:42.000 | This was 20, that paper, by the way,

01:20:45.000 | folks will provide a link to in the show note captions,

01:20:47.000 | as well as some of Robin's other papers.

01:20:49.000 | I think the 2022 New England Journal paper

01:20:52.000 | is really fabulous given the different dosages

01:20:55.000 | and the comparison to essentially what is microdosing

01:21:00.000 | and the comparison to escitalopram.

01:21:01.000 | Yeah, that's interesting that you link

01:21:04.000 | the way we gave small doses of psilocybin to microdosing.

01:21:06.000 | We didn't think of it that way.

01:21:09.000 | We thought it was just a necessary placebo

01:21:11.000 | for the big dose, the 25 milligrams.

01:21:15.000 | Yeah, so that we could say to everyone

01:21:19.000 | we're giving you psilocybin and not be lying.

01:21:21.000 | Yeah, for those who got escitalopram,

01:21:24.000 | Lexapro for six weeks, they got a very, very low dose.

01:21:29.000 | But it allowed us to standardize all the psychotherapy and so on.

01:21:30.000 | But the other study that you're referring to

01:21:34.000 | was in healthies, healthy volunteers,

01:21:37.000 | middle aged, average age, I think was 40.

01:21:40.000 | So not your typical student study

01:21:43.000 | that is so often the case in psychology research.

01:21:46.000 | All the undergrads end up volunteering for your study.

01:21:49.000 | So this is more of an age range and also,

01:21:58.000 | I think it was an equal proportion of male and female.

01:21:59.000 | All the staff actually were female,

01:22:03.000 | which the staff were very proud of.

01:22:05.000 | Although it produces its own potential confound, right?

01:22:07.000 | To have all one sex of staff.

01:22:10.000 | Possibly.

01:22:14.000 | They did a good job in the sense

01:22:16.000 | that we saw significant improvements in wellbeing

01:22:18.000 | at the end of the trial.

01:22:22.000 | So let me describe the design.

01:22:24.000 | It was a repeated measures design

01:22:27.000 | meaning people come in, you collect your baseline data

01:22:28.000 | and do a brain scan and you give people a placebo.

01:22:32.000 | We gave people a placebo.

01:22:37.000 | Actually, let me rewind a little bit.

01:22:39.000 | Everyone's healthy volunteers, middle aged,

01:22:41.000 | never taken a psychedelic in their life.

01:22:43.000 | None of them.

01:22:45.000 | Entirely fresh, virgin people coming in

01:22:47.000 | and the plan is to give them

01:22:50.000 | their first ever psychedelic experience.

01:22:53.000 | So that's what we did in the study.

01:22:56.000 | But to do it, we have this repeated measures design

01:22:57.000 | where they'll first get a placebo.

01:23:00.000 | And we have the placebo

01:23:02.000 | so that we can do all the procedures,

01:23:04.000 | all the therapy, all the music listening

01:23:06.000 | but not give a whopping dose of psilocybin.

01:23:08.000 | Again, we gave them a placebo dose

01:23:11.000 | of psilocybin, one milligram.

01:23:13.000 | We stick EG headsets on during the experience

01:23:15.000 | to record the brain activity from the scalp,

01:23:19.000 | the oscillating electrical activity

01:23:25.000 | and we do the MRI scanning before and after

01:23:26.000 | to see deeper into the brain

01:23:31.000 | and we can look at the functional connectivity

01:23:33.000 | that we were referring to earlier

01:23:35.000 | and also properties of brain anatomy

01:23:37.000 | which we did in this study.

01:23:39.000 | So the short story is that all of the changes

01:23:41.000 | that we saw both psychologically and neurobiologically

01:23:45.000 | were seen with the 25 milligrams.

01:23:51.000 | It all happened with that big whopping dose.

01:23:54.000 | And what did we see?

01:23:55.000 | Well, we did see significant improvements

01:23:57.000 | in psychological well-being.

01:23:59.000 | We saw what I call the entropic brain effect

01:24:01.000 | which is actually formally quite accurate.

01:24:05.000 | We see an increase in the informational complexity

01:24:07.000 | of ongoing brain activity recorded with the EG

01:24:11.000 | on the dose of psilocybin.

01:24:16.000 | The activity becomes more complex.

01:24:19.000 | It's harder to predict across the brain

01:24:22.000 | and it's harder to predict across time.

01:24:23.000 | It's more informationally rich

01:24:25.000 | and that effect correlates as it does very reliably

01:24:28.000 | with the magnitude of the subjective effect.

01:24:30.000 | So the bigger the trip,

01:24:32.000 | the bigger the entropic brain effect,

01:24:34.000 | now pretty well replicated finding.

01:24:37.000 | But then the MRI seeing deep into the brain

01:24:41.000 | was probably our most exciting result

01:24:45.000 | where we didn't just see some functional brain activity

01:24:49.000 | but we've seen some anatomical brain changes as well.

01:24:50.000 | And we used a technique called diffusion tensor imaging

01:24:54.000 | that looks at the cabling of the brain,

01:24:57.000 | the white matter tracks.

01:24:59.000 | And we saw a change in major tracks

01:25:01.000 | so we sort of limited our search space

01:25:04.000 | to really thick tracks, really thick fibers.

01:25:07.000 | And the fibers that came through as changing

01:25:11.000 | were ones that traveled between the brain

01:25:14.000 | and the brain.

01:25:18.000 | They traveled between the prefrontal cortex

01:25:19.000 | and the thalamus and the striatum.

01:25:22.000 | There were two tracks, two prefrontal tracks

01:25:26.000 | that changed and they changed in the direction

01:25:30.000 | of a decrease in axial diffusivity

01:25:32.000 | which could be interpreted as tract integrity

01:25:35.000 | where a decrease would be an increase in tract integrity.

01:25:41.000 | It is something that you see in the developing brain

01:25:47.000 | that axial diffusivity decreases

01:25:48.000 | as a brain goes from being a baby to being an adult,

01:25:51.000 | axial diffusivity goes down.

01:25:55.000 | And then in aging and pathologies of aging,

01:25:58.000 | axial diffusivity goes up.

01:26:01.000 | - So this is in the opposite direction

01:26:04.000 | of the results you talked about earlier

01:26:06.000 | in terms of brain connectivity

01:26:08.000 | of a sort of increased communication across areas.

01:26:10.000 | If I understand correctly,

01:26:13.000 | and I'm perfectly happy to be wrong by the way,

01:26:16.000 | that this decrease in axial diffusivity

01:26:17.000 | translates to a higher fidelity of communication

01:26:20.000 | between the prefrontal cortex

01:26:24.000 | and the thalamus and striatum as opposed to less.

01:26:26.000 | And your description of this is somewhat

01:26:30.000 | like the transition from babyhood

01:26:32.000 | and childhood to adulthood speaks to the same

01:26:35.000 | where we know that there's a massive culling

01:26:39.000 | of connections as opposed to growth of connections.

01:26:41.000 | So in other words, as we get older,

01:26:45.000 | we get better at doing certain things

01:26:46.000 | and less good at doing potentially most everything else.

01:26:48.000 | Is that right?

01:26:51.000 | - Ish, because the change was anatomical

01:26:53.000 | and not functional.

01:26:57.000 | So the other stuff is really measuring

01:26:59.000 | communication in the brain by looking

01:27:03.000 | at how the activity fluctuates across time

01:27:06.000 | and whether those fluctuations in activity

01:27:10.000 | are synchronous between regions.

01:27:14.000 | And when we say they are,

01:27:15.000 | we say they're functionally connected

01:27:17.000 | and we infer that they're talking to each other

01:27:19.000 | 'cause they go up and down in synchrony.

01:27:21.000 | But when it comes to the anatomy,

01:27:24.000 | we're talking about the just static material stuff.

01:27:26.000 | And so we're seeing the fibers

01:27:31.000 | and a property of the fibers change.

01:27:35.000 | At least that's what we think.

01:27:39.000 | And recently we had an independent person

01:27:43.000 | reanalyze the data 'cause one of those things,

01:27:44.000 | incredible finding requires credible evidence,

01:27:47.000 | really strong evidence.

01:27:53.000 | And I would say the evidence at the moment

01:27:55.000 | is one study, so we need to be cautious on that.

01:27:57.000 | But we did reanalyze it and use this correction procedure,

01:28:00.000 | free water correction, to be more sure

01:28:05.000 | that it was a change in the actual microstructure

01:28:09.000 | rather than something to do

01:28:12.000 | with the extracellular space,

01:28:13.000 | the water surrounding the fibers.

01:28:15.000 | And it came through.

01:28:18.000 | In fact, the change was strengthened

01:28:20.000 | by doing this correction step.

01:28:22.000 | - So these are, this is neuroplasticity

01:28:24.000 | as the consequence of one first-time session

01:28:27.000 | with 25 milligrams of psilocybin.

01:28:30.000 | - Yeah, yeah, so we're excited.

01:28:33.000 | - Understandably so.

01:28:35.000 | - And the two different,

01:28:37.000 | you know, the second analyst coming in

01:28:39.000 | wasn't sure she believed it

01:28:41.000 | and then she, you know, thought this correction technique

01:28:42.000 | might kind of kill the result

01:28:44.000 | and then it came through and she's like,

01:28:46.000 | "Okay, now I'm excited too."

01:28:48.000 | So we'll see, we don't know what it means.

01:28:50.000 | What does it mean functionally, we don't know.

01:28:52.000 | How did the people change?

01:28:55.000 | Well, psychologically, as I said, well-being improved.

01:28:57.000 | We did look at their cognition

01:29:01.000 | and we used a cognitive flexibility paradigm

01:29:03.000 | that looks at people's ability to notice a rule change

01:29:10.000 | and then flexibly adapt their behavior

01:29:11.000 | based on noticing this rule change

01:29:14.000 | and people improved after the 25 milligrams

01:29:17.000 | and didn't significantly improve after the placebo dose.

01:29:20.000 | There weren't correlations with the DTI change,

01:29:24.000 | the cabling change and these psychological outcomes

01:29:28.000 | but, you know, with these studies in smaller sample sizes,

01:29:32.000 | you don't always see those correlations come through.

01:29:35.000 | So it's something we don't know.

01:29:39.000 | We don't know what it means

01:29:40.000 | but it's a change in brain anatomy

01:29:42.000 | that's in the opposite direction

01:29:45.000 | to what you see in an aging brain

01:29:47.000 | or with pathology of aging

01:29:50.000 | and it's what you see in a healthy brain

01:29:52.000 | as it goes from, you know,

01:29:54.000 | normal neurodevelopment into adulthood.

