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welcome to the huberman Lab podcast where we discuss science and science-based tools for everyday life

I'm Andrew huberman and I'm a professor of neurobiology and Ophthalmology at Stanford school of medicine today we are

discussing psilocybin psilocybin is a psychedelic meaning it modifies the psyche and in doing so it changes our

level of Consciousness psychedelics such as psilocybin change the way that we perceive the outside world and our

internal World our memories our thoughts our feelings Etc not just while one is

under the influence of psilocybin but it can also fundamentally change all of those things afterwards and for a very

long period of time afterwards as well which is one of the reasons why there's growing excitement about the application

of psilocybin and other psychedelics for the treatment of various mental health issues such as depression alcohol abuse

disorder and addictions of various kinds as well as things like OCD and eating disorders today we will discuss

psilocybin talking about what it is in fact you may be surprised to learn that psilocybin basically is serotonin now

for those of you that are familiar with psilocybin serotonin you might think wait that's not true but in fact psilocybin's main effect is to mimic

serotonin but it does it in a very specific way because it activates a subset of Serotonin receptors in a very

strong fashion leading to neuroplasticity at the level of the

neural circuits that is the brain areas and the connections that serve things like memory and perception so if any of

that is confusing at this point I promise to make it all clear in just a few minutes psilocybin is one of many psychedelics

of course there are things like LSD DMT 5meo DMT even MDMA while not considered

a classic psychedelic is considered a psychedelic in the general sense today's episode is going to focus on psilocybin

in particular I will tell you what psilocybin is how it works at the

molecular and cellular level I'll talk about how it changes brain circuitry I'll talk about the clinical effects

what's been demonstrated in controlled laboratory studies I'll talk about dosages and translating from psilocybin

mushrooms to actual psilocybin and the compound that actually exerts the effects of psilocybin which it turns out

is not psilocybin but something called silosin silosin is the actual compound that goes into the brain to create all

the changes in Consciousness and all the rewiring effects that we associate with

psilocybin so understanding how psilocybin is converted to silacin has tremendous impact on the duration of a

psilocybin Journey whether or not that psilocybin and journey is going to lead to a short or longer window for

neuroplasticity in fact many people don't realize this but much of the positive changes that are possible with

proper and I do want to underscore proper psilocybin therapeutic approaches takes place after the session in which

one feels all the you know typical or typically Associated effects of psilocybin like hallucinations and

changes in thought patterns Etc so today we are going to talk a little bit about chemistry but I promise to make it

accessible to anyone and everyone regardless of whether or not you have a background in chemistry or biology we're going to talk about some cell biology

the actual neuronal changes that occur when one takes psilocybin and

we're going to talk about how neural circuits change over time and how all of that impacts the changes that most

people are interested in when they go on a psilocybin Journey things such as long-standing improvements in mood

things such as tremendous insight into themselves and to others into their past

their present and their future and even changes in their levels of creativity or

their ability to experience Joy from music or their ability to dissociate in a positive way from things that formerly

were depressing or triggers for depression in fact we're going to talk quite a lot about the conditions inside

of a psilocybin Journey that make it actually positive and therapeutic this

is a very important point that I'll make several times throughout today's episode which is that just because something

invokes neuroplasticity changes in brain circuitry does not mean that it's therapeutic or I should say does not

necessarily really mean that it's therapeutic for neuroplasticity to be therapeutic it has to be adaptive it has

to allow someone to function better in life than they did previously so today we will talk about how the conditions of

a psilocybin Journey including whether or not it's done with eyes closed or eyes open or whether or not people

alternate between eyes closed and eyes open phases of that Journey as well as whether or not music is played during

that journey and even what types of music are played Will dictate whether or not somebody will feel better or worse

in the days and weeks and years following that psilocybin Journey as well as the dosage level because as

you'll soon learn as well there are clinical studies showing that just one psilocybin Journey can improve mood in a

long-standing way but most clinical trials involve two dosages spaced in

very precise ways from one another with appropriate follow-up but in both of

those particular Journeys the structure of the journey who's present who's not isn't eyes open or eyes closed the

particular music that's played all of those features make up part of a larger neuroplasticity trigger of which

psilocybin is critical but psilocybin is not the only variable so whether or not

you're interested in participating in a clinical study or whether or not you're interested in psilocybin for other reasons this is critical information to

understand so today we're going to talk about nearly every feature of psilocybin possible including what psilocybin is how it works at the

level of chemistry cell biology and neural networks and neuroplasticity we'll talk about the clinical studies

we'll talk about dosages we will talk about conditions of clinical studies and we will talk about the post-silocybin

journey period in which neuroplasticity and the various activities including

therapy or perhaps not therapy can contribute to positive therapeutic changes from psilocybin now as we go

into this discussion I do want to underscore the fact that at the time of recording this episode meaning now may

2023 psilocybin is still a schedule one drug

it is considered illegal in the United States there's perhaps just one exception to that maybe a few others but

the main exception is in the state of Oregon psilocybin has been approved in particular therapeutic settings for use

in particular conditions namely depression and some forms of addiction so in Oregon it's more or less in the

domain of a decriminalized as opposed to actually legal in other areas of the

country including Oakland California there's some areas in which it has been decriminalized and perhaps there are a

few others that I'm not aware of but in general psilocybin and other psychedelics are still considered

illegal and this is very important not just saying this to protect me I'm saying this to protect you possessing or

certainly selling psilocybin except for rare instances such as clinical studies and these decriminalized areas that I

talked about a moment ago is still very much not allowed under the law today

I'll also discuss safety issues I'll talk about whether or not young people meaning people 25 or younger should

consider psilocybin given that their brain is still in a rampant period of naturally occurring neuroplasticity

I will also talk about dosages as it relates to people who have formerly been on or may currently be on different

forms of antidepressants and I will talk about people who are at risk for psychotic episodes either because they

know they themselves have a propensity for psychosis or they have close family members who have psychosis which

includes things like schizophrenia bipolar depression as well as things like borderline personality and some

related psychiatric conditions so today's episode really will be a deep dive into psilocybin so whether or not

you think you're already familiar with psilocybin and its effects or whether or not you're just curious about them I do

encourage if you're willing to try and Ratchet through some of the understanding of how psilocybin works

and what it is leading up to some of the therapeutic applications and different patterns of dosing

spacing of different sessions Etc because I do believe that with that knowledge in hand you will be able to

make far better much more informed decisions about whether or not psilocybin is right for you before we

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Psilocybin Becomes Psilocin in the Gut, Serotonin

psilocybin and we're going to set aside all the other psychedelics for future episodes

psilocybin is what's called a tryptamine that refers to its chemical composition

not to the so-called psychedelic trip in fact it's spelled differently tryptamine is t-r-y-p trip TR IP of course

tryptamines include psilocybin but also things like DMT and 5mao DMT the

tryptamine psychedelics very closely resemble serotonin itself that's right

most of you have probably heard of the chemical serotonin and serotonin is what's called a neuromodulator which

means your brain and body naturally make it and that it modifies or changes the activity of other neurons and neural

circuits and it does that generally by either increasing or decreasing the activity of those neural circuits if I

were to show you a picture of the chemical structure of psilocybin or its active derivative silosin and I were to

also put right alongside it an image of the chemical structure of Serotonin provided that you weren't a chemist who

really likes to focus on the detailed differences between things you would say those look very similar and indeed

psilocybin and its active form silosin are very similar structurally and

chemically to serotonin itself now as I mentioned before serotonin is something that you naturally make and yes it's

true that about 90 percent of the serotonin in your brain and body is manufactured in your gut however

contrary to popular belief the serotonin in your brain is not

manufactured from the serotonin in your gut you have separate independent sources of Serotonin that is you have

particular neurons that make serotonin in your brain you also have serotonin in your gut and those work more or less in

parallel separately now what does serotonin do this is really important to understand because

of the similarity between psilocybin and its actin form silacin and serotonin

serotonin in that it's a neuromodulator changes the activity of other neurons and the

net effects of those changes are things that you're familiar with for instance satiety or the feeling that we've had

enough of various things such as food or a social interaction or sex or pleasure

of any kind serotonin is involved in all of that and an enormous number of other

things such as mood regulation such as our sense of pleasure itself or lack of

pleasure such as whether or not we feel motivated or not motivated it works in concert with other neuromodulators such

as dopamine and epinephrine and norepinephrine in fact if this were an episode about serotonin which it is not

you would soon realize that serotonin is involved in so many different functions that impact our daily life

and that is one reason why certain antidepressant medications which alter

either increase or decrease the amount of Serotonin Transmission in the brain will often have a lot of side effects

related to things like mood libido appetite sleep Etc it's because serotonin is involved in so many

different things and serotonin is involved in so many different things because there are a lot of different so-called serotonin receptors serotonin

is a chemical that we call a ligand and the chemical ligand is simply the thing that plugs into the receptor for that

chemical or ligand The receptors in this case serotonin receptors have the opportunity to do all sorts of different

things they can change the activity of neurons making them more active or less active they can cause growth factors to

be released making sure that those neurons reinforce or even build up stronger connections so that they're

more likely to be active in the future serotonin binding to particular receptors can even change the gene

expression in particular cells making those cells proliferate so make more of them making those cells more robust

making those cells interact with new elements of the brain and body basically

serotonin and all these different receptors that it binds to has dozens if not hundreds and maybe even thousands of

different functions so the fact that psilocybin so closely resembles serotonin leads to a very

important question that we should all be asking ourselves which is why is it that psilocybin which looks so much like

serotonin when one takes it in the form of magic mushrooms or some other form

maybe the synthetic form of psilocybin itself which nowadays is manufactured in Laboratories and placed in different

psilocybin containing foods and pills Etc why that leads to complex yet fairly

circumscribed sets of experience like Visual and auditory hallucinations changes in particular thought patterns

and neuroplasticity that in many cases in the clinical setting provided things

are done correctly improvements in mood relief from depression relief from various

compulsive disorders Etc right this is really what you need to understand if you want to understand psilocybin and

The Serotonin 2A Receptor, Therapeutic Outcomes SSRIs vs. Psilocybin

how it works and how to make it work optimally for a given condition or goal

you have to understand what it's actually doing and what allows psilocybin to do fairly specific things

in comparison to serotonin even though psilocybin and serotonin are so similar is that psilocybin mainly binds to and

activates the so-called serotonin 2A receptor the serotonin 2A receptor is

one of again many different serotonin receptors but serotonin 2A is expressed

in particular areas of the brain and even on particular areas of neurons in

the brain that allow for very specific types of changes in neural circuitry to take place not just when one is under

the influence of psilocybin but afterwards as well so really in order to have a useful discussion about

psilocybin we need to talk a lot about the serotonin 2A receptor but you know

fortunately for you unless you're somebody really interested in structural biology or cell biology that discussion is not going to be about The Binding

pocket for serotonin on serotonin 2A receptor or a lot of the downstream signaling of the serotonin 2A receptor

we'll talk a little bit about that where it's relevant but more importantly at least for sake of today's discussion

we're going to talk about how the serotonin 2A receptor is really the one responsible for triggering all the

changes in neural circuitry that lead to the changes that is the improvements in

mood the relief from compulsive disorders in many cases but really it's the serotonin 2A receptor selectivity of

psilocybin that is leading to all the excitement that you hear about in terms

of psilocybin as a therapeutic tool let me say that from a slightly different angle

there are data that I'll talk about today which show that one although in most cases two

psilocybin Journeys done with particular dosages of psilocybin lead to maximal binding or occupancy of those serotonin

