The Science of MDMA & Its Therapeutic Uses: Benefits & Risks | Huberman Lab Podcast

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 MDMA sometimes

referred to as ecstasy or Mali MDMA

stands for methylene dioxy

methamphetamine that's right you heard

the word methamphetamine in there and

MDMA has properties similar to

methamphetamine but also properties that

are very distinct from methamphetamine

just as a side note methamphetamine is a

commonly used drug of abuse it is an

illicit drug and it produces some of the

greatest and fastest increases in the

neuromodulator dopamine of any available

drugs on the street or in the clinic and

believe it or not methamphetamine is

prescribed as a prescription drug in

some very limited clinical uses

MDMA methylene dioxy methamphetamine has

properties similar to methamphetamine in

that it powerfully promotes the release

of dopamine and it is a stimulant and

yet it also powerfully controls the

release of Serotonin and in doing so

makes MDMA a distinct category of

compound from either classic

psychedelics like psilocybin or LSD

which largely work on the serotonin

system and tend to produce mystical

experiences and it's also distinct from

Pure stimulants such as methamphetamine

because MDMA by producing big increases

in both dopamine and serotonin acts as

what's called an empathogen it actually

can increase one sense of Social

connectedness and empathy not just for

other people but for oneself and in that

way MDMA is commonly used as a

recreational drug but also is now being

tested and is a achieving incredible

early results in clinical trials for its

use as an empathogen for the treatment

of PTSD in clinical therapeutic settings

I want to be very clear that at this

point in time June 2023 MDMA is still a

schedule one drug that is it is highly

illegal to possess or sell in the United

States and today we are going to talk

about some of the path to legality

that's underway we are also going to

talk about the history of MDMA and why

it became illegal and we are going to

talk about the key difference between

recreational use and therapeutic use and

the important components of the studies

exploring MDMA in the clinical setting

for the treatment of PTSD so during

today's discussion we will talk about

what MDMA really is how it works at the

level of neurons which brain circuits it

activates and deactivates and in doing

so you will come to understand why it is

so exciting as a treatment for PTSD will

you will also of course talk about the

results of of these clinical trials

using MDMA for the treatment of PTSD

they are incredibly exciting in fact the

field of Psychiatry has never before

seen the kind of success in treatment of

PTSD with any other compound that they

are seeing and achieving with the

appropriate safe use of MDMA and when I

say appropriate that means in

conjunction with nine therapy sessions

so this is an area that really deserves

some time for us to discuss because

again there is a distinct difference

between the recreational and the

therapeutic use of MDMA we will also

talk about the toxicity of MDMA this is

a very important issue because many of

you have perhaps heard that MDMA quote

unquote puts holes in your brain or

kills serotonin neurons or kills

dopamine neurons and indeed MDMA because

of its similarity to methamphetamine

which is highly neurotoxic MDMA can be

neurotoxic however there are ways to use

MDMA therapeutically that avoid avoid

its toxicity and yet there are still

questions about its toxicity and its

long-term effects both after acute use

meaning just one to three times as well

as chronic use meaning people who have

taken it many many times we'll talk

about the spacing between sessions of

MDMA we will talk about dosages we will

also talk about things that people do

and that can be done to offset some of

the potential toxicity of MDMA so by the

end of today's discussion you will have

a thorough understanding of what MDMA is

what it isn't what is known about what

it does

what is known about what it doesn't do

as well as some of the still outstanding

questions about MDMA that remain to be

resolved before we begin I'd like to

emphasize that this podcast is separate

from my teaching and research roles at

Stanford it is however part of my desire

and effort to bring zero cost to

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huberman to save 20 off again that's