01:29:56.000 | - Very, very exciting and intriguing

01:29:59.000 | and I appreciate that you highlighted

01:30:01.000 | that it's just one study,

01:30:03.000 | although from everything you've said,

01:30:05.000 | it sounds like it's been done with immense rigor

01:30:08.000 | so we will eagerly await the publication of that study

01:30:09.000 | and so we can peruse all the data

01:30:13.000 | and the subsequent studies.

01:30:15.000 | I want to hear a bit about the study

01:30:17.000 | that you have been carrying out

01:30:20.000 | on the use of psilocybin

01:30:22.000 | for the treatment of fibromyalgia.

01:30:24.000 | I'm intrigued by fibromyalgia

01:30:26.000 | because I have a good friend

01:30:28.000 | who also, I won't reveal who it is

01:30:30.000 | and no, it's not me.

01:30:32.000 | This isn't the I have a friend thing

01:30:34.000 | who also is a scientist

01:30:37.000 | in a very high position

01:30:38.000 | in the National Institutes of Health

01:30:40.000 | who quietly has expressed to me

01:30:42.000 | that they are incredibly frustrated

01:30:44.000 | with the fact that the standard medical community

01:30:46.000 | has largely ignored fibromyalgia

01:30:50.000 | and that for many years,

01:30:54.000 | it was kind of lumped with things

01:30:56.000 | like chronic fatigue syndrome

01:30:58.000 | and other so-called, again, so-called,

01:31:00.000 | I'm not saying this,

01:31:02.000 | but people often refer to these as,

01:31:04.000 | oh, it's psychosomatic, that's all in your head,

01:31:06.000 | that's a ridiculous statement to hear

01:31:07.000 | because it's all in your head,

01:31:09.000 | your brain is in your head.

01:31:11.000 | After all, your physiology

01:31:13.000 | and your psychology

01:31:15.000 | are influencing each other, of course,

01:31:17.000 | and the world is starting to appreciate that more.

01:31:19.000 | But first of all,

01:31:21.000 | maybe you could tell people

01:31:23.000 | what fibromyalgia is,

01:31:25.000 | what inspired you to do a study

01:31:27.000 | on fibromyalgia using psilocybin of all things

01:31:29.000 | because that's surprising to me

01:31:31.000 | and if you are allowed to

01:31:33.000 | or if you have access to the data

01:31:35.000 | in mind, share with us a little bit

01:31:36.000 | about what you're discovering

01:31:38.000 | in that study.

01:31:40.000 | - Sure, yeah, happy to.

01:31:42.000 | So again, it's psilocybin therapy

01:31:44.000 | and the population is fibromyalgia syndrome

01:31:46.000 | so this is people presenting

01:31:48.000 | with a generalized chronic pain.

01:31:50.000 | So unlike some other pain disorders

01:31:52.000 | where the pain is focused,

01:31:54.000 | you can say it's my lower back

01:31:56.000 | which is very common,

01:31:59.000 | chronic lower back pain.

01:32:01.000 | This is more generalized

01:32:04.000 | and for that reason,

01:32:05.000 | it's hard to sort of know what it is

01:32:09.000 | and that's why it's been

01:32:11.000 | a controversial space in medicine

01:32:13.000 | and it's been, yeah,

01:32:15.000 | it's had that charge thrown at it

01:32:17.000 | that maybe it's psychosomatic

01:32:19.000 | and just to your point,

01:32:21.000 | is anything ever independent

01:32:23.000 | of the mind anyway?

01:32:25.000 | But this is actually a fascinating space

01:32:27.000 | for how subjective experience,

01:32:31.000 | the lived experience

01:32:33.000 | of the mind can influence the body

01:32:34.000 | because there's some really interesting literature

01:32:37.000 | around the etiology,

01:32:41.000 | like how the pain has come about.

01:32:45.000 | In a sense, like what caused the pain?

01:32:48.000 | What's the story there?

01:32:50.000 | And ahead of the trial,

01:32:52.000 | I would say to my colleagues,

01:32:54.000 | let's just be careful

01:32:56.000 | because there is some fascinating literature

01:32:58.000 | around things like a background of trauma

01:33:01.000 | and how that can relate to issues

01:33:08.000 | related to inflammation

01:33:10.000 | and how that can express into things

01:33:12.000 | like fibromyalgia syndrome.

01:33:15.000 | I just said be very careful there

01:33:17.000 | because if you go in with an assumption

01:33:19.000 | that there's some buried trauma, for example,

01:33:21.000 | then there's that whole other side of psychoanalysis

01:33:24.000 | that massively tripped it up

01:33:26.000 | around false memory and so on

01:33:29.000 | so please don't hold prior assumptions

01:33:31.000 | that you're going to uncover buried trauma in every case.

01:33:35.000 | Now, the team have treated, I think, eight people

01:33:39.000 | and it is going very well.

01:33:43.000 | Again, I just want to be careful

01:33:46.000 | with how I describe it to manage expectations

01:33:51.000 | and not get too carried away.

01:33:53.000 | But I check in with the team every week

01:33:57.000 | and they're still based in London doing the work.

01:34:00.000 | And it's remarkable what I hear

01:34:04.000 | about the profound experiences

01:34:09.000 | that people have under the drug.

01:34:11.000 | In this study, we only give one dose.

01:34:13.000 | It's a very mechanistic study.

01:34:15.000 | We actually have the EEG cap on in the sessions

01:34:18.000 | like in the healthy volunteer study

01:34:20.000 | but this time now taking it into a clinical population.

01:34:25.000 | - So they're in the eye, they are wearing an eye mask

01:34:30.000 | under the influence of 25 milligrams of psilocybin.

01:34:34.000 | Most of them probably have not done psilocybin before

01:34:37.000 | so it's a little bit like the first time study in some sense.

01:34:41.000 | They have fibromyalgia that's debilitating in some way.

01:34:47.000 | They don't want it, obviously.

01:34:50.000 | And during the session,

01:34:53.000 | are they thinking about their pain?

01:34:55.000 | Are they being told to think about their pain?

01:34:57.000 | - They're not being told to think about the pain.

01:34:59.000 | In fact, as I understand it,

01:35:03.000 | while there is a therapeutic model

01:35:05.000 | around acceptance of the pain,

01:35:08.000 | it isn't, unlike some of the PTSD work,

01:35:11.000 | you aren't encouraging them to focus on the index trauma

01:35:16.000 | and then work through it and try and digest it.

01:35:20.000 | We don't do that with the pain.

01:35:22.000 | So the pain's there,

01:35:23.000 | but there isn't an invitation to focus on it.

01:35:27.000 | And that's probably one of the differences

01:35:29.000 | with classic psychedelic therapy versus MDMA therapy.

01:35:32.000 | Arguably MDMA therapy is more like,

01:35:36.000 | it's a bit closer to traditional talk therapy

01:35:39.000 | where there is more dialogue.

01:35:41.000 | People are able to talk on MDMA.

01:35:44.000 | - In the MDMA trials,

01:35:46.000 | do you know whether or not they used eye masks?

01:35:51.000 | Or because this seems to be an important distinction

01:35:54.000 | between as you described the therapeutic trip

01:35:57.000 | versus the trip that one does,

01:35:59.000 | going into the woods and taking psilocybin in the woods

01:36:03.000 | or at a party or while staring at a poster or a leaf.

01:36:08.000 | Again, I'm not trying to trivialize those experiences.

01:36:13.000 | I mean, obviously they can be profound, so I'm told.

01:36:18.000 | But the MDMA trials seem to involve, as you said,

01:36:23.000 | more directed dialogue

01:36:26.000 | and sometimes even kind of empathic connection

01:36:30.000 | between people by they're actually looking at one another.

01:36:33.000 | The eyes and eye contact being such a key part

01:36:36.000 | of the human social cognitive connective networks.

01:36:41.000 | So do you know if they put eye masks on people

01:36:46.000 | during the therapy?

01:36:47.000 | - I'm pretty sure that they have the eye masks there.

01:36:50.000 | - Because a lot of the MDMA work,

01:36:53.000 | and I was part of an MDMA trial,

01:36:55.000 | was, as I understand, geared toward developing,

01:36:59.000 | because it's an empathogen, empathy toward the self.

01:37:03.000 | - I'm pretty sure they have the eye masks there,

01:37:06.000 | but they probably, and it's a great question

01:37:09.000 | because you could formally test this,

01:37:11.000 | they probably don't use them as much.

01:37:13.000 | The thing is with the classic psychedelics,

01:37:16.000 | you're looking at your guides, your facilitators,

01:37:18.000 | and their faces are melting or whatever.

01:37:20.000 | - On MDMA, you just might really start to feel

01:37:23.000 | more connected to your stuff.

01:37:25.000 | - Yeah, they might look especially beautiful.

01:37:27.000 | - Sure, yeah.

01:37:29.000 | - And yeah, there's that fascinating effect

01:37:33.000 | of loving the people that you're with.

01:37:36.000 | And so yeah, I imagine they talk more

01:37:40.000 | and use the eye shades less.

01:37:42.000 | And it is more interpersonal

01:37:45.000 | rather than intrapersonal or going inside.

01:37:47.000 | They do use a fascinating terminology

01:37:49.000 | that some people have critiqued,

01:37:51.000 | but it's a very interesting phenomenon,

01:37:54.000 | and it's this notion of the inner healer.

01:37:56.000 | They use that language a lot.

01:37:58.000 | It's been critiqued 'cause it sounds very suggestive,

01:38:02.000 | and that's probably one of the vehicles here driving

01:38:05.000 | the therapeutic process is suggestion.

01:38:07.000 | I think we have to be honest about that.

01:38:13.000 | But so when they go inside, that's another term

01:38:16.000 | that we use very much in the classic psychedelic therapy work.

01:38:19.000 | You go inside, you put the eye shades on,

01:38:22.000 | and people are encouraged to go inside.

01:38:25.000 | But when they do that in the MDMA work especially,

01:38:29.000 | they might be told explicitly and listen to the inner healer

01:38:34.000 | in that kind of language.

01:38:36.000 | So you could see how a cynic or a skeptic could come in

01:38:41.000 | and see that as some kind of suggestive priming or biasing.

01:38:45.000 | I think they have a point.

01:38:47.000 | Skeptics often do, but I don't think it's all of the story.

01:38:53.000 | And just briefly, 'cause it's an interesting point,

01:38:57.000 | speaking to that point a bit,

01:39:00.000 | in our psilocybin therapy versus estetelopram trial,

01:39:04.000 | we measured pretrial expectancy,

01:39:07.000 | and we did it for both conditions.

01:39:10.000 | So what kind of improvement do you expect with the Lexapro,

01:39:14.000 | the estetelopram at the end of the trial,

01:39:17.000 | and what kind of improvement if you go into the psilocybin arm

01:39:20.000 | and get two big doses of psilocybin,

01:39:23.000 | what kind of improvement do you think you'll see in that arm?