2A receptors in ways that lead to significant and unprecedented relief for major depression in fact you'll soon

learn that the clinical trials for psilocybin are outperforming standard therapy and outperforming so-called

ssris and various other antidepressants in terms of providing depression relief in ways that are

frankly staggering not just to me but to the psychiatric community at large and this is where so much of the excitement

is coming from Now that statement could be taken one way which is to just say okay well here's a compound psilocybin

that outperforms ssris and therefore all the attention should be on psilocybin but

SSRI stands for Selective serotonin reuptake inhibitor in other words the

ssris of which there is now a lot of controversy things like Prozac Zoloft Etc I'm sure you've heard some of this

controversy there are people who are very Pro ssris although they're a growing number of people who really feel

that the ssris are probably most appropriate for things like obsessive-compulsive disorder where they

in fact can be very beneficial but there's a lot of kind of leaning back from ssris as the be-all end-all for the

treatment of depression nowadays because of the side effect profiles and the fact that it's not even really clear that

serotonin deficiencies are the major cause of depression in the first place now again we're talking about psilocybin

not about ssris but you should be thinking wait how is it that two molecules

psilocybin and some particular SSRI both of which look like and or increase

serotonin Transmission in the brain are leading to either incredibly positive and interesting outcomes or to kind of

troubling side effect riddled outcomes and again it all boils back down to the

selectivity of psilocybin to bind that serotonin 2A receptor and so in order to

understand how psilocybin works and in order to understand proper dosing profiles and spacing of sessions AKA

Journeys we really need to talk a little bit more about the serotonin 2A receptor where it is in the brain what sorts of

things happen when psilocybin binds the serotonin to a receptor and how those

things set in motion the various changes the neuroplasticity that allows people

to feel better in terms of their mood and as you'll soon learn can experience more pleasure and Joy from things like

music and enhanced creativity all the things that I do believe whether or not people are thinking about or maybe even

exploring I've been for recreational or therapeutic purposes all the things that people want and are really talking about

and perhaps even doing psilocybin in order to obtain so before going any further I just want to place an image in

Serotonin Receptor Expression; Visual Hallucinations & Eyes Closed

your mind you can place an image in your mind whereby when serotonin is released in the brain naturally not having taken

any compound any drug anything it's getting released at a lot of different sites binding to a lot of

different serotonin receptors doing a lot of different things when somebody takes an SSRI the net

effect of that selective serotonin reuptake inhibitor is that there's more serotonin around to exert its effects

because it's a reuptake inhibitor at the synapse the connections between neurons the serotonin can do its thing more

extensively and for longer periods of time but it's doing it kind of non-specifically so when you think about standard

antidepressant treatments at least for sake of this discussion you kind of think of a sprinkling or a kind of you

know spraying of Serotonin at different locations in the brain and binding to lots of different receptors

whereas when you think about psilocybin even though the subjective effects are pretty diverse we'll talk about those in

a few moments what you're really talking about is a molecule psilocybin that looks a lot

like serotonin that is selectively and very strongly binding to and activating

that serotonin 2A receptor so that's the image I'd like you to embed in your mind and then the next image I'd like you to

embed in your mind is wear these serotonin 2A receptors are located in

the brain now the serotonin 2A receptors are located in multiple brain regions

but they have a tremendous amount of expression in the so-called neocortex the outside of the brain that includes

things like our prefrontal cortex which is involved in understanding context right which behaviors thoughts and you

know speech patterns are appropriate for certain circumstances um how to switch context and category

switch when you go from you know playing sports to hang out with friends to being in a professional setting you change your behavior in the way that you speak

and perhaps even the way that you think you might think some things that are out of context but you probably keep those to yourself and your ability to keep

those to yourself are dependent on a functional prefrontal cortex there are a lot of 5ht 2A and by the way 5ht is the

abbreviation for serotonin so there are a lot of Serotonin 2A receptors in the prefrontal cortex also in other areas of

the cortex that are associated with sensation and perception that is hearing

of sounds that is seeing of particular things and in particular there is a very

very very high expression of Sarah tone and 2A receptors in the visual cortex

and that is one of the reasons why psilocybin triggers visual hallucinations and provided psilocybin

is present at sufficient enough concentration that is taken at a sufficient dosage

one will experience profound visual hallucinations regardless of whether or not

their eyes are open or their eyes are closed now that's an important fact because it explains one of the major effects of

psilocybin that people experience while they are on the drug now as I'll talk about a little bit

later in terms of what constitutes a useful psilocybin session useful meaning

that it's leading to Adaptive improvements in mood adaptive improvements in creativity and cognition

Etc is that people not have their eyes open

for at least the majority of the psilocybin session this is something

I've discussed with several experts who are running clinical studies on psilocybin in their Laboratories some of

whom are going to be guests on the huberman Lab podcast in upcoming episodes and I can't underscore this enough

because your visual cortex contains so many of these serotonin 2A receptors and

because psilocybin binds so strongly to that serotonin 2A receptor you're going

to experience a lot of visual hallucinations when you are under the influence of psilocybin there's no surprise there this has been known for

hundreds if not thousands of years it's one of the main reasons why people take psilocybin however as I mentioned

earlier these hallucinations occur even when the eyes are closed and it's now

fairly well established that if people are to take psilocybin and have their

eyes open much of their cognition much of their thinking much of the time spent

in that psilocybin Journey is focused on the altered perceptions of

things in the outside environment sometimes this looks like a sort of a

fracturing of the outside world into kind of geometric shapes sometimes it appears as a kind of melting of things

in the visual environment including people's faces or a morphing of people's faces all of that has a strong let's

just call it a draw for a lot of people who are looking for a highly unusual experience inside of the psilocybin

Journey but I think if one's goal is to derive the long lasting benefit from the

psilocybin experience it's very clear that having an eye mask or some other

eye covering or something that ensures that one's eyes are closed for the majority if not the entire psilocybin

session is going to be very useful because it's going to limit the extent to which one

is focused on those outside changes in visual perception AK hallucinations and rather will allow the person to go

inward to combine whatever it is that they happen to be seeing in their Mind's Eye with the different thoughts and

memories and changes in their emotions that are occurring and that going inward

by staying in the eye mask at least for the majority of the time it seems to be a very if not the critical feature of

making the psilocybin Journey effective in the therapeutic sense now once again I want to cue to some of the safety

Safety & Cautions for Specific Patient Populations

precautions here I'm going to say this at least three times throughout today's episode as I'm talking now and various

other times throughout today's episode you may get the impression that I'm all for everybody doing psilocybin and that

is simply not the case in order for a psilocybin journey to be therapeutically useful it does require certain

conditions and supports and there are certain people for which psilocybin use is going to be contraindicated meaning

they should not do psilocybin in particular people who have existing or

have a predisposition to psychotic episodes or bipolar episodes even having

a first relative who has bipolar or schizophrenic or schizotypal issues

can be a rule out condition that is can get someone eliminated from a clinical study on psilocybin for fear of

triggering psychotic episodes not just during the psilocybin Journey but potentially in a long-standing way so

again that's really critical the other thing is that everything I'm talking about today unless I say otherwise is really focused on adults meaning people

who are 25 years old or older that is their basic wiring and rewiring of the brain that we call developmental

neuroplasticity is completed all right most of the studies today that I'll talk about involve subjects ranging from 25

years of age out to about 70 years of age but no one younger so again

psilocybin and its use is certainly not for everybody it's still illegal it's being used in the clinical setting and

research setting they're these pockets of decriminalized areas and potentially suing legalization of psilocybin but

again only in the proper clinical setting okay again I say that not just to protect myself but I say that also to

protect all of you psilocybin is a powerful powerful drug not just to be under the influence of but also in terms

of its long-standing changes after the effects of psilocybin have worn off I'd

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Psilocybin, “Magic Mushrooms” Dosing, Micro-Dosing, “Heroic Doses”

talk a little bit about dosing of psilocybin and also about microdosing of psilocybin now this is an area that I

wouldn't say is controversial but that there's uh how should we say this there's a lot of

um loose thinking around this in the non-clinical non-research communities

but within the clinical and research communities there's a lot of data that's come out indicating what effective and

safe doses provided all other things are considered safe safe doses of psilocybin actually are and here we really can go

back to our discussion of psilocybin as quote unquote magic mushrooms or mushrooms and if one were to translate

from the mushroom form of psilocybin to the psilocybin that's actually used in

various studies because frankly in these studies people aren't eating mushrooms they're typically taking synthetic

psilocybin either intravenously injected into a vein or orally and that's how the researchers are able

to tightly control the amount of psilocybin and the typical dosage that's used in clinical studies ranges from one

milligram often given repeatedly from day to day over long periods of time so-called

micro dosing and really that one milligram per day or even up to three milligrams per day repeatedly over time

is what people generally think of as microdosing as compared to say a 10

milligram dose given once maybe twice in two separate sessions or a 25 to 30

milligram dosage that's given once or twice now those amounts of one to three

milligrams or ten milligrams or 25 to 30 milligrams might not mean much to those

of you that don't think about these things in the research terms perhaps you've heard of microdosing and you've

also heard of macro or quote-unquote heroic dosing okay that sort of a common uh or I

should say popular nomenclature for psychedelics and I'll Circle back to that in a few minutes but I think one of the questions that I hear a lot is how

much psilocybin is present in a given amount of mushrooms and so the way this typically works is that mushrooms are

often discussed in terms of grams or ounces so an eighth of mushrooms refers to an eighth of an ounce of mushrooms or

X number of grams of mushrooms the breakdown is actually quite simple

one thousand milligrams equals one gram and the concentration of psilocybin in

most so-called magic mushrooms is about one percent so one gram of mushrooms

being 1 000 milligrams means that it contains approximately again it's

approximately 10 milligrams of psilocybin and in most of the clinical studies it's been shown

that the dosage of 25 to 30 milligrams given or I should say taken once or

twice we'll talk about the spacing of sessions a little bit later Taken once or twice is what's leading to the most pronounced

therapeutic outcomes but of course with enhanced therapeutic outcomes one

also observes enhanced side effect profiles or what are called Adverse Events so there's an important nuanced

conversation that has to take place but right now we're talking about the conversion of grams of mushrooms to psilocybin so one gram of mushrooms

being one thousand milligrams containing one percent psilocybin

means that it contains 10 milligrams of psilocybin now the so-called heroic doses that you've heard about and this

is something that's discussed more with the let's call them traditional or classic Psychonauts these are people

that may have an advanced degree but typically are not running Laboratories exploring the effects of psilocybin in

controlled clinical trials these are people who um have been long time explorers and often writers and

people who have been spokespeople for psilocybin and other psychedelics and they will often refer to the so-called

heroic doses it's a little bit hard to translate from that informal Community to the scientific data but in discussing

that topic with various researchers who run Laboratories at major universities focused on psychedelic Therapies

what I was told is that the quote-unquote heroic dose that's often discussed really refers to a 5 gram or

so dose of mushrooms so what that translates to is 50 milligrams of

psilocybin so when you hear someone talk about a quote-unquote heroic dose they're probably referring to ingestion

of 50 milligrams or so of psilocybin but in its mushroom form so about five grams

of mushrooms and again it's important to point out that the concentration of psilocybin in different strains of

mushrooms and in different batches and depending on the age of those mushrooms and how they've been stored Etc can vary

tremendously from batch to batch in fact there are some Laboratories that have explored the range of psilocybin

concentration in different mushroom strains different so-called magic mushrooms and

that range is pretty broad it's anywhere from a half percent all the way up to two percent what that means is that

someone might get a hold of one gram of mushrooms thinking that they're taking 10 milligrams of psilocybin in those

mushrooms when in fact they're actually taking 20. or somebody could take three grams of mushrooms thinking they're taking 30 grams of psilocybin and in

fact they're only taking 10 or 15 milligrams of psilocybin so the sourcing

is really key obviously as Things become more legal and more regulated and more

used in the therapeutic setting or and this is what's happening more and more or as people start to rely on

synthetically made psilocybin as opposed to using mushrooms to ingest psilocybin

then certainly the dosaging is going to be more consistent from batch to batch because we're not talking about batches

of mushrooms we're talking about batches of psilocybin itself so now I'd like to take a step back from all this chemistry