01:39:27.000 | And of course it was a coin flip as to what arm people went into,

01:39:32.000 | and there was no crossover.

01:39:35.000 | And what we found was that it was true that we had a sample bias,

01:39:41.000 | so most people had higher expectations,

01:39:44.000 | on average there were higher expectations for psilocybin

01:39:47.000 | and its efficacy or effectiveness versus the SSRI, the Lexapro.

01:39:53.000 | However, when we looked at the correlation

01:39:57.000 | or the predictive relationship between pretrial expectancy and response,

01:40:03.000 | we saw that pretrial expectancy for the estetelopram

01:40:06.000 | predicted response to estetelopram across virtually every single measure,

01:40:12.000 | all these different measures of depression and anxiety and wellbeing,

01:40:17.000 | and I think none of the scales,

01:40:20.000 | I'm pretty sure it was none of about 12 or so mental health rating scales,

01:40:26.000 | was there a relationship between pretrial expectancy,

01:40:30.000 | even though it was high, it didn't predict,

01:40:33.000 | pretrial expectancy didn't predict response to the psilocybin therapy.

01:40:38.000 | So that was a bit of a smash on the head for the idea

01:40:44.000 | that classic psychedelic therapy is some kind of placebo response.

01:40:49.000 | I think it's so important to address that question

01:40:52.000 | because if it doesn't come through as it didn't come through,

01:40:59.000 | then it opens up even more intrigue about, well, what is it then?

01:41:04.000 | If it's not just a placebo response or a super placebo response,

01:41:08.000 | like an amplification of the placebo response,

01:41:12.000 | then it must be something else and how intriguing it has a direct therapeutic action,

01:41:17.000 | it must be something and we don't yet know what it is.

01:41:21.000 | I talked about the residual increase in global connectivity,

01:41:27.000 | that's one possibility, but the truth is we're just scratching the surface.

01:41:32.000 | And yet the therapeutic outcomes are, again, just so marvelously impressive.

01:41:38.000 | I'm curious as to why, well, there aren't that many labs,

01:41:43.000 | but the laboratories that are focused on classic psychedelics

01:41:47.000 | for the treatment of depression and now, as you mentioned,

01:41:50.000 | promising results for anorexia and fibromyalgia as well,

01:41:53.000 | although preliminary, very promising.

01:41:56.000 | Why the lack of attention toward LSD?

01:42:00.000 | Is it that the LSD trips are just too long?

01:42:04.000 | Is it that they are qualitatively different?

01:42:08.000 | Are there any data on non-microdoses of LSD?

01:42:14.000 | And here I want to be very careful

01:42:15.000 | because I learned through my interactions on social media

01:42:18.000 | that this term microdose is very misleading

01:42:21.000 | and in some cases can be dangerously misleading

01:42:25.000 | and as I mentioned earlier, the effective psychedelic dose

01:42:28.000 | or, you know, the effective meaning that can induce a real trip

01:42:33.000 | with hallucinations, et cetera, of LSD is actually in the microgram range.

01:42:41.000 | So some people hear microdose

01:42:43.000 | and they think microgram of LSD is a micrograms is a microdose

01:42:48.000 | when in fact a macrodose of LSD can be measured in micrograms, right?

01:42:53.000 | So this is where, you know, in the absence of scientific training,

01:42:56.000 | people can really go astray

01:42:58.000 | or even in just in the lack of understanding of the metric system

01:43:02.000 | and since now you're a recent rival to the US.

01:43:06.000 | Fortunate for us.

01:43:08.000 | Sorry, England's loss is the US's gain

01:43:11.000 | by Robin's lab move from England to the United States recently.

01:43:16.000 | So score one for us.

01:43:19.000 | But why isn't there more use of LSD in these trials?

01:43:23.000 | I think it probably is the duration of the trip.

01:43:27.000 | It used to be stigma

01:43:29.000 | and it was easier to get your psilocybin study through

01:43:34.000 | because others were, they were getting that through.

01:43:37.000 | So there was still like Franz Wallenweider in Zurich in Switzerland

01:43:41.000 | and then Roland Griffiths coming along

01:43:43.000 | and doing the psilocybin work at Hopkins.

01:43:47.000 | So you could appeal to that precedence

01:43:49.000 | and say well they're doing it over there, you know.

01:43:51.000 | Can we not do it in little England?

01:43:54.000 | So that's how it worked for us.

01:43:57.000 | We did actually go on and do an LSD study

01:44:00.000 | once we kind of laid the foundations

01:44:03.000 | for doing this kind of work

01:44:06.000 | and it was a brain imaging study.

01:44:08.000 | It was a really extensive one actually

01:44:10.000 | where we used both MRI and another modality called MEG,

01:44:13.000 | sort of super EG in a sense.

01:44:16.000 | But why didn't we, why didn't that turn our heads to think

01:44:23.000 | oh should we not be doing our trials with LSD?

01:44:26.000 | It does have something to do with the pragmatics.

01:44:30.000 | Like a study day with psilocybin is long enough.

01:44:34.000 | It's a four to six hour trip.

01:44:36.000 | Yeah and the FDA ask us to have the people in the lab

01:44:44.000 | until eight hours post dose,

01:44:46.000 | which personally I think could be quite excessive,

01:44:49.000 | especially if it's a low dose.

01:44:51.000 | You know if you have that in the placebo condition as well

01:44:54.000 | it becomes impractical.

01:44:56.000 | Yeah scientists are not paid nearly enough to warrant the,

01:45:00.000 | there's no such thing as overtime

01:45:02.000 | for the graduate students and postdocs.

01:45:04.000 | Yeah it's often that there's more junior members

01:45:07.000 | that are doing that really hard work.

01:45:09.000 | It was described very well to me by a student

01:45:13.000 | a graduate student said to me,

01:45:14.000 | "They really can't afford to pay us by the hour."

01:45:17.000 | Because we used to work, he was an electrophysiologist

01:45:20.000 | so he would run experiments, no joke folks,

01:45:22.000 | three to five day experiments,

01:45:25.000 | sleeping in bouts of two hours here or there

01:45:28.000 | in a dark room with a bunch of equipment and recording.

01:45:32.000 | So these are long, long,

01:45:34.000 | acute electrophysiological recordings.

01:45:37.000 | So yeah no scientist does it for the money I promise you.

01:45:42.000 | There's money in pharma, there is not money in personal income,

01:45:48.000 | it's not lucrative for the basic scientist.

01:45:51.000 | So yes LSD is what, anywhere from eight to 15 hours,

01:45:57.000 | something like that.

01:45:58.000 | Yeah 15 would be a little long, you'd be a bit worried

01:46:00.000 | if you were still tripping at that time,

01:46:02.000 | maybe with a really big dose.

01:46:04.000 | Oops, no just kidding.

01:46:06.000 | But yeah, eight hours plus and dose dependent,

01:46:10.000 | yeah if it's a bigger dose it's a longer experience.

01:46:12.000 | But if you're going to dose at say 10am in the morning,

01:46:17.000 | which is more or less how it often goes,

01:46:19.000 | then at 6pm still feeling the effects

01:46:23.000 | and then how long do you wait now to close things out

01:46:28.000 | before they can go home.

01:46:30.000 | Even with psilocybin you have people still at work

01:46:33.000 | into the evening and the staff are always there later

01:46:36.000 | of course because they've got to pack up.

01:46:39.000 | And yeah, so these are long days and it's just,

01:46:42.000 | it's too much you know.

01:46:44.000 | - That makes sense, practical constraints.

01:46:47.000 | I learned from a recent guest on this podcast

01:46:50.000 | that we recorded with Dr. Satchin Panda

01:46:53.000 | who was a colleague of mine when I was down

01:46:55.000 | at the Salk Institute, pioneered a lot of the studies

01:46:57.000 | on so-called intermittent fasting.

01:46:59.000 | That the reason the intermittent, that the eating period

01:47:02.000 | in these studies in animals and now on humans

01:47:05.000 | is eight hours, the sort of feeding window

01:47:08.000 | in these studies is because the graduate student

01:47:10.000 | was going to otherwise lose their relationship

01:47:13.000 | because their significant other says,

01:47:15.000 | "Listen, you can be in the lab for 12 hours."

01:47:17.000 | That meant some hours before the experiment,

01:47:19.000 | then eight hours and then some hours afterwards,

01:47:21.000 | but you can't stay in there longer.

01:47:23.000 | And many people use the eight hour feeding window

01:47:25.000 | as a consequence.

01:47:27.000 | So the science has to exist and be carried out

01:47:29.000 | in real world frame.

01:47:31.000 | - It does, it does.

01:47:33.000 | - MDMA is a little bit, a little bit shorter, right?

01:47:37.000 | It's also about four to six hours, correct?

01:47:38.000 | - Yeah, it's kind of similar to psilocybin.

01:47:40.000 | Yeah, it is, and actually in the MAPS work,

01:47:42.000 | they redose after a certain point.

01:47:44.000 | - Or the boost, the booster.

01:47:46.000 | - They have a booster, optional booster, yeah.

01:47:48.000 | So there is that.

01:47:50.000 | And now people are thinking, well,

01:47:52.000 | even these psilocybin sessions are long and expensive

01:47:57.000 | and if you have to have two staff members there

01:48:00.000 | all the time, that's expensive.

01:48:02.000 | That's where most of the expense is, is in the staffing.

01:48:06.000 | So can we abridge the experience, make it shorter,

01:48:09.000 | and get away with it,

01:48:11.000 | and get similar kind of therapies outcomes.

01:48:14.000 | So there's a lot of interest in that direction.

01:48:17.000 | - May I ask about, sorry to interrupt,

01:48:19.000 | but I want to make sure I don't forget too,

01:48:21.000 | ask about combination psilocybin MDMA therapies.

01:48:25.000 | The reason I ask about this is, and here truly not me,

01:48:29.000 | but I know people who do self-administered combination

01:48:35.000 | psilocybin and MDMA.

01:48:36.000 | I think I have this right.

01:48:38.000 | I think it's called a hippie flip.

01:48:40.000 | There's another one that involves LSD too.

01:48:42.000 | Again, I'm not suggesting people

01:48:44.000 | do these kind of drug combinations,

01:48:46.000 | but the way it was described to me was that the psilocybin,

01:48:50.000 | because it's so serotonergic sometimes can be not a downer,

01:48:55.000 | but can have a bit of a kind of a murky feel to it,

01:48:59.000 | some real deep introspection sometimes

01:49:02.000 | in the darker realms of one's psyche, depressive thoughts,

01:49:05.000 | et cetera.