Psychedelic Journey: Set, Setting & Support

and cell biology and talk a little bit about the structure of a psilocybin Journey itself and relate that to what

we now know about what's happening in the brain during the psilocybin journey and then a little bit later we will

return to that serotonin 2A receptor when we talk about some of the more lasting changes in brain chemistry and

brain wiring that occur after the psilocybin journey is over so let's take a couple of minutes and

just discuss the various components of an effective therapeutic psilocybin

journey and here I'm not detailing a menu of things that people should do in order to pretend that they are a

psilocybin assisted therapy coach or to do self-administered psilocybin therapy

that is not what I'm doing what I am trying to do is to share with you the consistent components that are present

in the clinical trials that have demonstrated the effectiveness of psilocybin for the treatment of

depression and for other compulsive and addictive disorders and those data meaning the specific data related to

those trials and the references themselves we'll get into a little bit later but we can't really have a

conversation about psilocybin and what it does without talking about the so-called set and setting as it's often

referred to that is known to at least bias the probability of the journey being

beneficial and not a so-called bad trip so what are the variables that make up an effective and safe psilocybin journey

and again when we say safe we're referring to people who are not prone to

psychotic episodes that don't even have a first relative that's prone to psychotic episodes

we're talking about people that are 25 years or older we're talking about people that for instance are not taking

antidepressants that impact the serotonin system this is very important to understand I think a lot of people don't know this but as far as I know all

of the studies that have explored psilocybin for its ability to positively impact brain chemistry and mood and

function have required that people either not be on or abstain from

antidepressants in the weeks leading up to the psilocybin Journey now that is

not to say that if you are currently taking ssris or something similar that you should cease taking them and do psilocybin I'm absolutely not saying

that that could be very very very dangerous if not catastrophic anytime you're going to take anything or stop

taking anything for that matter you do need to consult with your physician this case a psychiatrist as well so let's

talk about psilocybin Journeys from the subjective side and from the structural side and when I say the structural side

what I mean is what does a psychedelic Journey actually include and here are

the words set and setting become extremely important some of you may have heard that set and setting are the

foundation of a well done or even therapeutically beneficial psychedelic

journey and all of that really hinges on safety and outcomes so set refers to

mindset the mindset of the person taking the Psychedelic and setting refers to as

the name suggests the setting in which they're taking it in and the people that are present there so let's talk about setting first the setting for a

psychedelic Journey needs to be one in which the person under the influence of the psilocybin or other psychedelic is

safe that means no windows they can jump out of that means no streets of moving

cars they can run out into that means no opportunity for getting lost that means

no opportunity for getting into bodies of water in other words it requires that there be

at least one and perhaps even two or more other individuals who are not also

taking psychedelics right who are not also taking psychedelics present

in that setting to ensure that the person taking the psilocybin is not going to harm themselves or others I say

this not to sound like a school teacher even though technically I'm a school teacher but because of course I don't want

anyone to get harmed and I'm also aware that there's a lot of interest nowadays

in psychedelics such as psilocybin becoming legal or decriminalized for

their therapeutic applications and if we look back to the late 1960s and early 1970s when the Controlled

Substances Act was invoked to make psychedelics like psilocybin illegal one

of the bases for that was not just the geopolitical unrest at the time and

things like the Vietnam War but also some highlighted instances in which people did not take set in setting into

consideration took things like LSD stared at the sun went blind or took

psilocybin went out and harmed somebody else again these are very very isolated

instances but these are the exact sort of instances that lead to criminalization or the fact that things

like psilocybin and LSD and MDMA for that matter are considered illegal again I completely acknowledge that there are

a number of different factors making them illegal we could have a whole discussion about that um we talk about the drug trade the War

on Drugs but right now is such a critical time in the history and the use

of psychedelics for therapeutic and other reasons and getting setting correct meaning making it absolutely as

safe as possible for the person taking the Psychedelic is absolutely key and one of the best ways to ensure that it's

safe is to have responsible individuals who are not under the influence of psychedelics present in that environment

so that's one component of setting the other component of setting that we talked about earlier which turns out to be very important is the opportunity and

perhaps even the bias toward the person on the Psychedelic being seated or ideally lying down and being

in the eye mask or at least having their eyes covered so that they can combine any spontaneous visual hallucinations

that occur with the various thought processes that are occurring while under the influence of psychedelics

this is Far and Away different than quote unquote taking mushrooms and going into the woods or taking mushrooms and

going to the beach what we're talking about today is the use of psychedelics for a particular brain rewiring outcomes

that yes can involve things like changing one's relationship to Nature we're changing one's relationship to

somebody else by interacting with nature or somebody else and while I'm not trying to diminish the potential value

of those sorts of psychedelic Journeys if we look at the scientific data the vast majority of it not just in the

clinical setting but in terms of understanding the safety and efficacy and positive rewiring of brain circuitry

that allows people to feel better to understand themselves better and to interact with life in more adaptive ways

going forward out of the Psychedelic Journey involve these very let's say

um you know subdued settings that are typically in one room a closed

environment with one or two other individuals acting as sort of guides or helping the individual by talking to

them from time to time if they feel like they have to sort through a particular aspect of the Psychedelic Journey that's

creating anxiety and we'll talk about the Contour of the Psychedelic Journey that almost everyone who takes psilocybin at somewhere between 20 and

30 milligram dosages tends to experience but the setting that I'm describing is

not just a list of things to you know make sure you're safe but they're really the list of things that also ensure that

one can get the maximum benefit out of the psilocybin Journey now other things included in setting that are known again

Music & the Psilocybin Journey; Duration of Effects

from scientific literature to be very influential in terms of the experience that one has and to bias things towards

a positive experience are again safety eye mask but also the

presence of music now when I first heard about this from one of the Premier researchers on psilocybin and other

psychedelics which is Robin cardard Harris he's a professor at University of California San Francisco who's one of

the major Pioneers in the studies of psychedelics and when he first started telling me about the critical role that music plays I thought okay that makes

sense you know music can impact our emotion impact um the way that we think and could

therefore impact what one experiences during the Psychedelic Journey but he really underscored for me the extent to

which music is not just a sort of incidental feature of the setting in

psychedelic set and setting but that it is one of the but that it is one of the major drivers of the actual cognitive

and emotional experience that somebody has on something like psilocybin that allows

the psilocybin journey to be looked at or viewed not just as beneficial but and this is quoted in the scientific

literature as one of the most profound and important positive experiences that one ever experienced in their life so

let's talk about the sorts of music that have been used in these clinical studies well first of all we need to think about

how long the psilocybin Journey itself is going to be and the typical duration of the psilocybin journey is anywhere

from four to six hours it's going to depend somewhat on dose it's going to depend somewhat on variability in

people's liver metabolism and it's also going to depend somewhat on how much

food people have in their gut in all the clinical studies that I read it was advised that people not have any

food in their gut at the time in which they ingest or injected with the

psilocybin it's particularly true if people are going to be taking psilocybin mushrooms in order to get their

psilocybin and that has been done in a few studies most studies however use synthetic psilocybin taken orally

again that's converted to silacin in the gut by the acidity of the gut and the acidity of the gut is going to be

impacted by the various foods that people eat and so that's one of the major reasons why people are advised to

not eat for at least four hours prior to the psilocybin Journey so here we've got this six hour what we're calling Journey

because that's what everyone calls it or trip that people start experiencing about 30

to 45 minutes after ingesting psilocybin or taking psilocybin there's a peak

component in which there's a maximal intensity of emotion and often that's

also associated with anxiety and this is very important to understand the anxiety component is part of what in the

therapeutic setting they refer to as ego dissolution and that anxiety around the peak and I think most people would

probably hear Peak experience and think oh we're talking about a peak positive experience but no we're referring to a peak

experience and anxiety that people stay with and then come down from

gradually as one goes from the second or third hour after taking psilocybin and

that tapers off slowly toward the six hour mark what sometimes people refer to

as parachuting back in of course um they're not hopefully I would very much hope people aren't

actually parachuting back in while on psilocybin but I think you get the idea

the music that's typically played in the clinical studies using psilocybin for

the treatment of depression or for compulsive disorders or addiction tends to have a particular Contour that

matches with and can also drive that Contour of the psilocybin Journey that I

just described again we're talking about people wearing an eye mask with guides

present so people who are not taking psilocybin there as well to ensure that the person feels supported and is safe

the person is typically lying down sometimes sitting down but more often than not lying down wearing an eye mask

and the music that's played at the beginning of the psilocybin session tends to be music that doesn't have a

lot of vocalizations it tends to be things like classical music it tends to be fairly low volume but that then

transitions into music that has a lot of percussion so often drums that tends to

be higher volume that has a lot of intensity at about the time that one would be

experiencing the peak in emotion and in perception the so-called peak of the

journey that intense music tends to be played for about 45 minutes to 90 minutes

depending on the study one looks at and then tends to transition into softer

music again sometimes Coral type or more melodic music often female voices in particular

and then transition into nature sounds and things that more or less mimic the outside natural world and less so

um synthetic things like drums or instruments and vocalizations and things of that sort so why would it be so

Psilocybin & the Brain: Subjective Experiences, Perception

important that music match and even contribute to the subjective experience that people have on psychedelics and

here we should probably take a couple of moments and just talk about what those subjective experiences are like so for

people that haven't done psilocybin or any psychedelics it's a little hard to describe but one

way to describe it is that there's a lot of so-called perceptual blending so for instance people in the eye mask will

report seeing some geometric shapes and colors but perhaps the music they're listening to will then start to change

the intensity or the movement of whatever it is that they're seeing hallucinating inside of the eye mask in

ways that are linked this is referred to as synesthesia or the merging of different senses that are not ordinarily

merged in addition people under the influence of psilocybin or other psychedelics for that matter often will

report that their pattern of breathing becomes linked to the perceptions of

things that they are hearing or seeing or feeling so for instance if they take a big deep breath in and then a long

exhale out they may find that during the long exhale out that the notes of music that they're hearing in those moments

are also drawn out for the duration of the breath and they'll inhale and that they're getting at least what they

perceive as control over the music which of course they are not actually controlling by using their breath and

that perhaps their visual perceptions are also being merged with that so those are just a couple of examples of how

perceptual blending AKA synesthesia can occur while under the influence of psilocybin and this really is highly

individual from one person to the next some people for instance will find that if they take their fingertips and rub

them across the couch or the chair that they happen to be lying down or sitting on that they will experience a change in

the music maybe even if they you know they move their hand up they hear an increase in frequency of sound they move

their hand down they hear a decrease in frequency of sound and that all of this is linked to their emotional state at

the same time and vice versa okay so we're talking about a lot of perceptual and emotional blending and some sense of

control over one's perceptions and emotions in a way that's very unordinary

even extraordinary we can step back from all of this very subjective description

of the Psychedelic journey and ask what is going on that would allow these sorts of things to occur and there you are

already equipped with an understanding of the cell biology and the chemistry that makes all of this possible and that

is that when psilocybin is ingested and then converted to silacin and it's the

silacin that crosses the blood-brain barrier and then even though silacin looks a lot like serotonin silacin has

this incredible ability to predominantly activate the serotonin 2A receptor well

we can understand much of what's happening at a subjective level during the Psychedelic Journey even right down

to the sorts of emotions and perceptual blending the synesthesia we can understand a lot of that by

understanding where the serotonin 2A receptors are expressed on neurons and

what those particular neurons are doing and the simplest way to describe this is that there's a category of neurons that

we call pyramidal neurons pyramidal neurons are found lots of places in the brain but they're called pyramidal neurons because they're shaped like a

pyramid they have a cell body which is the part of the cell that has the DNA in it and a lot of other important things

like the organelles mitochondria Etc and then they also have what are called dendrites dendrites are the little

branches or processes that reach out both from the bottom of these cells and then

these pyramidal cells are interesting because they also grow a branch up up up up into layers of neural tissue above

them and they have what's called an apical Branch that's the part that grows up and then they fan out at the top and

that Fanning out at the top allows them to communicate with other neurons in their environment okay so if you're not getting a good picture of this in your

mind for my description I apologize but simply think about putting your arms out to the side and by

doing that you're able to interact with things that are some distance from your body sort of an obvious thing in that case

these cells are effectively doing the same thing by extending little processes out into layers above them and to the

sides and this is really important because much of the serotonin 2A receptors that are present on neurons in

the brain are present in those apical dendrites those branches of these pyramidal neurons that are above and

that extend out to the side of those neurons and so when somebody is under the influence of psilocybin that means

that silosin has bound to The receptors on those apical dendrites and it's

increasing lateral communication across brain areas in fact this is perhaps one

of the most well-documented effects of psilocybin and other psychedelics which is that there's a shift from the brain

being more modular meaning more segmented like auditory neurons or communicating electrically and

chemically largely with other auditory neurons of course they'll communicate with other types of neurons too right

when I hear something off to my right you know like a snap of fingers off to the right I'll turn my head and my ability to do that depends on my

auditory neurons being linked up with things like my motor system and my visual system but the key thing to understand is that when

there is psilocybin present in one system that the communication of any of these

pyramidal neurons the ones involved in hearing the ones involved in thinking the ones involved in memory the ones

involved in visual perception or in the generation of visual hallucinations with eyes closed those are all talking to

many many more other neurons more extensively

so what happens effectively is that there's a reduction in the modularity the separateness of function in the

brain and an increase in what's called integration of communication across what would

otherwise be disparate brain regions we can say that really simply by saying psilocybin increases communication

across the brain now in addition to that there's a reduction in What's called the

hierarchical organization of the brain typically sensory information comes in from the outside environment so we hear

something we see something we taste something we smell something and in what's called bottom-up fashion

meaning bottom from the periphery up meaning it propagates up Through The

Eyes through the nose through the ears through the skin or the senses in those regions I should

say up into areas of the brain that sit deep to the cortex like the thalamus

and then the thalamus is sort of a Way Station it's like a switchboard that sends visual stuff to the visual centers

and auditory stuff to the auditory centers and touch stuff to the touch centers and things that maybe trigger a memory off

to the memory centers of the brain Etc that's the typical organization it's hierarchical because it goes from the

periphery up to the more complex processing regions of the brain that make decisions that link all of that

stuff to Prior experience maybe plans about the future when psilocybin is present in the system

there is a broadening of the flow of that information from the bottom up as

well okay and that has to do with what's called thalamic gating the thalamus is a very interesting structure we probably

don't want to go into it in too much detail right now but it really is like a switchboard in a way station saying hey

pay attention to the visual stuff pay attention to the auditory stuff or just to the visual and auditory stuff and ignore

um you know touch sensation for the time being or vice versa when psilocybin is present in the system

and when serotonin 2A receptors are activated very strongly there's a

tremendous broadening of the flow of information up and through the thalamus so not only is there more communication

of so-called higher order brain centers we refer to them as higher order because they're involved in thinking and

decision making and emotion Etc but there's also a shift in the flow of sensory information into the brain that

can generally be described as a broader and including more blending of the

different senses and when I say blending of the senses I'm also referring to blending of the sense of interception of

our sense of our body and what's happening inside of our body and this without question at least partially

explains why went under the influence of psilocybin one's breathing can be linked to a sound

and then suddenly the sound one thinks is being controlled by one's breathing or that the sound itself can

be linked to something that we see in our Mind's Eye while in the eye mask essentially what I'm describing here is

that serotonin 2A receptor activation allows for more Broad

less precise and less hierarchical activation of brain circuitry and when I

say hierarchical what I mean is that normally things go from periphery from eyes to Thalamus to visual cortex

however when under the influence of psilocybin as I mentioned before even in

the eye mask the visual cortex is going to be very activated even in the absence of any visual input so then if one hears

a sound perhaps from music particular Motif for voice and that's

linked to a particular emotional state that is now being blended with visual phenomenon occurring within the brain

that have no external stimulus and so while the patterns of activation in the brain while under the influence of

psilocybin aren't random they are far less channeled far less modular and far

less hierarchical than would ever be the case when not under the influence of psilocybin I'd like to just take a brief

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Brain Networks & Therapeutic Outcomes

scientific literature they're not one not two not three but four prominent theories of which brain networks are

most activated during a psilocybin or other psychedelic journey and so for those of you that are interested in

those different models first of all please know that they are not competing models while some of them disagree about

some of the details it's very likely that all of these models are true they include things like changes in the so-called default mode Network there's a

lot of interest in this I've talked about it before on this podcast the default mode Network because the network in the brain that's thought to be

responsible for spontaneous imagination for daydreaming and that reflects sort of the base activation state of the

brain when there's no drugs in our system and the default mode network is one of the systems or networks rather

that is thought to be rewired under conditions of psilocybin or other psychedelics again if you're interested

in these models and comparing and contrasting them there's a very nice review from Brian Roth's Lab at Duke

entitled the neural basis of psychedelic action we'll provide a link to this in the show note captions and again I just

want to emphasize that all of these models have been shown to be true in different studies and what

they all point to is more extensive communication between areas of the brain that normally are not as

active at the same time while under the influence of psychedelics such as psilocybin

the controversy in the field relates to which of these networks is the one that changes the most to explain the

therapeutic outcomes that have been discovered in recent years so again check out that review if you're interested in that sort of thing in the

meantime we can cut a broad swath through all of those models and just say that psilocybin expands the functional

connectivity of the brain while one is under the influence of psilocybin and it does seem that some of that expanded

functional connectivity persists after the effects of psilocybin have worn off and that statement about the functional

connectivity of the brain being more expanded not just during the psilocybin session but after as well has been

substantiated in a number of papers but one of the key papers in this area is one that I recommend people check out if

they're interested in this sort of thing is entitled the effects of psilocybin and MDMA on between Network resting

state functional connectivity and healthy volunteers and I like this paper for a number of reasons first of all it's a very high quality paper carried

out in the laboratory of Robin cardart Harris at UCSF again one of the Premier researchers in this area of psychedelics

and their function what they do in the brain and also their therapeutic applications but also because it focuses

on healthy volunteers they explored using brain Imaging what brain areas are active in a resting state so things like

default mode Network then they had people take psilocybin or

MDMA and then they looked at the connectivity between those brain areas in those same individuals when they were

not under the influence of these drugs and found more extensive connectivity all of which pointed to an enhanced

lateral connectivity less hierarchical organization effectively more

interconnection and communication between different brain areas I think not only is the fact that they looked at

healthy volunteers very interesting and important but also that they looked at this resting state of the brain they

weren't providing a particular auditory or visual stimulus for people to hear or look at while they were in the brain Imaging scanner as it's called

rather they were simply looking at how the brain was behaving at rest and so it's very clear that for people that do

two or even just one of these psilocybin Journeys at a particular dose that the brain is actually getting rewired you

know we hear this a lot psilocybin or other psychedelics lead to plasticity they rewire your brain well

let's go back to what we said at the beginning rewiring of the brain is not the goal adaptive rewiring of the brain is the

goal right rewiring that leads to new ideas that are interesting that are

accessible after the Psychedelic Journey new ideas and new ways of thinking or feeling that allow people to function

better in their lives that that's the goal of effective psychedelic therapies not simply rewiring of the brain you

know a brain injury for that matter will lead to rewiring of the brain but that's maladaptive rewiring the use of things

like amphetamines or methamphetamines in particular will lead to rewiring of the brain but that is strongly maladaptive

rewiring so now there are really dozens of studies conducted in humans using

brain Imaging and other techniques have evaluated how things like psilocybin change connectivity in the brain and I

think the take-home message is it expands that connectivity however it seems to do so in ways that

still allow people to function in their daily lives one of the key things that I glean from the literature on the

therapeutic use of psilocybin for the treatment of depression is that very seldom do people who take

psilocybin experience long-term issues with memory why is that so critical well

you could imagine that increasing connectivity in the brain reducing modularity reducing hierarchical

organization of the brain would lead to disruptions in memory right it's as if you're shuffling books on the bookshelf so to speak but that doesn't seem to be

the case rather it seems that the increase in connectivity is leading provided set and setting are correct

provided safety Protocols are followed to positive rewiring or adaptive

rewiring of neural tissue so that's one of the things that makes psychedelics and psilocybin in particular very

exciting from the therapeutic standpoint and of course we have to acknowledge it's also what has a lot of people excited about psychedelics not just for

the treatment of depression but for expanding the brain's capabilities more generally so along those lines I want to