01:49:07.000 | Not that it necessarily stays that way throughout the trip,

01:49:09.000 | but that the MDMA,

01:49:11.000 | because it has a very strongly serotonergic,

01:49:13.000 | but also dopaminergic.

01:49:15.000 | I mean, it has an amphetamine component,

01:49:17.000 | cocaine-like in fact.

01:49:19.000 | If you've ever seen someone in MDMA,

01:49:21.000 | their pupils are about the size of quarters for a reason.

01:49:25.000 | They're in extremely, extreme autonomic arousal

01:49:29.000 | compared to a sedative.

01:49:31.000 | Which by the way, would constrict the pupils.

01:49:34.000 | So they described the use of MDMA

01:49:37.000 | to kind of balance out the kind of affect component of it.

01:49:41.000 | What are your thoughts on combination psilocybin MDMA?

01:49:46.000 | Does this hold any therapeutic potential?

01:49:48.000 | This is obviously a backyard chemistry

01:49:51.000 | in the sense that people are,

01:49:53.000 | kind of cowboying this stuff on their own,

01:49:56.000 | which again, I don't really recommend.

01:49:58.000 | I like to see the science go first,

01:50:00.000 | but I understand this is how it works in the real world.

01:50:02.000 | Yeah, what are your thoughts on combining compounds?

01:50:05.000 | - Yeah, well, I guess they're cowboying it

01:50:07.000 | in recreational context,

01:50:09.000 | but also underground therapists do work with this combo.

01:50:13.000 | - That's what I'm referring to.

01:50:15.000 | I'm not talking about people partying with this stuff.

01:50:17.000 | I'm talking about, there are thousands now of therapists

01:50:21.000 | that offer psychedelic therapies illegally, really,

01:50:24.000 | 'cause it's not legal, at least not in the US,

01:50:26.000 | to possess or sell, but that are doing this.

01:50:29.000 | So that's really why I'm asking.

01:50:30.000 | - Yeah, and I think there's something to be said

01:50:32.000 | for one who has to be careful with this as a scientist,

01:50:35.000 | but if they're doing it,

01:50:37.000 | are they using some kind of trial and error?

01:50:39.000 | The same is true, of course,

01:50:41.000 | with the longer history of psychedelic plant medicine use.

01:50:46.000 | By plants, we include the fungi as well,

01:50:50.000 | so in the extended sense, plants.

01:50:52.000 | There will have been trial and error there.

01:50:55.000 | It might not be as systematic

01:50:58.000 | as the science we do today,

01:50:59.000 | but maybe there's been a learning process,

01:51:01.000 | and maybe what they do,

01:51:03.000 | they've come to because they found it works.

01:51:06.000 | So by that principle, I'm interested in that combination

01:51:10.000 | and whether it does offer some advantages,

01:51:13.000 | maybe in certain patients.

01:51:15.000 | One of the buzz terms in medicine these days

01:51:19.000 | is precision medicine, precision medicine

01:51:22.000 | and personalized medicine.

01:51:24.000 | So maybe there are certain cases

01:51:27.000 | where introducing, say, psilocybin after the MDMA

01:51:33.000 | or the other way around could offer some advantages,

01:51:37.000 | and the differences are interesting.

01:51:39.000 | Psilocybin can get you to deep places,

01:51:45.000 | maybe the kernel of your suffering

01:51:48.000 | and major life experiences and complexes

01:51:55.000 | that are causally linked to whatever the pathology

01:51:59.000 | that you're presenting with,

01:52:01.000 | but it can do it sometimes quite aggressively.

01:52:05.000 | And if it's, say, post-traumatic stress disorder,

01:52:09.000 | it can be overwhelming, and you can fight it,

01:52:12.000 | and really it's that.

01:52:14.000 | The resistance is really challenged,

01:52:17.000 | and they fight back.

01:52:20.000 | The therapeutic breakthrough and the progress

01:52:24.000 | isn't happening because you've agitated

01:52:26.000 | the defense mechanisms.

01:52:28.000 | Whereas what MDMA offers is something,

01:52:31.000 | arguably, more directionally reliable

01:52:35.000 | in terms of the valence.

01:52:38.000 | It's more directionally positive,

01:52:40.000 | generally, in MDMA experience.

01:52:42.000 | Hard to have a bad time on MDMA.

01:52:44.000 | To be quite blunt.

01:52:46.000 | One of the concerns I had with MDMA,

01:52:49.000 | I've never done it recreationally.

01:52:51.000 | I have had not and have not ever done it recreationally.

01:52:54.000 | But when it was done in this therapeutic setting,

01:52:56.000 | I realized, because there was music on at the beginning,

01:52:59.000 | I actually asked them to turn it off

01:53:02.000 | because I realized that the music

01:53:04.000 | was becoming such an attractor to my attention

01:53:07.000 | that I suddenly was starting to think about music

01:53:09.000 | and my love of music, which was not the focus

01:53:11.000 | of the session that I was there for.

01:53:15.000 | And I'm glad that they did turn the music off

01:53:17.000 | because the moment they did,

01:53:19.000 | I was able to drop in within the IMS

01:53:22.000 | inward and address some certain issues

01:53:23.000 | that at least to me felt key and productive.

01:53:26.000 | So that seems to be the kind of hazard with MDMA

01:53:29.000 | is that it's such an empathogen

01:53:32.000 | that one could start to,

01:53:35.000 | you could go down any number of different rabbit holes.

01:53:38.000 | - Yeah, yeah, but it's also,

01:53:41.000 | it's a strength because you,

01:53:43.000 | well, you know, the classics like psilocybin

01:53:46.000 | can take you there very reliably

01:53:48.000 | but maybe a bit aggressively.

01:53:51.000 | MDMA makes it easier to go there

01:53:54.000 | and that's its strength

01:53:56.000 | and that's why that marriage of MDMA therapy

01:53:58.000 | for PTSD in particular is a good combo.

01:54:03.000 | It works because you are gonna go there.

01:54:05.000 | In a sense, you have to really make the therapeutic progress.

01:54:09.000 | You're gonna have to go back there

01:54:11.000 | but we're gonna set it up so that you can go back there

01:54:16.000 | and feel safer and more trusting

01:54:20.000 | and be able to go back there

01:54:21.000 | whereas you've never otherwise been able

01:54:24.000 | to go back there without dissociating

01:54:26.000 | or having horrible flashbacks and so on.

01:54:30.000 | So that's the strength that it offers.

01:54:33.000 | I guess the limitation would be

01:54:35.000 | that maybe it doesn't take you as deep

01:54:37.000 | as the classic psychedelics

01:54:40.000 | and I tend to think, I'm biased on this one,

01:54:43.000 | that there's a kind of honesty to the classics

01:54:45.000 | in that it is hell as well as heaven.

01:54:49.000 | And that's the psyche.

01:54:51.000 | It isn't all roses.

01:54:53.000 | - I really appreciate that you bring that up

01:54:56.000 | because I think that there's such a fear

01:54:58.000 | of so-called bad trips.

01:55:01.000 | There's such a fear in non-psychotic states

01:55:05.000 | to avoid the painful

01:55:08.000 | and everything we know from trauma

01:55:13.000 | and the treatment of trauma

01:55:15.000 | and we've had several guests on here.

01:55:18.000 | I have a close, close colleague at Stanford,

01:55:19.000 | Dr. David Spiegel, our associate chair of psychiatry,

01:55:22.000 | he's a clinical hypnotist, amazing,

01:55:24.000 | amazing human being and scientist and clinician

01:55:26.000 | has really just embedded this in my mind

01:55:31.000 | that the only way to deal with trauma

01:55:33.000 | is to get right up next to that trauma

01:55:35.000 | to the point where some relief is experienced.

01:55:38.000 | There is no other real way.

01:55:40.000 | And so I really appreciate that you're saying

01:55:43.000 | that the classic psychedelics may offer

01:55:46.000 | with a very strong nudge perhaps,

01:55:48.000 | the opportunity to get into the uncomfortable

01:55:51.000 | in a way that MDMA or some non-classical psychedelics

01:55:55.000 | perhaps do not.

01:55:57.000 | We were talking about timeframes

01:55:59.000 | or duration of trips and these different compounds

01:56:02.000 | and how they differ and how they're similar.

01:56:05.000 | I'd love for you to educate me on DMT

01:56:08.000 | and some of the work that you're doing with DMT.

01:56:10.000 | My understanding is that it's a very brief trip, minutes,

01:56:15.000 | people I know who have done this, again, therapeutically.

01:56:18.000 | Actually, I'll just point to one very exciting,

01:56:21.000 | I think, group and initiative,

01:56:24.000 | which is the Veteran Solutions Initiative,

01:56:26.000 | which is a group, this is carried out in Mexico,

01:56:29.000 | but in conjunction with laboratories at Stanford

01:56:31.000 | and elsewhere who are evaluating the neural changes.

01:56:34.000 | And this involves Ibogaine, which is Iboga,

01:56:37.000 | which is a very long duration psychedelic,

01:56:39.000 | 22 hours or more, followed by a,

01:56:44.000 | I think, one or two doses of DMT.

01:56:46.000 | This is for veterans to deal with any number of issues.

01:56:50.000 | Appears to be working with great success

01:56:52.000 | and I've spoken to several people who've gone through this

01:56:54.000 | and the way that they described DMT,

01:56:56.000 | almost across the board, was quote,

01:56:59.000 | here I'm just pulling quotes, right? Anecdota.

01:57:03.000 | The most profound experience of my entire life,

01:57:06.000 | even greater than the birth of my children,

01:57:10.000 | quote, like being attached to the shockwave of an atom bomb,

01:57:15.000 | quote, there's no way I would do another dose

01:57:19.000 | because the first one was so unbelievable.

01:57:21.000 | Interesting, by the way.

01:57:23.000 | I think most of us, including me, would think,

01:57:25.000 | why wouldn't you want to do it again then?

01:57:27.000 | But this idea that that was just beyond anything.

01:57:29.000 | So these are significant, excuse me,

01:57:31.000 | these are significant statements

01:57:33.000 | coming from individuals who have existed

01:57:36.000 | at the extremes of human experience to begin with, right?

01:57:39.000 | These are so-called tier one operators

01:57:41.000 | within the special operations who exit

01:57:43.000 | and may or may not have trauma,

01:57:45.000 | but DMT sounds like a big deal.

01:57:50.000 | Short duration, really big deal.

01:57:53.000 | What do we know about its chemistry?

01:57:55.000 | What do we know about how it's impacting brain networks

01:57:57.000 | and what in the world is going on

01:58:00.000 | that people are describing it as

01:58:02.000 | the ways I just mentioned a few moments ago?

01:58:06.000 | Yeah, it's a rocket ship.

01:58:09.000 | If the psalocybin is like a ship leaving port,

01:58:13.000 | then yeah, this is a rocket ship into craziness.

01:58:19.000 | Is it serotonin 2A?

01:58:21.000 | It is, yeah.

01:58:23.000 | So it is a classic psychedelic.

01:58:25.000 | It's a direct agonist, a direct stimulator

01:58:27.000 | of the serotonin 2A receptor.

01:58:30.000 | It's an order of magnitude less potent

01:58:35.000 | than psalocybin, but potency is a funny thing

01:58:39.000 | because it's dose dependent.

01:58:41.000 | So that doesn't mean that the experience with DMT

01:58:43.000 | is less than that of psalocybin.

01:58:45.000 | It's just that you give more of the drug.

01:58:49.000 | But it has, that's matched by its stickiness

01:58:53.000 | for the serotonin 2A receptor,

01:58:55.000 | which is this kind of golden rule in psychedelic sciences

01:58:58.000 | that it was discovered in the mid 1980s,

01:59:00.000 | this tight relationship between the affinity

01:59:04.000 | and the stickiness or the binding potential

01:59:05.000 | of a psychedelic for the 2A receptor in particular,

01:59:08.000 | serotonin 2A, and its potency.

01:59:11.000 | And the stickier the drug, the more potent.

01:59:13.000 | So LSD really sticky, very, very potent.

01:59:16.000 | You only need those tiny microgram doses.

01:59:20.000 | So DMT by its affinity is a little less potent,

01:59:25.000 | but by its effects when you give a standard dose,

01:59:30.000 | it's just wild.

01:59:34.000 | And DMT, because there's another compound

01:59:36.000 | called 5-methoxy DMT, which is a bit different

01:59:40.000 | pharmacologically and subjectively.

01:59:43.000 | Similar in terms of its kinetics.

01:59:45.000 | It's another rocket ship.

01:59:47.000 | Both compounds in the wild, so to speak,

01:59:52.000 | are smoked often, DMT and 5-MeO.

01:59:59.000 | They're keeping both actually now.

02:00:01.000 | There are vape pens that have been developed

02:00:05.000 | for people to administer this,

02:00:08.000 | but more traditionally it's been a smoking thing.

02:00:11.000 | This is clinically, not recreationally, or both?

02:00:15.000 | Both now, I mean, you know,

02:00:17.000 | underground practitioners are using the vape pens.

02:00:20.000 | They like them because people titrate the dosage.

02:00:23.000 | They get a feel for what it is to be going into this state

02:00:28.000 | that they feel they can let go and go into it.

02:00:30.000 | And actually I think some of the veterans' work

02:00:34.000 | might be giving 5-MeO after the eye began.

02:00:39.000 | Phenomenologically, if there's a difference

02:00:43.000 | between DMT and 5-MeO, people might put it on

02:00:46.000 | 5-MeO being more of a reliable ego dissolution experience,

02:00:51.000 | less visual, and more kind of all-round immersion

02:00:57.000 | in the greater whole loss of self-identity

02:01:01.000 | and just immersion in everything.

02:01:03.000 | Yeah, maybe we could just talk about

02:01:05.000 | ego dissolution for a second,

02:01:07.000 | because it's such a sticky, interesting idea.

02:01:09.000 | I can take a step back as a neuroscientist

02:01:12.000 | and say, okay, ego dissolution,

02:01:15.000 | this idea that from a very early age

02:01:18.000 | we have a concept of self,

02:01:20.000 | and that I wake up every morning

02:01:22.000 | and I know I'm me and not somebody else,

02:01:24.000 | and presumably you do the same,

02:01:26.000 | and most people do the same, I would hope,

02:01:28.000 | and that there are objects in the world

02:01:31.000 | and people in the world beyond us.

02:01:33.000 | But every time I hear about ego dissolution,

02:01:35.000 | it sounds like it's kind of a temporary

02:01:39.000 | elimination of the idea that things start and stop

02:01:45.000 | between us and everything else,

02:01:47.000 | almost like in a kind of a,

02:01:50.000 | here I'm not trying to sound philosophical or metaphysical,

02:01:53.000 | but there's sort of the molecular continuity

02:01:55.000 | of life, right?

02:01:56.000 | We're all just little bits.

02:01:58.000 | - Which is true. - Which is true, right?

02:02:00.000 | Not a functional way to go through the day, right?

02:02:04.000 | Because you want to make a cup of coffee,

02:02:06.000 | you don't really want to get lost in that

02:02:08.000 | if your goal is to make a cup of coffee.

02:02:10.000 | But what is the power of ego dissolution?

02:02:14.000 | Is it the idea that we belong?

02:02:21.000 | Is it a sense of meaning?

02:02:24.000 | Is it the sense that we're not as important as we think,

02:02:26.000 | which of course could be a wonderfully useful

02:02:29.000 | way to go through life,

02:02:31.000 | to think that we're not as,

02:02:33.000 | like we are vitally important,

02:02:35.000 | but we're not the only thing, right?

02:02:37.000 | Because I do believe connection is vital,

02:02:39.000 | as most people do.

02:02:41.000 | What is ego dissolution,

02:02:43.000 | and why would this serotonin 2A activation cause that?

02:02:48.000 | That's remarkable.

02:02:50.000 | - Yeah, great questions.

02:02:53.000 | You alluded to it with the start-stop, I think,

02:02:58.000 | because you could define it by boundaries,

02:03:02.000 | in a sense, what isn't me is as valid here

02:03:07.000 | as a developing sense of what is me

02:03:12.000 | that a child develops at whatever age.

02:03:14.000 | And so a major characteristic

02:03:21.000 | of ego dissolution experience, rather than just a negative,

02:03:23.000 | a thing going away, my sense of self going away,

02:03:27.000 | is the positive, oh, now I feel interconnected

02:03:31.000 | with other people and the world at large,

02:03:33.000 | and I realize that there is that molecular continuity,

02:03:37.000 | and actually that's a ground truth.

02:03:39.000 | And oh, maybe the ego thing is somewhat illusory,

02:03:44.000 | or at least a construction of my mind.

02:03:47.000 | - And indeed it is, right?

02:03:50.000 | - Yes, yeah, I mean, there's no transcendentalism about that.

02:03:54.000 | It's just like logic.

02:03:56.000 | - I think about it a little bit like family.

02:03:59.000 | I mean, we all know what immediate family is,

02:04:01.000 | but sort of like, forgive me for interrupting myself,

02:04:04.000 | I do it all the time anyway,

02:04:06.000 | when I teach neuroanatomy,

02:04:08.000 | some clever student always figures out,

02:04:11.000 | okay, well, that's connected to that and that's connected,

02:04:13.000 | but ultimately everything in the brain

02:04:15.000 | is connected to everything else.

02:04:17.000 | There's just no way around that.

02:04:19.000 | That's a true statement.

02:04:20.000 | And so you really just have to decide

02:04:22.000 | where you draw the boundaries between nuclei.

02:04:25.000 | Where are the modules?

02:04:27.000 | What are the modules?

02:04:29.000 | You could say the brain is just one big macro module,

02:04:31.000 | and then you also want to include the body.

02:04:33.000 | And now, fortunately,

02:04:35.000 | people are starting to embrace this idea

02:04:37.000 | that it's not mind-body, it's both,

02:04:39.000 | because the nervous system extends through both, of course.

02:04:41.000 | So the same could be said of family.

02:04:44.000 | Like we're related, right?

02:04:46.000 | Not just by virtue of the fact that we're human beings.

02:04:48.000 | We have genealogical charts.

02:04:49.000 | We would find a convergence at some point.

02:04:51.000 | And of course, this becomes a bit of a game,

02:04:56.000 | but then one realizes that where you draw the boundaries

02:05:00.000 | and if you draw them at brother, sister, parents,

02:05:04.000 | biological parents, et cetera, that's a game too.

02:05:07.000 | And so it is just a construct.

02:05:09.000 | Yeah, I mean, it is a fun game.

02:05:11.000 | Where do you draw the line and when to pass

02:05:14.000 | and when to collapse?

02:05:17.000 | It's also a classic consideration in science, when to pass.

02:05:20.000 | The lumber versus the splitter.

02:05:22.000 | There you go, it's brilliant.

02:05:24.000 | Yeah, but you asked this question like,

02:05:26.000 | well, why do psychedelics do it?

02:05:28.000 | And there we think psychedelics do it

02:05:32.000 | because the target receptors,

02:05:34.000 | at least classic psychedelics do it,

02:05:37.000 | and that's important to stress.

02:05:39.000 | So MDMA doesn't really do it in the same way.

02:05:42.000 | It might soften the ego a bit,

02:05:45.000 | but yeah, that's debatable.

02:05:47.000 | My experience with MDMA

02:05:49.000 | is that it's such a strong in pathogen

02:05:51.000 | and that it can cause empathy for others.

02:05:57.000 | Certainly you could imagine situations

02:06:00.000 | where one in MDMA journey and afterwards says,

02:06:03.000 | "Oh, my oppressors are the people that harmed me."

02:06:08.000 | And here I'm not referring to my experience,

02:06:10.000 | but they did the best with what they have.

02:06:12.000 | Actually have empathy for them, forgiveness,

02:06:14.000 | but also for oneself, that there's an empathy for self.

02:06:18.000 | I know I said this earlier,

02:06:20.000 | that is very hard for most people to access.

02:06:23.000 | Perhaps it's not the narcissists out there listening.

02:06:26.000 | They'll be like, "Of course, empathy for self."

02:06:28.000 | But everyone else, I think,

02:06:30.000 | all the other healthy people

02:06:33.000 | or the healthy people other than narcissists

02:06:36.000 | and not picking on narcissists,

02:06:38.000 | I have to imagine they suffer too.

02:06:40.000 | In fact, I think that's the root of their narcissism.

02:06:43.000 | Empathy for self is not something

02:06:44.000 | that comes reflexively for most people.

02:06:46.000 | And here I'm not talking about self-love or self-respect,

02:06:49.000 | but this notion of being able to see the self

02:06:51.000 | as not just deserving of love and care,

02:06:56.000 | but actually holding that in place

02:06:59.000 | while in confrontation with something challenging

02:07:02.000 | in a way that allows more, not less access

02:07:05.000 | to adaptive responses to that challenge.

02:07:07.000 | I think that's the way I kind of conceptualize it.

02:07:11.000 | But I mean, drugs offer a great,

02:07:14.000 | they offer great, they are great scientific tools

02:07:18.000 | for tackling this question.

02:07:20.000 | What is ego dissolution and why do drugs modulate it

02:07:23.000 | and what does that tell you about the brain?

02:07:25.000 | Because other drugs like cocaine

02:07:27.000 | releasing more of a different neurotransmitter,

02:07:30.000 | dopamine, more than serotonin,

02:07:33.000 | the opposite is the case with MDMA,

02:07:36.000 | is more of an ego inflator, right?