Creativity; Music, Emotionality & Psychedelic Journeys

touch on the issues of creativity and the experience of life outside of psychedelic Journeys is impacted by

psychedelic Journeys and here this relates to a question that I heard a lot when I put the call out on social media

that I was going to do this episode and I asked people what do you want to know about psilocybin and one of the more common questions that I got was does it

increase creativity does it increase our experience of life in ways that are beneficial aside from its now documented

positive effects in treating depression and compulsive disorders and addiction and the short answer to this is yes but

that the positive effects of psychedelics psilocybin in particular on creativity and our experience of Life

have only been explored in a fairly narrow set of dimensions however where it's been explored there's

some really interesting findings so one of the more interesting findings I think is a paper entitled increased low

frequency brain responses to music after psilocybin therapy for depression I think this is a really interesting paper

because what the authors did is they took advantage of the fact that in these therapeutic psilocybin sessions that are

carried out for the treatment of depression music is being played and there are prior studies

showing that when music is played you activate different brain areas depending

on what sort of music is being played it's somewhat obvious perhaps you know sad music versus you know intense

um you could think about heavy metal versus choir music versus Gregorian chants versus punk rock music and on and

on it makes sense that different brain areas would be activated when different patterns of Music are played however

there do seem to be some Universal features of brain activation in response to music This should probably be the topic of an entire episode of The

huberman Lab podcast and indeed it will be for instance there are areas of the auditory cortex

that are activated no surprise there and areas of the brain's reward circuitry the so-called ventral striatum and the

so-called mesolimbic reward pathway talked a lot about these in the episodes about dopamine that I've done previously

these are brain areas that lead to the release of dopamine in other brain areas and that reinforce certain experiences

and that tend to give us the subjective feeling of yes I like this I want more so in this particular paper

what the authors did is they took advantage of the fact that people are in the clinic they're on psilocybin

they're listening to music and as you recall the music played at different stages of the psilocybin Journey are

different they have a different emotional component and music is a really nice stimulus in the laboratory

as we say because like with visual stimuli you can break it down into high frequency low frequency right sounds

like these kinds of things that was my attempt at low frequency versus high frequency auditory stimuli or at the

spatial frequency or what in the auditory domain would be called the temporal frequency is it

or is it all we've changed there is the temporal

frequency the sound was somewhat the same but the distance between those sounds was different you get the idea

so they have access to these people in these different conditions and they can put them in the brain scanner and they can do that before and after having

taken psilocybin and the long and short of this study is that

psilocybin changes one's experience of music not just during the psilocybin

Journey itself but thereafter and in fact it changes one's emotional response

to music in very interesting ways for instance one of the more common features of major depression is that people don't derive as much pleasure from different types of experiences whether or not it's food or

sex or social experiences to the point where sometimes they just stop trying to seek out those experiences

people with depression often feel as if music no longer has the same impact it just doesn't really lift them up very

much this study found that people who have taken psilocybin according to the parameters we talked

about earlier can get a return of the elevated emotionality the positive emotions associated with music that

formerly made them feel good in other words they can feel music again they can feel good in response to music again now

this is interesting because in theory could be that psilocybin simply allowed

them to access the emotions around music again more generally but that's actually not what this paper and some other

papers that have been published report rather it seems that taking psilocybin

can increase one's positive perception of music that one likes

and can tone down or reduce the depressiveness or the sadness of music that tends to make one sad

even after the psilocybin has worn off and for a long period of time afterwards maybe even forever although no study of

course can be carried out forever because forever is forever what we do know however is that psilocybin can

rewire the connections between the emotion centers in the brain and the networks that control auditory

perception of music and leads to this condition in which people who felt like I was depressed or

I couldn't feel the music I just wasn't getting the same lift and Joy from it again they can start to experience more joy from that music again and that music

that made them feel sad and depressed has a diminished capacity to make them feel sad and depressed and there's a lot

of neuroimaging data in this paper that point to the specific brain areas that include areas like the ventral tegmental

area that can explain why these sorts of effects would occur so this isn't just subjective reports of people saying oh

yeah you know I was depressed and music didn't feel really good and now it feels great or that used to make me feel so

sad and now I feel like I have a capacity to listen to that without being you know crushed by feelings of sadness

the paper included some subjective reports of that sort but then was able to link those to changes in brain

circuitry and brain activation in response to music using neuroimaging so in that way it really points to both the

subjective and structural and functional changes that psilocybin can bring about through that expand did connectivity

between brain errors because remember during the psilocybin session it's not as if music or the perception

of music is specifically being looked at or focused on in these studies rather music is playing people are in the eye

mask they're feeling all sorts of things they're breathing they're hearing their touch it's all happening all at once

there's a peak it's long there's a long taper the music's changing okay all of that took place in this study as well

but it is after the session When comparing brain activation states to

music of a particular type sad or happy and comparing that to the patterns of brain activation that occurred before

the psilocybin Journey that they discover that people's brains have rewired during the psilocybin

session in a way that allows them to experience joy in response to music again so that's one of the more rigorous

studies I was able to find that addresses this question of whether or not psilocybin really does rewire the

brain in ways that allows us to be more creative and experience life differently after the psilocybin session now that

Depression & Psychedelics as Neuroplasticity “Wedge”

paper didn't Focus specifically on creativity I did an entire episode on creativity that talked about different

types of meditation like open monitoring meditation it talked about different patterns of thinking that one can

actually practice to increase creativity we had arguably one of the most creative people on the planet Rick Rubin

came on this podcast talked about the creative process from the perspective of music and his role in producing music so

you can check out those episodes if you're interested in the neural circuitry related to creativity at least at the time of recording this episode

there haven't been a lot of studies looking specifically at the brain networks that we think are involved in

creativity and how those change in response to psilocybin and other psychedelics I imagine those studies are

either happening now or will happen in the future but the studies I just described referring to the changes in

emotionality and responses to music I think provide a nice template for what's likely happening

both during psilocybin Journeys and after those psilocybin Journeys when we talk about less hierarchical organization more connectivity between

brain areas what it's pointing to is the fact that during the psilocybin Journey people

have the opportunity to learn new relationships between different sensory and emotional states

and those new relationships seem to persist long after the Psychedelic Journey has been finished

and a lot of people researching psilocybin in the clinical setting think that that's one of the major reasons why

psilocybin and other psychedelics can rewire our relationship to things more broadly it allows for new learning new

contingencies and when we look at depression we often think you know diminished mood people now have an

appetite they're not interested in Social relationships or romantic relationships they're really struggling and all of that of course is true but

another lens to look at depression through is that a lot of that thinking and a lot of those emotional states that

are negative are somewhat habitual they relate to a sort of implicit understanding and living out of the idea

that a leads to B leads to C okay you seek out a relationship it doesn't work out try a new job you don't get the job

you get the job it's no good all these negative outcomes of if a then B then C and it does seem that psilocybin can

have this effect of invoking new patterns of learning new considerations about what might be possible and indeed

may even lead to actual rewiring of the emotion centers in the brain with these other brain areas and vice versa in ways

that eject people from the psilocybin session thinking oh you know yeah I used to feel this way about something work

relationships myself Etc but I'm willing to consider this other possibility or this other possibility seems at least

partially true to the extent that I'm willing to go out and evaluate that now here I'm speaking very subjectively but

remember we have to tie back the subjective experiences and changes of things like music and motion and our

relationship to life and jobs and relationships back to the cell biology and chemistry of psilocybin because ultimately it really is just a chemical

activating receptors those receptors changing networks in the brain and the journey itself seems to be the time when

all of those changes are put in motion it's like a boulder that gets rolling in fact I think the best way to think about

psilocybin and other psychedelics is that they initiate the neuroplasticity

process but they are not the neuroplasticity process itself and the journey itself is not where all the

neuroplasticity occurs we know that for sure in fact if you want to imagine how psilocybin and other psychedelics work

to change the brain think about them as a wedge that gets underneath the boulder that is the neuroplasticity that gets

rolling forward and then think about whether or not the plasticity is adaptive or maladaptive whether or not

it actually serves you in your life on a daily basis or not depending on whether or not you're using your conscious brain

to move that Boulder in a particular direction right not just bulldozing through things and destroying them but

clearing a path through old ineffective maybe even destructive patterns of thoughts or emotions Etc I give you that

analogy because I think it more accurately captures what psychedelics like psilocybin are doing rather than

the typical discussion around psychedelics that we tend to hear which is that oh it creates plasticity and

plasticity is what you want for the next couple of minutes I'd like to focus on some of the key and stereotype that is

Positive Psychedelic Journeys, Unity, “Oceanic Boundlessness”

characteristic experiences that people tend to have during a psilocybin Journey because there's some really interesting

research on this these are phrases that perhaps you've heard before things like letting go ego dissolution feelings of

connectedness well all of that is very subjective on the one hand those words

are heard often enough and repeatedly enough in psilocybin sessions and after

psilocybin sessions along with this description of this psilocybin experience as one of the most profound

of one's life where one of the most positive in the ideal case of one's life that they are worth exploring we should

also of course explore the so-called bad trip the possibility that someone will have a not good time or even very

frightening time while under the influence of psilocybin so there have been some scientific studies that have

explored what sorts of subjective experiences that is thoughts and feelings

insights that people have that relate to positive therapeutic outcomes and more

generally with the sense that the psilocybin Journey was positive or maybe even tremendously positive in one's life

so while there's a century or more of writings about psychedelics that describe things like enhanced feelings

of connectedness or dissolution of the ego the loss of one sense of self and then the regaining of one sense of self

and so on there's a particular paper that describes some of those things in terms of rating scales that is the sorts

of tests that people can take in which they answer particular questions and that link back to things like feelings

of connectedness and ego dissolution that allows us to put some numbers to those experiences and to look at some of

the statistics associated with those experiences and this is really what's important about scientific studies whether or not a measure is subjective

so someone's self-reporting how they felt or feel or whether or not it's measure of blood pressure or of a

chemical in the bloodstream Etc it's the use of numbers and statistics that allows comparison between different

groups and that can be compared between studies that allows us to make some firm

conclusions about what sorts of things psilocybin may or may not be doing when it's effective or not so the paper I'd

like to highlight is entitled quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for

treatment resistant depression I'll put a link to this paper in the show note captions but the basic Contour of this

paper is that they looked at subjects that underwent two different psilocybin sessions one at a relatively low-ish

dose of 10 milligrams of psilocybin and that would be equivalent to about one gram of psychedelic mushrooms more or

less and a second session involving subjects taking 25 milligrams of psilocybin or

what's roughly equivalent to somebody taking two and a half grams of psilocybin mushrooms

those people then answered What's called the Altered States Of Consciousness questionnaire which allowed them to

address and here I'm paraphrasing the quality of experiences in the 25 milligram psilocybin session so without

going into too much detail it's often the case in these sorts of two session studies that subjects will take a

slightly lower dose of psilocybin to familiarize themselves with the experience and then the higher dose that

leads to the more intense experience intense meaning a bigger more intense Peak a longer session overall greater

distortions in emotionality and perceptual experience all the stuff we talked about before so what this study found is that one of

the key features if not the key feature of a positive quote unquote

psychedelic experience is this sense of oceanic boundlessness occurring at some

point during the Psychedelic Journey now Oceanic boundlessness doesn't necessarily mean anything to any of us

it probably means different things to different people it's this idea that one is experiencing

something extremely unusual even mystical kind of Beyond this world and

one's normal experience but that it's not aligned with any specific outcome in the moment it's not

directly attached to anyone feeling or memory or thought process it's this it's a little bit tough to describe because I

can guarantee you I'm not on psilocybin or any psychedelics right now and I can only imagine that you're not

although some of you might be I can't even imagine what this uh podcast would um be like for somebody on psilocybin at

this moment but in any case Oceanic boundlessness a feeling of The Experience being mystical and not

really heading in any one particular direction just a feeling of massive connectedness with one's environment

both in the room and session perhaps with the guides with oneself with one's past with one's present people outside

the room with the entire world maybe even the universe that sort of thing

the intensity of that experience of oceanic boundlessness the mystical experience

seems to be positively correlated with positive therapeutic outcomes that is

relief from major depression now during the Psychedelic Journey as we talked about before there are a number

of steps that one typically goes through so there's the build up to First experiencing the effects of the drug