02:07:40.000 | So people become hyperlinear,

02:07:41.000 | hyperlinked to their own desires and wishes,

02:07:44.000 | and future outcomes become an obsession.

02:07:47.000 | It's the stuff of kind of American psycho

02:07:50.000 | and the kind of cliches and stereotypes

02:07:53.000 | of the '80s cocaine culture.

02:07:57.000 | - Yeah, yeah.

02:07:59.000 | We did a study once actually looking

02:08:01.000 | at dose-dependent relationship with ego inflation

02:08:03.000 | on one axis and ego dissolution on the other

02:08:07.000 | and saw that it just massively passed or differentiated

02:08:10.000 | between cocaine and the psychedelics.

02:08:13.000 | It's quite a neat study.

02:08:15.000 | - So cocaine makes people's egos super inflated.

02:08:17.000 | - Yeah, and doesn't touch dissolution

02:08:19.000 | and the opposite is the case with psychedelics.

02:08:23.000 | - Is there any neuroimaging to explain

02:08:25.000 | how cocaine does that?

02:08:27.000 | - That would be a great study, yeah.

02:08:29.000 | Great idea. - We should do that.

02:08:31.000 | I have a sabbatical coming up.

02:08:33.000 | I've got 12 months of sabbatical coming up

02:08:36.000 | and I'm gonna show up in your lab.

02:08:37.000 | - Yeah, that's a really good one.

02:08:39.000 | If it's right to finish the thread

02:08:41.000 | on why psychedelics and ego dissolution,

02:08:43.000 | we do know some things or we have some hypotheses

02:08:46.000 | and it's that the target receptors,

02:08:48.000 | the serotonin 2A receptors that classic psychedelics hit

02:08:51.000 | are heavily expressed in what these days

02:08:53.000 | I like to call recent brain

02:08:56.000 | because evolutionarily it's recent brain.

02:08:58.000 | It's cortex that humans have more than any other species.

02:09:03.000 | If you look at a mapping of cortical expansion

02:09:06.000 | from say macaque or chimp to human,

02:09:09.000 | it's the very same map that you'll find the 2A receptors in.

02:09:14.000 | So that's the target.

02:09:17.000 | And it's just easy to think that,

02:09:20.000 | oh well that could be the egoic brain, you know,

02:09:23.000 | and the classic psychedelics come in,

02:09:27.000 | they kind of, they scramble up the activity.

02:09:30.000 | That's the entropic brain action.

02:09:32.000 | And in terms of the start, stop, the boundaries,

02:09:36.000 | that entropic action sort of spreads out the system.

02:09:41.000 | It doesn't shut it off.

02:09:43.000 | It sort of spreads it out, you know.

02:09:45.000 | - Dissolution.

02:09:47.000 | - Yeah, and you were talking about the head space as well.

02:09:51.000 | So that fits.

02:09:53.000 | If it's more capacious, it sort of fits.

02:09:59.000 | - The big qualifier with psychedelic therapy

02:10:02.000 | that people rightly bring up is it doesn't last, you know.

02:10:07.000 | That's the paradox of it.

02:10:09.000 | The paradox of ego dissolution.

02:10:11.000 | The ego might go away during the trip

02:10:15.000 | and you have these profound insights

02:10:17.000 | about the molecular continuity

02:10:19.000 | and how we're all one and interconnected.

02:10:22.000 | And then you come down and however long later,

02:10:26.000 | you know, the ego comes back, but maybe with a vengeance.

02:10:29.000 | And sadly, you know, things can go awry

02:10:33.000 | when people haven't done the work,

02:10:35.000 | perhaps haven't done the integration work

02:10:37.000 | and maybe ego defenses come back and, you know,

02:10:41.000 | and it's not a pretty picture.

02:10:44.000 | - How often do you see that in the trials that you do?

02:10:48.000 | What percentage of people coming through,

02:10:54.000 | do you think end up with worse than they were

02:10:57.000 | before the trial?

02:10:59.000 | - It's very rare in the trials that we've done.

02:11:02.000 | Yeah, but you see defenses come back.

02:11:06.000 | So you do see people relapse.

02:11:09.000 | That's more, you know, if you're pushing out

02:11:12.000 | to like three months plus

02:11:15.000 | in something like treatment-resistant depression,

02:11:17.000 | that's more the rule than the exception, sadly.

02:11:19.000 | People relapse.

02:11:22.000 | So if your histories are, you know,

02:11:24.000 | histories of chronic depression,

02:11:26.000 | then while you might give them a window of wellness,

02:11:29.000 | sadly, it doesn't last.

02:11:31.000 | That's not to say that it doesn't ever last.

02:11:34.000 | It does.

02:11:36.000 | And we have people who were in our first

02:11:38.000 | treatment-resistant depression trial who are well,

02:11:40.000 | to my knowledge, today, back at work,

02:11:42.000 | doing fantastically well.

02:11:44.000 | But sadly, the majority have relapsed, to my knowledge.

02:11:48.000 | - And need to do more psychedelic journeys.

02:11:51.000 | - Well, they can't because it's illegal.

02:11:52.000 | That's been the really difficult situation

02:11:55.000 | that we've been up against is that we do a trial

02:11:57.000 | where all of a sudden this Schedule 1 drug

02:11:59.000 | becomes a medicine in the trial,

02:12:01.000 | or at least an experimental medicine.

02:12:03.000 | We give the treatment, it works fantastically well,

02:12:06.000 | gives people a remission that they've never really had

02:12:10.000 | for however long, and then the trial ends

02:12:15.000 | and they're denied that treatment.

02:12:17.000 | And worse still, if they were to have that treatment,

02:12:20.000 | they would be committing a crime.

02:12:21.000 | It's sort of a sick joke in a way,

02:12:23.000 | but that's the situation that we've been in.

02:12:26.000 | - That's a perfect segue for what I want to talk about now,

02:12:30.000 | which is what is the current state of legality

02:12:35.000 | or the progression towards legality?

02:12:37.000 | I'd also like to touch on the role of,

02:12:40.000 | let's just say, incoming big pharma.

02:12:42.000 | There are a lot of startup companies now

02:12:44.000 | trying to capitalize on these discoveries

02:12:46.000 | that you and others have made.

02:12:48.000 | The landscape out there is very unclear to me.

02:12:53.000 | Maybe I'll just call out some silos as I see them,

02:12:58.000 | and maybe we can draw some bridges between them

02:13:02.000 | if they exist.

02:13:04.000 | At the ground level, not the grassroots,

02:13:07.000 | but at the ground level, I look to laboratories like yours,

02:13:11.000 | Matthew Johnson's, Roland Griffith's,

02:13:14.000 | some laboratories at Stanford, Nolan Williams,

02:13:17.000 | laboratories studying the effects of psychedelics

02:13:21.000 | in human beings, so not animal models,

02:13:23.000 | in terms of their clinical application

02:13:25.000 | for the treatment of depression, anorexia,

02:13:29.000 | I now know fibromyalgia, trauma.

02:13:31.000 | Let's lump MDMA in there as well,

02:13:33.000 | assuming that it all works in an equivalent way

02:13:36.000 | at the level of kind of where the legislature

02:13:38.000 | is taking things.

02:13:40.000 | So labs using government money, philanthropy, et cetera.

02:13:46.000 | Then there are the sort of the therapists out there

02:13:51.000 | that are accessing what we believe are clean sources

02:13:54.000 | of MDMA, psilocybin, LSD to do this.

02:13:57.000 | They are doing it illegally.

02:13:59.000 | This is in the US or other Western European countries

02:14:03.000 | 'cause obviously it's gonna differ by country,

02:14:06.000 | who are administering these things

02:14:08.000 | sort of on the basis of what they're reading

02:14:10.000 | in these studies that you all are publishing,

02:14:14.000 | but also expanding on and experimenting hippie flips

02:14:16.000 | and combination drugs and ketamine and et cetera.

02:14:19.000 | But let's leave ketamine out for right now

02:14:21.000 | because it's legal, but there's that.

02:14:23.000 | Then there's the, I don't wanna say,

02:14:26.000 | it's a recreational/open market, black market.

02:14:31.000 | And here I wanna raise a flag to the fact

02:14:34.000 | that Dr. Peter Attia did a terrific podcast on this recently

02:14:37.000 | in his own podcast, The Drive.

02:14:39.000 | The fact that fentanyl, lacing with fentanyl

02:14:43.000 | is now showing up in MDMA and psychedelics

02:14:45.000 | that are purchased on the street.

02:14:47.000 | So serious caution to those getting it

02:14:49.000 | from uncertain sources.

02:14:51.000 | And then you've got pharma.

02:14:55.000 | And then as an umbrella for all of this,

02:14:58.000 | you've got the FDA and law enforcement agencies,

02:15:01.000 | which currently say this stuff is illegal

02:15:04.000 | unless it's being used in a clinical trial.

02:15:06.000 | Selling it or possessing it

02:15:08.000 | can get you charged with a crime ranging from,

02:15:12.000 | because I don't know, but I'm up to felonies, right?

02:15:14.000 | Years in prison, okay.

02:15:16.000 | So can't take it through airports,

02:15:19.000 | don't get caught with it, don't buy it,

02:15:22.000 | don't sell it kind of thing.

02:15:24.000 | So where are we going from that picture of these silos?

02:15:28.000 | I know things are in clinical trials now.

02:15:31.000 | Most people, including myself,

02:15:33.000 | are not familiar with how the different phases

02:15:35.000 | relate to the proximity to legality.

02:15:37.000 | Could you just kind of give us the landscape

02:15:40.000 | and touch on how long you think it will be

02:15:42.000 | before the people that come through your trials

02:15:45.000 | could then go get a prescription for psilocybin

02:15:47.000 | or potentially buy it without the risk

02:15:50.000 | from a reliable source one would hope,

02:15:52.000 | but without the risk of getting thrown in jail.

02:15:55.000 | I used to live in Oakland, California.

02:15:58.000 | My understanding, and please correct me if I'm wrong folks,

02:16:01.000 | don't trust this information and get in trouble.

02:16:03.000 | My understanding is that psilocybin

02:16:05.000 | is decriminalized in Oakland,

02:16:07.000 | but that's not the same as being legal.

02:16:09.000 | So what is going on out there?

02:16:10.000 | - Wow, well, so much.

02:16:12.000 | - Yeah, I just asked 55 questions.

02:16:14.000 | - I know.

02:16:16.000 | - But feel free to answer just a sub-side of them

02:16:18.000 | if you like.

02:16:20.000 | - Well, Oakland's a funny one.

02:16:22.000 | I live close to Oakland.