about maybe 20 to 45 minutes into the journey or trip then the peak and it is

during that Peak that people often feel the sense of oceanic boundlessness however

it's also often the case that it is during the peak where the maximum

intensity of emotion and we know based on Direct measurements also increases in

blood pressure and heart rate often very significant increases in anxiety and

fear as well that people will experience things like ego dissolution and the

guides role at that point is of course to keep the person safe make sure they don't run out of the room jump out of a

window run into traffic sadly these are things that have happened outside of a strong healthy safe set and setting but

the guide's role is to keep the person safe but also to encourage them to let go and move through that experience to

experience the anxiety allow it to Peak allow them to see that they're not going to die from that anxiety they're not

going to dissolve they won't lose their sense of self completely or they may temporarily feel as if they lose their

sense of self but then they feel it restored at various intervals during the peak or

as they exit that Peak and move toward the say second third fourth fifth hour

of the session so when exactly these feelings of oceanic boundlessness and ego

dissolution occur varies from person to person but typically it's during the peak that the ego dissolution the fear

and the need to quote unquote let go is most typical I think perhaps the best

way to describe the data in this paper in a way that's meaningful to everybody is to refer you to figure two which if

you're not looking at the paper won't mean anything to you but I'll describe it and if you do want to take a look at figure two again you can access the

paper in the show note captions what they did is they looked at a number of different subjective measures things

like experience of unity the feeling that one is connected to others into the

world things like spirituality whether or not the whole thing felt like a spiritual experience whether or not it

was a blissful State whether or not there were insights whether or not somebody felt disembodied out of body

whether or not somebody had a lot of anxiety whether or not they had these synesthesias these blending of visual

auditory touch and breathing and things of that sort and they addressed which of those measures related to the positive

clinical outcomes that were observed later after the psilocybin wore off and while I'm not going to go Point by Point

through each one of these measures there's a general feature to emerge from the study which is that

the experience of unity sense that the psilocybin Journey was spiritual

an experience of bliss at some point inside of the psilocybin Journey

the sense that there were insights that there were learnings about one's life and oneself

when those things were experienced very strongly that correlated with the person being what was called a responder to the

psilocybin treatment meaning they got relief from their depression whereas people who felt less of that okay so the

non-responders as they're called the people who do not benefit so much in the long run from the psilocybin

treatment tended to report less of an experience of unity less of a spiritual experience less of a blissful State less

insightfulness and so on whereas there were very few differences between the people that derived benefit

“Bad Trips”, Anxiety & Physiological Sighs

from the psilocybin treatment and those did not along the dimensions of synesthesia this blending of different

perceptions that ordinarily doesn't occur for most people or complex imagery right put simply

everyone who took psilocybin in this study at 25 milligrams saw a complex imagery they saw a lot of hallucinations

but just seeing hallucinations did not lead to the positive clinical outcomes in terms of mood

anxiety was a very interesting measure here because ordinarily we think of the ego dissolution the letting go is such a

key component of the Psychedelic journey in terms of the positive therapeutic outcomes this has been discussed quite a lot and in full disclosure Robin Carter

Harris has already come on to record an episode of the Hebrew and Loud podcast that episode hasn't been released yet but it will be released soon and he

talks about the importance of this letting go in terms of the positive clinical outcomes of the psilocybin

journey and indeed that is true and I should also mention that Dr Matthew Johnson from Johns Hopkins who also runs

a laboratory exploring psychedelics and their role in treating things like eating disorders and depression Etc also

doing incredible work also talked about the importance of letting go during the psilocybinary this ego dissolution this

ability to move through the anxiety and again I can't underscore this enough because it's been told to me over and

over again by the top researchers in this area that people head into that peaking phase of the psilocybin journey

and oftentimes it is not pleasant for them their feeling like it's uncomfortable it's scary and their heart rate is up and their blood pressure is

up and they're having a hard time calming down then they want to calm down but it does seem that while the guides

should not ramp them up and get them more stressed that the ability to move through that stressful period to

somewhat guide oneself or to be encouraged to guide oneself through that Peak and that anxiety and the fear of

losing oneself and the so-called ego dissolution that occurs is an important feature for an effective therapeutic

session in this study anxiety itself was inversely correlated

with a positive therapeutic outcome okay so this is important and somewhat nuanced on the one hand I'm telling you

that the Letting Go the ego dissolution does seem to be important in terms of reporting a psychedelic experience as

effective as having accomplished something and perhaps even explaining some of the long-term positive effects

to emerge from that psychedelic journey in this case psilocybin cherny however

non-responders that is people who did psilocybin but did not have a positive

therapeutic outcome in comparison to the responders those non-responders tended to have

higher subjective ratings of anxiety than did the responders so this is

important and what it speaks to is the fact that well yes letting go during the session experiencing some anxiety

perhaps even ego dissolution and the of dissolving of self and then the return of self is important

it is also important it seems that anxiety not be so so high or

subjectively experienced as so high that one does not experience the positive neuronal rewiring that leads to a more

pervasive elevated mood okay so I'm definitely saying two things at once because I'm trying to capture the data

accurately it would not be fair for me to say just let go experience as much anxiety as is possible and that's part

of the process yes Letting Go Again an air quote seems to be important for one's experience of

the Psychedelic journey in particular around the peak that occurs about two hours in or so however extreme levels of anxiety

seem inversely correlated or negatively correlated would be the better way to put it with the Positive therapeutic

outcome or really from depression so this takes us back to all of the things we've been talking about thus far

not just the chemistry and biological action of psilocybin but the key importance of getting dosage right the

key importance of making sure that you're in a safe environment but also one in which the guides really know what

they're doing I think this is one of the biggest and most important reasons for

having well-trained guides who really understand the Contour of the Psychedelic Journey but are also trained

in how to help somebody with their anxiety in real time while they're under the effects of psilocybin and of course

to help people integrate those feelings of high anxiety and maybe guide them back down to a calmer State during the

Psychedelic session itself here I can just mention some unpublished data in studies and again these are very

preliminary but through discussions with Dr Matthew Johnson who's running these psilocybin and other sorts of

psychedelic trials at Johns Hopkins he and I discuss the importance of having a real-time tool to adjust

anxiety while under the influence of psychedelics like psilocybin and there

he asked and they've started to incorporate is my understanding some of the real-time respiration tools that is

breathing tools that we know based on work in my laboratory Dr David Spiegel's laboratory can reduce anxiety very

quickly in real time and that involves the use of the so-called physiological Psy I've talked a lot about this before on previous podcasts so rather than

explain it to you again here now we'll put a link to the physiological side I do a demonstration of it in the show

note captions I'll also link to a recent paper that we published in cell reports medicine this was a collaborative work

that my laboratory did with Dr David Spiegel's Laboratory at Stanford School of Medicine showing

that the physiological size among the different deliberate respiration techniques one of the fastest and most

effective ways to reduce levels of autonomic arousal AKA anxiety or stress and Dr Matthew Johnson's laboratory

started to incorporate physiological size Within These psychedelic sessions as a tool that the guides can refer

people to before the session begins teaching it to them so they realize they can calm

themselves down if necessary in real time it works the first time it works every time this is not because it's some

magic breathing technique that I created it certainly is not this is a naturally occurring pattern of breathing that

occurs in sleeping and waking but that when done deliberately leads to very rapid and quite significant decreases in

Stress and Anxiety and then when people are inside of the Psychedelic session if they feel their anxiety levels are going too high they're heading toward what

might be called a quote unquote bad trip they're starting to panic or really think they're going to have a panic

attack or die again the subjective experience is going to be layered on top of the physiological experience of one's

heart rate being really elevated saw a stress and agitation by using the physiological site inside of the

Psychedelic session Dr Johnson's laboratory and I believe at least one other laboratory are starting to use

breathing techniques such as the physiological side as a way for these people who are under the influence of

psilocybin to self-direct their own calm and to bring that level of anxiety down

so that they can continue to move through the peak and move through the other phases of the Psychedelic journey in ways that could be most beneficial

for them so to close out the description of this really wonderful study and by the way it's another one from the

cardhart Harris laboratory about the subjective experience of ego dissolution or Oceanic boundlessness

this mystical State as so key as a component of a positive psilocybin

Journey I'll just read for you the final sentence of this paper because it captures it so well quote it seems vital that appropriate

consideration is paid to the importance of promoting a certain kind of experience as the quality of that

experience may be the critical determinant of therapeutic success now before we move into what will be a very

Therapeutic Use of Psilocybin

brief description of some of the other rewiring phenomena that psilocybin can induce

and then into some of the therapeutic applications of psilocybin as they relate to these recent really exciting

clinical trials for depression and addictive disorders and things of that sort I just want to cue everybody to a paper

that I think many people will want to take a look at in thinking about psilocybin and I'll provide a link to this paper as

well in the show note captions this paper is entitled therapeutic use of psilocybin practical considerations for

dosing and administration and this is a wonderful paper because it really goes step by step through the pharmacology of

psilocybin of which you now understand a bit but it goes in to a bit more detail but then it also really nicely describes

the Contour of a psilocybin session and what's happening at the level of chemistry early middle Peak and toward the end of

the psilocybin session and then also importantly it gets into issues of dosage and translating from mushrooms to

psilocybin itself to silacin things I talked about earlier but in a bit more detail if you'd like to see that detail

and then perhaps most importantly there's a section on contraindications where it points out that of course women

who are pregnant or breastfeeding people who have a predisposition to psychosis

those people should really avoid the use of psilocybin and other psychedelics entirely it also talks about where the

evidence is strong moderate and weak for the use of psilocybin for treatment

of various disorders and I can just summarize that very quickly because it's where we're going ahead in a few minutes which is that the most evidence for

positive therapeutic outcomes in response to psilocybin taken and conducted in the manner that we've been

describing today in terms of dosage and journey set and setting is for cancer-related depression

cancer related anxiety and treatment resistant depression that's where most

of the evidence resides there's also some evidence for the use of psilocybin Journeys and again this is typically one

or two psilocybin Journeys spaced in the cases of two Journeys anywhere from one

to two weeks apart and again with all of the same Contour of supports and set and

setting that we've been talking about today and there there's some evidence for improvement in terms of outcomes in

alcohol use disorder Independence and tobacco addiction and then finally there's the least amount of evidence although there is clinical trial support

for relief or partial relief for obsessive-compulsive disorder

cluster headaches and migraines and demoralization due to AIDS diagnosis

okay so this paper has a lot of really interesting information in terms of different conditions in terms of dosage

and again contraindications and what's called Adverse Events what sorts of bad

things can and do happen as a consequence of psilocybin and other types of psychedelic Journeys both

during and after those psilocybin or psychedelic sessions we'll talk a bit more about this when we go into some of

those clinical studies because adverse reactions is always a key measure in any clinical study so very soon we'll get

into the more recent clinical studies related to psilocybin for the use of treating depression and some other conditions but