02:16:24.000 | There are head shops in Oakland

02:16:26.000 | that might be selling cannabis

02:16:28.000 | and cannabis-related paraphernalia

02:16:32.000 | that are selling mushrooms as well, psilocybin.

02:16:38.000 | Mushrooms as well, psilocybin mushrooms.

02:16:39.000 | - That's a fact. - Openly, yeah.

02:16:41.000 | - That's a fact.

02:16:43.000 | I can verify that.

02:16:45.000 | I haven't purchased them,

02:16:47.000 | but I've gone in and kind of checked it out

02:16:49.000 | like what's going on here.

02:16:51.000 | - Yeah, so the police aren't going to prioritize

02:16:54.000 | that activity, the purchasing of those mushrooms

02:16:59.000 | as a crime now in Oakland

02:17:02.000 | because of the decriminalization.

02:17:05.000 | So those head shops shouldn't strictly be selling.

02:17:08.000 | Well, they shouldn't be selling.

02:17:10.000 | They won't have a license to be selling.

02:17:12.000 | Licenses don't exist yet for that here.

02:17:16.000 | But let's see whether they get shut down.

02:17:21.000 | They probably will, I don't know.

02:17:23.000 | But there's a church in Oakland

02:17:26.000 | that say that they're selling

02:17:29.000 | and it's part of sort of religious rights

02:17:34.000 | and they're using that church model as a loophole,

02:17:37.000 | you know, the way that Native Americans can use peyote

02:17:42.000 | and they have a more genuine case, I think,

02:17:46.000 | because there is a history there.

02:17:48.000 | They're trying to kind of piggyback on that.

02:17:50.000 | Anyway, that's sort of close to where we are right now.

02:17:54.000 | But federally, which is really the major inflection point,

02:18:00.000 | is the FDA and the licensing of psychedelics as medicines

02:18:05.000 | to be legally prescribed across the country,

02:18:09.000 | across the US and beyond.

02:18:11.000 | That is close because the key phase,

02:18:15.000 | so there are different phases of clinical trials

02:18:18.000 | and the key one to know about is phase three.

02:18:22.000 | Phase three trials are licensing trials.

02:18:25.000 | If they're successful, and typically you have to do

02:18:28.000 | at least two successful ones, show the results

02:18:31.000 | to the regulators who are the FDA, the medicine regulators,

02:18:35.000 | and say is this good enough now for you to give me a license

02:18:38.000 | so that I can sell and provide this medicine

02:18:42.000 | that we've demonstrated is a medicine.

02:18:45.000 | So that work has been done with MDMA therapy

02:18:49.000 | for post-traumatic stress disorder.

02:18:51.000 | MAPS have led that work and done two phase three trials.

02:18:56.000 | I think they've already publicly announced

02:18:58.000 | that the second trial had results consistent with the first.

02:19:01.000 | We know the results of the first because they're published

02:19:04.000 | and they were remarkably good,

02:19:06.000 | something like 67% remission rates.

02:19:09.000 | - And long-term, my understanding is

02:19:11.000 | some of those remission rates for trauma were years,

02:19:14.000 | which is different than what you're describing for psilocybin

02:19:17.000 | where people might need ongoing dosing.

02:19:19.000 | - That's true, yeah, yeah.

02:19:22.000 | - But of course, just for trauma in those trials,

02:19:25.000 | my understanding is those MDMA trials

02:19:26.000 | were not focused on depression.

02:19:28.000 | - Yes, yes, focused on the trauma.

02:19:31.000 | So that's something because that data is being filed now

02:19:37.000 | to my knowledge, like as we speak,

02:19:39.000 | and they're anticipating a decision maybe this year

02:19:44.000 | with rollout happening as early as next year.

02:19:47.000 | I mean, that's sort of best case, I think.

02:19:49.000 | - Could I ask you, when you say rollout,

02:19:52.000 | and it's the appropriate term for MDMA,

02:19:55.000 | so-called rolling, about 20% of my audience,

02:19:59.000 | maybe 50 will understand that not funny joke that I made,

02:20:03.000 | who's going to roll it out?

02:20:06.000 | Where would one get the clean source of MDMA,

02:20:11.000 | meaning not laced with fentanyl,

02:20:13.000 | not laced with methamphetamine,

02:20:15.000 | not undergone any chemical conversion to some other drug

02:20:20.000 | that might happen with extended shelf life, et cetera?

02:20:22.000 | Are people going to go to their psychiatrist to get MDMA,

02:20:26.000 | and who's going to be providing it?

02:20:29.000 | Is it going to be some big major pharma?

02:20:32.000 | This seems like a serious set of issues.

02:20:35.000 | - It is, and I don't have all the answers.

02:20:37.000 | I do know that MAPS would be providing

02:20:40.000 | because they've done the work,

02:20:42.000 | and they have set themselves up, in a sense,

02:20:46.000 | to potentially become the provider,

02:20:50.000 | whether as a pharma company,

02:20:52.000 | which is the big question they're wrestling with

02:20:54.000 | at the moment.

02:20:56.000 | It's very expensive to become a pharma company.

02:21:00.000 | - And yet they probably deserve to make the choice

02:21:03.000 | because they put in so many years of hard work

02:21:06.000 | when all of this stuff was considered

02:21:08.000 | like raver culture, party drug.

02:21:11.000 | They were the ones that spotted the therapeutic potential.

02:21:15.000 | I mean, we knew there was therapeutic potential

02:21:16.000 | based on work going back many decades,

02:21:18.000 | but points to them, and I think, in my opinion,

02:21:21.000 | they should have the agency to make those decisions.

02:21:24.000 | - It's such a remarkable thing that's been achieved,

02:21:27.000 | and I think they've done it all on philanthropic donations.

02:21:32.000 | I think so.

02:21:34.000 | Yeah, so there is this big question mark,

02:21:40.000 | and the FDA are also asking questions

02:21:43.000 | about, to your question, who can provide this?

02:21:48.000 | Because in the phase three work and up until this point,

02:21:52.000 | there's been a MAPS training, a MAPS therapist training,

02:21:55.000 | and you have to do this formal training

02:21:59.000 | in order to be a practitioner within the trials.

02:22:03.000 | But now there's a question from the FDA

02:22:05.000 | whether that MAPS training can be the training

02:22:10.000 | that a clinician has to have to now be a provider.

02:22:14.000 | And when I say rollout,

02:22:16.000 | it's like offering this as a service, essentially.

02:22:21.000 | And so where would the referral come from?

02:22:23.000 | That's a good question that I'm not 100% on the answer,

02:22:26.000 | whether it would have to come from a psychiatrist

02:22:29.000 | or whether someone's sort of general physician

02:22:34.000 | could do that referral.

02:22:38.000 | So there will be going to a provider who is licensed

02:22:41.000 | and certified and will have done some training,

02:22:44.000 | and there will be a consensus on what constitutes

02:22:48.000 | good enough training to provide.

02:22:50.000 | There will also be some stipulations

02:22:52.000 | on the basic underlying professionalism

02:22:55.000 | of the clinician who provides.

02:22:58.000 | So I imagine they'll have to be a mental health professional.

02:23:02.000 | I don't think they would have to necessarily

02:23:04.000 | be a psychiatrist.

02:23:07.000 | I'm a clinical psychologist.

02:23:08.000 | For all the dosings, I think, without question,

02:23:11.000 | there would have to be a physician present

02:23:13.000 | or at least within ready access in case of an emergency.

02:23:18.000 | Yeah, especially with MDMA,

02:23:20.000 | because of the propensity for cardiac issues,

02:23:23.000 | because of the amphetamine properties.

02:23:25.000 | And where is psilocybin in terms of the phase trials?

02:23:30.000 | Is it in phase two, phase three?

02:23:32.000 | It's in phase three.

02:23:35.000 | It's psilocybin therapy work being done

02:23:37.000 | for treatment-resistant depression

02:23:39.000 | by a company called Compass.

02:23:41.000 | Those trials, which are always multi-site,

02:23:45.000 | so there's always a bunch of teams or labs,

02:23:48.000 | in a sense, geographically spread out

02:23:52.000 | that are each contributing to data

02:23:54.000 | that then gets masked together

02:23:56.000 | and is then submitted as part of the phase three trial results.

02:24:00.000 | So that's happening with Compass right now.

02:24:03.000 | It's the second phase of psilocybin therapy

02:24:05.000 | for treatment-resistant depression.

02:24:07.000 | Those trials have just started

02:24:09.000 | and I think the earliest estimate that I heard

02:24:12.000 | in a journalistic article was,

02:24:15.000 | because I don't think Compass would say

02:24:17.000 | or they wouldn't say publicly,

02:24:19.000 | something like 2026.

02:24:21.000 | 2026, wow.

02:24:23.000 | So MDMA is ahead of psilocybin.

02:24:25.000 | Oh, yeah.

02:24:27.000 | Yeah, it's quite a few years ahead

02:24:29.000 | and it's more of a, not a certainty,

02:24:32.000 | but it's a very, very strong position with MDMA,

02:24:35.000 | whereas the work's only just begun with psilocybin

02:24:38.000 | in terms of the phase three trials.

02:24:40.000 | But then you have this other situation

02:24:42.000 | of like however many psychedelic research centres

02:24:45.000 | there are now across the globe.

02:24:47.000 | It was nice to, you know,

02:24:51.000 | we had the first one in London in 2019.

02:24:53.000 | First one in 2019 is 2023 now

02:24:56.000 | and I don't know how many there are,

02:24:59.000 | but so much has happened in such a small space of time.

02:25:02.000 | Yes, but, you know, all these different indications

02:25:06.000 | I've been able to tell you about anorexia

02:25:08.000 | and fibromyalgia syndrome,

02:25:10.000 | trying to do a trial with a colleague of mine at UCSF

02:25:16.000 | in methamphetamine use disorder.

02:25:18.000 | He's got a trial going on in Parkinson's disease

02:25:21.000 | and chronic lower back pain and bipolar disorder.

02:25:26.000 | I mean, there's so much going on, OCD,

02:25:29.000 | almost the full gamut of psychiatric disorders,

02:25:32.000 | not schizophrenia to my knowledge,

02:25:35.000 | are being looked at.

02:25:37.000 | So there's so much ground, you know,

02:25:40.000 | groundswell of activity

02:25:42.000 | and I think these small investigator-led studies,

02:25:46.000 | typically they're small because trials are expensive,

02:25:49.000 | are going to be reporting positive results.

02:25:52.000 | I know what we're seeing and it will be, you know,

02:25:56.000 | four, let's see now, at least four trials,

02:25:59.000 | all with really positive results

02:26:02.000 | and very difficult to treat disorders

02:26:04.000 | and that's just us and I know there's so much elsewhere,

02:26:07.000 | addiction disorders as well, you know,

02:26:09.000 | Matt Johnson's work obviously, Michael Bogan shoots.

02:26:13.000 | So all this compelling groundswell,

02:26:16.000 | it's really something and yet, you know,

02:26:18.000 | the system to really make a big breakthrough

02:26:21.000 | in terms of licensing is, of course, slow

02:26:25.000 | and that can frustrate people, but it has to,

02:26:29.000 | it has to be done properly.

02:26:33.000 | - Yeah, else we revert back to what happened in the '70s

02:26:38.000 | where there was a lot of interest in psychedelics.

02:26:42.000 | It's kind of interesting to me,

02:26:44.000 | there was a close juxtaposition of meditation

02:26:46.000 | and kind of behavioral approaches

02:26:49.000 | to self-directed state change and psychedelics.

02:26:54.000 | Meditation kind of made it through the hatch.

02:26:56.000 | I mean, there were some years where it was considered

02:26:58.000 | kind of counterculture, woo, magic carpet, weirdo stuff

02:27:03.000 | by Western science, but now, I mean,

02:27:06.000 | there are probably tens of thousands,

02:27:08.000 | it's not an overstatement of quality studies

02:27:10.000 | exploring how meditation can provide advantages

02:27:13.000 | for the mind and even for mental health

02:27:16.000 | and psychedelics are now catching up,

02:27:19.000 | but they used to be close cousins

02:27:22.000 | in the cultural framework.

02:27:24.000 | But the problem was, I think,

02:27:27.000 | psychedelics were viewed as making people crazy

02:27:31.000 | and university professors lost their jobs

02:27:34.000 | for having discussions like the one

02:27:36.000 | that you and I are having right now.

02:27:38.000 | And some people went to jail, but mostly people

02:27:42.000 | either left academic institutions or lost their jobs,

02:27:45.000 | whereas now these are some of the studies of the sort

02:27:49.000 | that you are doing and that are taking place at Stanford

02:27:51.000 | and Hopkins and elsewhere are some of the greatest

02:27:54.000 | magnetic pull for philanthropy for universities.

02:27:57.000 | Donors are very interested in supporting these sorts

02:28:02.000 | of studies because they and their family members

02:28:05.000 | and people they know suffer from psychiatric illness

02:28:07.000 | for which the current big pharma approaches

02:28:12.000 | simply have not worked.

02:28:14.000 | So it's sort of interesting to me that what once was seen

02:28:18.000 | as kind of poison is now being viewed

02:28:21.000 | as a potential therapeutic.

02:28:24.000 | It's not just interesting.

02:28:27.000 | I think it's, hopefully it speaks to the evolution

02:28:30.000 | of the human species.

02:28:32.000 | People seem to be becoming more open-minded

02:28:34.000 | about becoming more open-minded.

02:28:36.000 | - Right, that's a good one.

02:28:39.000 | Yeah.

02:28:41.000 | And yet, yeah, it's, there's so much that's happening

02:28:47.000 | so fast and there's, you know, there are elements of,

02:28:51.000 | it's complexifying the space.

02:28:54.000 | There is critique, there's been some bad practice

02:28:57.000 | in psychedelic therapy, boundary crossing issues

02:29:00.000 | that have caused some scandals.

02:29:02.000 | - That's too bad.

02:29:04.000 | - Isn't it?

02:29:06.000 | - Yeah, well, you know, I think to the gene therapy, right,

02:29:08.000 | it just takes one bad incident.

02:29:10.000 | You know, gene therapy was on a fast track three decades ago

02:29:14.000 | and then sadly a child died in a gene therapy trial

02:29:18.000 | and it's like shut down gene therapy practically

02:29:21.000 | for half a decade and then it slowly started ratcheting

02:29:24.000 | up again, gene therapy broadly defined it.

02:29:27.000 | Now we're in the age of, you know,

02:29:29.000 | potential directed gene therapy using CRISPR

02:29:31.000 | and things of that sort, which makes people,

02:29:33.000 | some people cringe and other people very excited.

02:29:35.000 | You know, if you have Huntington's in your family,

02:29:37.000 | CRISPR is like the most exciting technology ever

02:29:39.000 | because you could potentially eliminate it

02:29:41.000 | from your family line.

02:29:43.000 | Going forward, of course.

02:29:44.000 | - So I just really hope that we can be balanced

02:29:47.000 | as this all plays out because it could go a similar way

02:29:51.000 | given the stigma, given the history,

02:29:53.000 | that people be very twitchy with some isolated incidents

02:29:58.000 | and, you know, over-generalize them perhaps.

02:30:04.000 | In a sense, shining a light on them I think is important

02:30:11.000 | that that has happened recently is important

02:30:14.000 | because it really drills home how important it is

02:30:17.000 | that this work be done right

02:30:19.000 | and what the necessary safeguards

02:30:22.000 | and standards should be.

02:30:25.000 | Yeah, it won't be an easy road forward

02:30:31.000 | but let's hope, you know, we've got to hope that it succeeds

02:30:38.000 | because current treatments, you know,

02:30:41.000 | people talk about the mental health crisis

02:30:43.000 | and to your point earlier about anorexia rates,

02:30:47.000 | it's not always actually the case

02:30:49.000 | when you look at the epidemiology,

02:30:51.000 | when you look at the data that you see a big inflection

02:30:54.000 | in, you know, diagnoses or cases of psychiatric illness.

02:30:59.000 | I would say it's more that the treatments haven't moved.

02:31:02.000 | They haven't really progressed.

02:31:04.000 | They haven't got any better since the 1950s more or less

02:31:07.000 | and new drugs have been more of the same.

02:31:11.000 | So there haven't been any paradigm shifts

02:31:14.000 | and that's why I get a little impassioned

02:31:16.000 | when I talk about psychedelic therapy

02:31:18.000 | and that point that this is something different.

02:31:21.000 | It's not, you know, a drug every day.

02:31:24.000 | That system is not cutting it, you know.

02:31:27.000 | Do we really want to keep on with that system?

02:31:31.000 | Sure, you know, not everyone will want to trip

02:31:36.000 | and that will terrify some people so much

02:31:38.000 | that they'll just want to be on their Lexapro

02:31:41.000 | or a non-psychedelic psychedelic or whatever

02:31:44.000 | and of course you should be allowed to have those options,

02:31:47.000 | of course, and the more options the better.

02:31:50.000 | But I think there is great value

02:31:55.000 | in really understanding what psychedelic therapy is

02:31:58.000 | and I think when you do,

02:32:01.000 | you realise that it is a major paradigm challenge

02:32:05.000 | on many levels and the fact that it's different

02:32:09.000 | might be its greatest appeal at the moment, I think.

02:32:13.000 | Well, I am certainly grateful for your passion

02:32:17.000 | for the potential for psychedelics

02:32:19.000 | to be added to the array of potential treatments

02:32:22.000 | and I really also appreciate how much you put it in there

02:32:26.000 | alongside the other treatments.

02:32:28.000 | Maybe even in combination with other treatments

02:32:30.000 | as opposed to saying this is the thing

02:32:32.000 | that's going to cure everything

02:32:34.000 | and yet the passion that you have

02:32:36.000 | for this potential paradigm shift,

02:32:39.000 | the one that really appears to be happening

02:32:41.000 | at the level of clinical data now is so important.

02:32:45.000 | So I want to extend a voice of gratitude for that

02:32:50.000 | and for the work that you're doing.

02:32:53.000 | I mean, I've been outside of this field

02:32:56.000 | but as a neuroscientist,

02:32:58.000 | I've been paying careful attention to it

02:33:00.000 | really for the last five, seven years or so

02:33:03.000 | and it's abundantly clear that it is a small group

02:33:06.000 | of individuals who are really thinking

02:33:08.000 | in terms of how the system works now

02:33:10.000 | and what needs to be done in order to change the system

02:33:13.000 | for the better, like yourself,

02:33:15.000 | that are really the driving force

02:33:18.000 | behind this new movement or paradigm shift

02:33:21.000 | that without question is going to lead to improvements

02:33:25.000 | in mental health and physical health outcomes.

02:33:27.000 | So I just want to say thank you for that.

02:33:31.000 | Also, thank you so much for joining us today

02:33:33.000 | to share this immense knowledge set

02:33:36.000 | about the history of psychedelics,

02:33:38.000 | what they are, what they aren't,

02:33:40.000 | their clinical applications

02:33:42.000 | as seen in your laboratory and other laboratories.

02:33:45.000 | I'm sure people already noticed this

02:33:47.000 | but you're incredibly generous in terms of attribution

02:33:49.000 | and also in your caution about explaining

02:33:52.000 | how some of the results in particular

02:33:54.000 | on anorexia fibromyalgia are perhaps preliminary

02:33:56.000 | but very exciting.

02:33:58.000 | They're not published yet anyway.

02:34:00.000 | We wouldn't call them preliminary.

02:34:01.000 | And also for touching on mechanism

02:34:04.000 | that is not just about people feel better

02:34:06.000 | but pointed to some potential underlying mechanisms

02:34:09.000 | in terms of connectivity changes and on and on.

02:34:13.000 | So thank you so much for your time today.

02:34:16.000 | Thank you for the work that you're doing

02:34:18.000 | and thank you for the work that is sure to continue.

02:34:21.000 | We will provide links to studies in your laboratory,

02:34:24.000 | links to your laboratory so people can learn more

02:34:27.000 | and support in the ways that they deem appropriate for them.

02:34:30.000 | But just thank you, thank you, thank you.

02:34:33.000 | Such important work you're doing, Robin.

02:34:35.000 | - Thank you, Andrew, it's been a pleasure.

02:34:37.000 | - Thank you for joining me today

02:34:39.000 | for my discussion with Dr. Robin Carhart-Harris.

02:34:41.000 | I hope you found it to be as informative

02:34:43.000 | about the science and clinical uses of psychedelics as I did.

02:34:47.000 | If you'd like to learn more about Dr. Carhart-Harris' research

02:34:50.000 | or support that research

02:34:52.000 | or inquire into being a research subject

02:34:54.000 | in one of his laboratory studies,

02:34:56.000 | please see the links in the show note captions.

02:34:58.000 | In addition, please see the links to his Twitter account

02:35:01.000 | and other social media accounts also in the show note captions.

02:35:04.000 | Also in the show note captions,

02:35:06.000 | you'll find a link to Dr. Carhart-Harris' Twitter account

02:35:08.000 | where he regularly posts about new advances

02:35:10.000 | in the field of psychedelic science.

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02:36:55.000 | Thank you once again for joining me

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02:37:03.000 | [upbeat music]

02:37:07.000 | you

Dr. Robin Carhart-Harris: The Science of Psychedelics for Mental Health | Huberman Lab Podcast

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