Neuroplasticity, Structural Brain Changes & Psilocybin

before we do that I'd be remiss if I didn't talk about how psilocybin does

and does not change the brain what is and what is not known about that in fact when I put out the call for questions

about psilocybin many of the questions related to these issues the first thing to understand is that a

psilocybin Journey is really a way to try and put that wedge under the boulder as I described

it to try and invoke neuroplasticity of a particular kind and in that way it's kind of remarkable if you think about it

that everyone has different lives different experiences psychedelics in this case psilocybin are activating

these brain networks that each of us has more broadly than they would normally be activated these are very abnormal

patterns of thinking and perceiving and experiencing our emotional and physical life Etc

and yet so often the outcomes are positive not always but the outcomes are positive the experience is positive even

though it might have these anxiety moments or components within them it's very important to understand that

psilocybin and the journey while important are not really what all of this is about

it's really about neuroplasticity so researchers in particular neuroscientists are very intensely

interested in understanding what sorts of neuroplasticity psilocybin creates

because it turns out there are lots of different types or processes involved with neuroplasticity for instance

brain networks Behavior thinking emotion Etc can change because of the addition

of new neurons that's one form of neuroplasticity that's referred to as neurogenesis the production of new neurons most typically in the so-called

dentate gyrus or other sub-regions of the hippocampus a brain area involved in learning and memory

neurogenesis in other regions of the adult human brain are exceedingly rare

and to be honest may not occur at all this is a debated area or we could do an entire episode about

this but for the most part neuroscientists don't really believe that your neocortex your striatum your

cerebellum has that much neurogenesis that's related to learning and memory of new

things or new experiences and we don't actually think that occurs as a consequence of taking psilocybin

either now some of you who are familiar with for instance the cerebellum might be

saying wait what about granular cell proliferation in the cerebellum or what about the rostral migratory stream from

The soverentricular Zone where there are neuroblasts you know spitting out little new neurons that migrate into the nose

to replenish the olfactory in our own population yes that's all true that does occur it's been observed in mice it's

been observed in monkeys and to some extent it's been observed in humans but it's not again I repeat it is not a

prominent feature of learning an acquisition of new skills new ideas

or new emotional states perhaps the best supported evidence for neurogenesis underlying new thoughts

experiences abilities emotions Etc is the production of new neurons in that dentate gyrus sub-region of the

hippocampus and that probably does occur in humans but neurogenesis is not really

the dominant mode of changing neural circuitry in adult humans it might be

a player in adolescence in young childhood it is certainly a player before we are born when we are still in

utero but then the brain is being wired up in many different ways including the addition of new neurons and changing of

connections all this is to say that while neurogenesis is a really sticky idea and

it makes great headlines the addition of new neurons is not really the way that the brain changes under psilocybin

other psychedelics or just generally it's perhaps responsible for maybe one

to two percent and I'm being generous there of the rewiring events that are going to be most important for all of us

so we need to set that down and cement that there until further Evidence comes out to the contrary that's certainly

where I and here I feel comfortable speaking for the majority of neuroscientists out there professional neuroscientists that is

the paper showing adult neurogenesis are interesting but they don't really explain most of the plasticity that

occurs in the adult human brain so if neurogenesis ain't it what is well it's

very clear that psilocybin other psychedelics and any sort of Behavioral or drug intervention that can induce

neuroplasticity does so largely through the addition or strengthening of new

neural connections or through the elimination or weakening of other neural connections and if you look at the data exploring

the mechanistic basis for psilocybin-induced neuroplasticity

it's mostly focused on animal brains animal models mice and rats in particular a little bit on primates but

mostly mice and rats because that's where the interventions can be done of knockout animals of you know Imaging the

brain in real time of course there are the beautiful studies of Robin cardard Harris and others exploring

neuroplasticity at the level of brain Imaging at the level of ultrasound measurements of how active are certain

brain areas in humans how extensive was you know the modularity or not extensive is the modulator et cetera the stuff we

talked about earlier so in other words there are neuroplasticity studies the effects of psilocybin in humans but in

terms of underlying mechanisms of neuroplasticity I think the predominant theory is that

psilocybin induces neuroplasticity through the addition of Novel Connections in those pyramidal neurons

of the frontal cortex elsewhere in the cortex and certainly also in the visual cortex probably also subcortically as

well below the cerebral cortex in areas like the thalamus maybe even in the brain stem as well

and that those neuroplasticity events are structural and functional and they involve a couple of basic events the

most prominent of which is the growth of dendrites dendrites are those little branches or processes that come out of

the the neurons not just the pyramidal neurons but other neurons as well but since we're talking mainly about pyramidal neurons today both the apical

those ones that top they're called the apical Tufts they're the ones that reach laterally to connect with other neurons

communicate with other neurons so we talked about before as well as the dendrites that come out of the base of those pyramidal neurons those processes

grow in response to psilocybin as well as the addition of what are called dendritic spine so the dendrites

are the branches the spines are these little protrusions that grow out they actually in here I don't know if this is coincidence or not again I always say I

wasn't consulted the design phase but these little protrusions actually look like little mushrooms they have a little stalk and they have a little head a

little uh spine head and those little spines so think of these as like little tiny mushroom appearing okay they aren't

actual mushrooms okay the first person that puts in the comments oh my goodness I learned today that mushrooms grow out

of our neurons when we take magic mushrooms that is not what I'm saying what I'm saying is that these little mushroom-shaped protrusions that we're

calling dendritic spines do in fact grow out of dendritic branches of neurons

when animals ingest psilocybin or are injected with psilocybin and that those

little mushroom-shaped protrusions are the sites of new excitatory connections

new locations for input from other neurons to activate those neurons that

have those little mushroom shaped protrusions if you'd like to see examples of this both movies and still

shots it's pretty remarkable there's a paper that I'll provide a link to in the show note captions this was published in the journal neuron cell Press Journal

excellent Journal entitled psilocybin induces rapid and persistent growth of dendritic spines in the frontal cortex

in Vivo so these measurements were done in the mouse equivalent more or less of the prefrontal cortex there's some

interesting details in this paper for instance that those new connections persist so they don't just grow out

during the psilocybin being active in the bloodstream and brain of the animal they persist okay so this may again may

explain some of the persistent changes that occur in people after psilocybin Journeys they may too grow new spines I

should also mention that a reduction in the number of dendritic spines these little mushroom-shaped protrusions in the frontal cortex neurons of humans

occurs in depressed patients we know that from postmortem tissue and that drugs that relieve depression or that

treatments including behavioral treatments that provide some relief from depression do seem to be correlated with

increases in spine growth in frontal cortex neurons as well so this raises a very interesting idea which is

perhaps it's the growth of new connections these new dendritic spines in particular neurons that's created by

administration of psilocybin that explains the relief from depression that people experience so this is just one

paper but it's one paper of a growing body of work showing that yes indeed

psilocybin induces both structural and functional plasticity in the human and animal brain

it does that in the human brain at therapeutic doses of anywhere from 10 to 25 perhaps even 30 milligrams per

session one or two sessions I should mention that the mouse studies tended to use quite high doses of psilocybin I was

actually I wasn't shocked but I was somewhat wide-eyed for a moment to realize that most of the studies looking

at changes in plasticity in the mouse brain in response to psilocybin use the equivalent of one

milligram per kilogram of body weight which is if you do the math and you translate what we were talking about

before in terms of dosages I'll just spare you all the time it's about double the sorts of dosages

that are typically used in humans maybe even triple in some cases now it's often the case in animal studies because of

the metabolism of animals being different but also because you know seeing effects of drugs in

animal studies can be difficult they did use a dose response anywhere from zero to 0.25 to

half to one to two milligrams per kilogram of psilocybin in the study so they had a dose response curve but

focused mainly on this one milligram per kilogram dosage in any event the point is that many of the studies that

describe these pretty dramatic structural changes in the animal brain most typically the mouse sprain in

response to psilocybin used dosages of psilocybin that if translated to humans would be about double the human

therapeutic dose so that is something that we need to take into consideration nonetheless it's very clear that in both

animal studies and humans psilocybin is inducing both structural and functional changes in brain circuitry and that in

humans the network connectivity is being changed dramatically we talked about those data earlier and that the

underlying basis for that might be again might be we don't know for sure the addition of new dendritic spines on

these pyramidal neurons that we've been talking about repeatedly throughout today's episode although neurogenesis

perhaps and other modes of neuroplasticity such as the elimination of certain connections perhaps related

to unhealthy maladaptive thoughts or or feeling that a particular sad song is

overwhelmingly sad it could be the case that those sorts of things change subjectively because of the removal of

neural connections if you're going to think like a neurobiologist or scientist for that matter you don't ever want to

think that one mechanism can explain all the effects of a given drug or a given experience is almost certainly likely to

be the consequence of multiple mechanisms acting in parallel and because I know there are people out

there who would like to know even more about the neuroplasticity induced by psychedelics including psilocybin

there's a wonderful review that I provide a link to in the show note captions entitled psychedelics and neuroplasticity a systematic review

unraveling the biological underpinnings of psychedelics this review is great because it goes a

Step Beyond just psilocybin silosin binding to the serotonin 2A receptor and

things like brain derived nootrophic Factor it actually talks a lot about the intracellular signaling and exactly how

neurons change their excitability patterns based on this activation of the serotonin to a receptor it's probably

more detail than most of you out there are interested in but if you are interested in that level of detail this

is a wonderful Open Access review so a few minutes ago I talked about where there is strong modest and somewhat weak

Psychedelics: Therapeutic Breakthroughs & Depression

or rather I should say minimal evidence for the therapeutic use of psilocybin to

treat various disorders and across the board it really appears that major depression and

so-called intractable depression in some cases is where we're seeing the most exciting research to date now keep in

mind that because of the controlled substance act being invoked in 1970 in the United States and because it was

only just a few years ago really only about five years ago that psychedelics

including psilocybin received what's called breakthrough status at the FDA that there are now a lot of clinical

trials exploring how psilocybin can impact various things like mood disorders addictive disorders and so on

prior to 2018 when that therapeutic breakthrough potential was established in the United States

I think a lot of people in the so-called psychedelics Community had the sense and the Really the belief that these drugs

had enormous potential but they just weren't being explored that extensively so I do want to give a

nod to the incredible researchers such as Robin carder Harris but also Matthew Johnson Roland Griffis Nolan Williams

and many others okay I'm certainly not listing off everybody that would take hours but

those researchers have really pioneered both the legal efforts and the funding efforts and most importantly the

research efforts defining the clinical data that I'm about to describe and here I'm going to summarize the clinical data

in a bit of a top Contour fashion just giving you the kind of highlights we will of course provide links to the

papers if you'd like to look into it further but I'm only giving you the top Contour because I've had the great

Fortune of having Matthew Johnson on this podcast before you can find that episode at hubermanlab.com

just simply put Matt's name or psychedelics into the search function it'll take you to that episode in all

formats or links to all formats rather I've also had the great Fortune of sitting down recently with Dr Robert and

cardart Harris to talk about his work at University of California San Francisco on psilocybin LSD

Ayahuasca and DMT as it relates to depression and other disorders and that

episode which also will be released at hubermanlab.com and on all platforms YouTube Apple Spotify really goes in

depth into these clinical studies and what those studies really look like you know who's in the room whether or not

people just get one dose or two doses how far apart those are separated all of

that is covered in extensive detail in that what I found to be wonderful discussion with Dr Robin Carhart Harris

so if you're interested in all of the details as it relates to clinical application of psychedelics stay tuned

for that episode soon again you can find that at hubermanlab.com and on all Platforms in the meantime I would be

remiss if I didn't include a bit of discussion about what has been observed in terms of using psilocybin Journeys as

a way to treat depression because the data are just oh so exciting again these data really started to

surface as the consequence of studies that were initiated around 2006 in just a few select Laboratories

and then really picked up in terms of the number of Laboratories and number of studies

between 2018 and now so what you'll notice is that most of the papers I'm about to describe were published in for

instance phenomenal journals New England Journal of Medicine in 2021 New England

Journal medicine November 2022 um Journal of the American Medical

Association Psychiatry just very recently 2021 so these are very recent papers

essentially all of these clinical studies involve either one or two

psilocybin sessions the dosages that were explored range from zero milligrams of placebo if you

will 10 milligrams some cases 25 milligrams in some cases 30 milligrams

and most typically people receive the same dosage for both sessions if indeed

they did both sessions however there's at least one study looking at just one

single episode of psilocybin Administration so this is the paper entitled no surprise single dose

psilocybin for treatment resistant episode of major depression this is published in the New England Journal medicine in November of 2022.

I'll just summarize the results of this single Application Study they randomly

assign subjects who had treatment-resistant depression so they'd resisted treatment to other things to receive a single dose of a synthetic

formulation of psilocybin so they're not eating mushrooms they're getting a synthetic dose of psilocybin but the

dose is known of either 25 milligrams 10 milligrams or one milligram which was the control

and they receive psychological support there were a number of different tests subjective tests of depression

taken before and after the psilocybin Journey they had about

75 to 79 participants in each group again at the three different doses 25 10

or one milligram and they looked at the changes in these scores these depression related scores

on these tests there are many results from this paper one could summarize but among the most important results I can summarize from the discussion and here

I'm paraphrasing that the change in Baseline levels of depression that is at week three

following the psilocybin session was significantly better that is people experienced more relief or more people

experienced more relief from the 25 milligram dose than from the one milligram dose

and this is important there was no significant difference between the 10 milligram dose and the one milligram

dose this really points to the fact that the 25 to 30 milligram dose that's used in

the largest numbers of studies exploring treatment resistant depression really seems to be I don't want to say the best

dose but the most effective dose at least in this clinical context in this set in setting and with this particular

patient population so we want to be careful to say that so that one doesn't just translate that 25 milligrams is

better than 10 milligrams although in this study it was for sake of treatment resistant depression relief

there were a number of other key aspects of this paper in particular the exploration of so-called Adverse Events so things like

headaches propensity for self-harm actual self-harm anxiety and so on

it's worth mentioning that there were Adverse Events in essentially every group

the number of Adverse Events was highest in the 25 milligram dose group this is

observed in other studies as well with higher dosages there tends to be greater relief from

depressive symptoms but also a greater chance for Adverse Events some of those

Adverse Events can be quite severe so feelings of suicidal ideation Etc some of them one could consider a little less

severe mild headache or severe headache that was transient or anxiety that was

transient again highly individual responses we could go line by line and table by

table through this paper which we won't because there's a lot of data again we'll provide a link to this paper if

you'd like to peruse it yourself it's fairly straightforward to read that's one thing that's nice about these um clinical trials is they tend to be

written in Fairly non-technical language although there's a little bit of technical language the important point is that a single

dose of 25 milligrams of psilocybin provided significant relief from treatment-resistant depression in this

particular patient population but it is not the case that 100 of the people who took 25 milligrams of psilocybin

experience that relief however the majority of them did now when you say majority in science you really need to

look to numbers and the reason I'm not telling you oh it was 75 or 60 percent or 50 percent is because it depends on

which time Point people were analyzed people were asked about their level of

depression relief immediately after one week after two weeks after three weeks after

and the degree of relief tended to change over time in fact it tended to diminish over time but it was also

stable or remarkably stable I should say at least by my read in the 25 milligram dose group and that

is summarized nicely in figure two of the paper because they explored these people's levels of depression out to

week 12 and they still saw a significant degree of depression relief 12 weeks after the single 25

milligram psilocybin dose session so as I mentioned earlier there are now about

Combining Psilocybin Therapy & Talk Therapy, Antidepressant Effects

a dozen or so excellent studies clinical trials exploring the use of single or

two session psilocybin treatment in that 25 to 30 milligram range which seems to

be the most effective dose for long-lasting relief from depression

each one of those studies explored something different as is important replication is also important of course

in order to validate previous studies but for instance there have been comparisons of psilocybin versus ssris

or other antidepressants there have been comparisons of psilocybin Plus psychoanalysis or cognitive behavioral

therapy versus cognitive behavioral therapy alone or psychoanalysis alone and so there's a lot of evaluation now

of the clinical outcomes and the statistical outcomes of these subjective

measures and even some objective measures of neurochemistry where that's possible in terms of trying to

understand if and how psilocybin is effective for the treatment of depression and the

major takeaway is that indeed it does seem to be the case and the numbers that I feel comfortable not throwing out

there but putting out to you reflect my conversation with Robin cardhart Harris again that will be released soon at

hubermanlab.com as well as takeaways from what I would say are the six

broadest studies meaning they have the widest range of age groups the broadest

demographic in terms of the subjects their backgrounds their levels of Education men women ethnicity Etc

and a lot of that can be summarized in the paper entitled effects of psilocybin assisted therapy on major depressive

disorder this was a particular randomized clinical trial but in the discussion I think they

summarize it quite well which is that if you look at the number of people who

take this 25 milligram dose twice in session spaced about a week apart

what you will find is that anywhere from 60 to 75 percent of the people who have major depressive disorder who do these

psilocybin sessions in the proper setting report a good experience with it have minimal Adverse Events coming out

of those sessions and in the weeks following those people experience substantial

positive relief from major depression in ways that other treatments that they'd explored including

antidepressant drugs cognitive behavioral therapy and other types of therapy alone could not provide now it's

a general feature of these clinical trials focusing on psilocybin that people are asked to stop taking their

antidepressants prior to participating in the trial it's also a general feature of these

trials that people are encouraged to not suddenly start their antidepressant treatment immediately afterwards because

of course that could confound the results of the psilocybin treatment however and this is a very important thing to note all subjects were

encouraged not to avoid taking those antidepressant medications if in fact

their clinician felt that it was important for their immediate and long-term survival so you know no one

should be reckless in thinking about what to add or delete from their drug protocol when dealing with depression

all right the outcomes could be very severe in that case nonetheless we can paraphrase from the discussion of

the paper I just mentioned because it really highlights the incredible results that psilocybin

applied in these particular therapeutic settings are providing and here again I'm paraphrasing the present trial

showed that psilocybin administered in the context of supportive psychotherapy consisting of approximately 11 hours of

psychotherapy so this is going to be two sessions of the psilocybin with proper

therapeutic support produced large rapid and sustained antidepressant effects the effect sizes reported in the study were

approximately 2.5 times greater than the effects sizes found in psychotherapy

and more than four times greater than the effect sizes found in psychopharmacologic depression treatment

studies in other words four times the positive effect observed with typical ssris or other pharmacology of

that sort these findings are consistent with the literature that show that combined pharmacotherapy and Psychotherapy were

more efficacious in the treatment of major depressive disorder than either intervention alone so again this points

to the fact that combining drug therapy with talk therapy as it's often called

is going to be more effective than either treatment alone here the drug therapy psilocybin therapy and again

please don't take the fact that in these studies they tended to ask people to not take their antidepressant medication heading into the study as a sign that

one should stop taking their antidepressant medication rather I think this study and other studies like it again which will provide links to you in

the show note captions that are discussed extensively in the episode with Dr cardart Harris soon to come really point to the incredible role that

psilocybin can have in creating an experience inside of the session the

journey or the trip as it's called as well as initiating neuroplastic events perhaps the addition of dendritic

spines maybe even some new neurons maybe although I don't think that's the predominant mode but that leads to these more extensive

connectivities in the brain the so-called reduction in modular networks enhanced

activity in brain areas that normally wouldn't be talking to one another but not doing that in any kind of haphazard

way it really does seem that the one or two sessions of psilocybin that induce these feelings of ego dissolution that

induce these feelings of oceanic boundlessness right so mystical right and in many ways it's what I find so

incredible about psilocybin and other psychedelics is that despite the highly

mystical highly subjective and still at this time somewhat top Contour

understanding of how they might exert their effects you can highlight boldface and underline might there right because

it hasn't really been firmly established what the exact cell biological rewiring events are but there is now what I would

refer to as a center of mass of data that point to the fact that psilocybin when taken in the appropriate set and

setting at the appropriate dosages can invoke the sorts of neuroplasticity and changes in emotionality in

perceptual experience not just during the Psychedelic session but for long periods of time after the Psychedelic

session that can provide really remarkable relief from things like major depression and perhaps other psychiatric

issues as well and of course I realize that many of you are listening to and are watching this episode and you're not

Psilocybin Experience & Mental Health

necessarily depressed or thinking about psychedelics like psilocybin in the context of depression I hope today's

discussion allowed you to better understand how psychedelics and psilocybin in particular because

that's what we've been talking about are able to exert these incredible effects that they seem to exert

this is not a call for everyone to run out and do psilocybin it is absolutely not that it is however my attempt to

really put a magnifying lens on this incredible area of research that's happening not just in the context of clinical trials but in the context of

trying to understand how serotonin and how drugs like psilocybin which in many

ways mimic serotonin and more particularly the activation of particular receptors in the brain like the serotonin 2A receptor I mean just

sit back and think about that the selective activation of this receptor which is by the way associated with the

expansion of the neocortex across Evolution didn't mention that before but indeed it is how that can lead to

enhanced ways of thinking changed ways of thinking actual learning inside of this short four hour or six hour session

that we call the psilocybin Journey so as is often the case perhaps as is always the case here on the huberman Lab

podcast we did a deep dive into a topic today into the topic of psilocybin what

it is how it works the different ways in which changes brain circuitry how it creates the

experiences that we think of as the psilocybin Journey what the safety issues are what the so-called set and setting are

that can lend themselves to positive therapeutic outcomes and in doing so my goal was really to highlight several

things first of all I am very excited about the potential for psychedelics such as psilocybin to

provide relief for mental health issues that to date have been very hard for people to access in addition to that I'm

just fundamentally interested in the brain and how it works and how it can change this thing we call neuroplasticity to me neuroplasticity is

the Holy Grail of the human nervous system as far as we know we are the

animal that can have long lasting neuroplasticity throughout the lifespan and if it requires the use of compounds

in a safe and controlled way such as psilocybin in order to achieve maximal plasticity in a short amount of time

that's exciting but of course that also needs to be considered with all of the safety precautions in mind that we

talked about earlier including the fact that people who have a predisposition or who have psychosis or bipolar disorder

or a relative that has psychosis or bipolar disorder younger people meaning

people 25 years of age and younger and really anyone who's not working with a dedicated and highly trained physician

needs to be very cautious about these com pounds as well they're very exciting I think psilocybin is an exciting and

super interesting compound for basic and clinical reasons and for other reasons as well but

they are sharp blades as we say and with sharp blades you can do incredible things but you can also cut yourself

very badly so all those considerations need to be taken to mind so I consider the science and use of psilocybin to be

an exciting but still preliminary area that I certainly am paying a lot of

attention to and I know there's a lot of excitement about so stay tuned for the episode with Dr Robin carder Harris and

we will probably revisit psilocybin and we will certainly revisit the other psychedelics and non-classical

psychedelics including LSD DMT 5meo DMT ketamine MDMA mescaline and all the rest

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