hvmn.com huberman to save 20 let's talk

about MDMA MDMA or ecstasy is a

fascinating compound and I say

fascinating from the perspective of its

chemical structure which is highly

unusual

I say fascinating because it has an

incredible set of subjective effects in

terms of how it makes people feel and it

has a fascinating history so let's just

briefly start with the history of MDMA

MDMA was synthesized by the drug company

Merck in the early 1900s but it actually

was never applied to any particular

clinical use and it wasn't really

explored much in any Laboratories at all

and then it was later rediscovered by a

guy named Alexander shulgin

who was a bit of a renegade drug chemist

who was designing different drugs for

the purpose of understanding their

subjective effects on humans so there's

a long history of Shogun designing drugs

he was after all a chemist and then

taking those drugs himself and then if

he liked the effects of a particular

drug or rather if he thought that it had

potential clinical utility he would give

it to his wife then she would give him

her notes about those drugs and then

they would share them with their friends

and it was a small group of friends who

consisted of therapists and Physicians

so this was a really underground kind of

operation it was technically not illegal

when it started because MDMA wasn't

illegal when it started but over the

several decades that Shogun and his wife

and this group were doing this kind of

exploration MDMA did become illegal and

he fell under well let's just say

scrutiny by the DEA

now here's the important thing to

understand about MDMA and its history

first of all

MDMA is a synthetic compound as far as

we know it does not exist anywhere in

nature so unlike similar compounds such

as mescaline because MDMA and masculine

are very similar in their chemical

properties and to some extent their

subjective properties

unlike mescaline which can be found in

the plant kingdom or LSD which comes

from ergot or psilocybin which of course

can be found in magic mushrooms MDMA is

a unique chemical in that again as far

as We Know

only exists in its synthetic form it is

human made and as we get into the

chemical effects and the subjective

effects of MDMA a little bit later in

the episode I think you'll understand

why it is such a unique and to some

extent exciting compound from the

perspective of clinical treatment put

differently there's really no other

compound that we know of in nature or in

the pharmaceutical industry shelf or

options of drugs that are prescription

drugs that produce the kinds of effects

that MDMA does and by the way if you're

interested in the story of Alexander

Shogun and the drugs he synthesized and

the group that he built up to take these

drugs and try them and actually had

several members of this group using

these drugs in therapy with their

patients

for a long period of time both before

and after MDMA became illegal

there's a wonderful book called pikal

that stands for

p-i-k-h-a-l p call is the title of the

book which Shogun wrote which describes

his discovery of MDMA I confess it also

describes the synthesis of MDMA and for

that reason was a book that for a long

time was not available but is now

available again in audible form and in

printed form pcall stands for

phenylethylamines I have known and loved

phenylethylamines is the category of

drug for which MDMA belongs to and it's

a long book but a very interesting one

both from the perspective of

understanding the history of MDMA and

what MDMA is and the effects that it

produces but it's also an interesting

book because it will teach you a lot

about the history of the pharmaceutical

industry the War on Drugs in the United

States and the interaction between

illegal drug exploration and drugs for

clinical treatment of psychiatric

challenges so right now this is a very

important issue because MDMA is

currently granted breakthrough status

which means it's now something that

scientists and clinicians can study if

they have authorization to do that it is

as I mentioned earlier still a schedule

on drugs so it's illegal to possess

unless you are one of these scientists

who has been granted permission to study

it in the clinical setting or the

laboratory setting and right now we are

on the cusp of MDMA becoming legal but

again it is not yet legal and this is

something I'm going to touch back on a

few times during today's episode

later for instance when we talk about

the potential toxicity of MDMA its

ability potentially to kill neurons

the neurons it has been hypothesized to

kill are neurons of the serotonin and

dopamine type so this is something you

would not want let's just recall that

killing off of or death of dopamine

neurons is the underlying basis for

Parkinson's Disease which is a movement

disorder where people have difficulty

generating smooth movements and in very

severe form they can't move at all they

sort of become locked in to some extent

and it also has cognitive effects so you

don't want to lose dopamine neurons and

loss of serotonergic neurons is known to

impact mood negatively mood regulation

negatively Etc

the story of MDMA and its potential

neurotoxicity comes slam right up

against this issue of legality and what

we'll get into a little bit later is

that there has been a sort of race in

the scientific Community consisting of

two groups one set of groups trying to

establish the toxicity of MDMA so that

it does not become legal again and

another group trying to establish the

utility and the lack of toxicity in MDMA

so that it does become legal again for

the treatment of PTSD so even though the

story P call relates to events that took

place largely in the 1970s 80s and 90s

right now MDMA and its toxicity or lack

of toxicity its legality or lack of

legality are really key issues so as

you're listening to this I'm giving you

a real-time blow-by-blow of what led up

to where we are now but we will also

want to think about how what's happening

right now including the description of

these data on MDMA may or may not impact

the potential legal status of MDMA okay

so what is MDMA MDMA is 3 4 methylene

dioxy methamphetamine but unless you're

a chemist that's not going to mean much

to you nor should it

MDMA has some very interesting

properties the first of which is that

methamphetamine component which because

it's a methamphetamine and acts like

other amphetamines what it does is it

blocks the reuptake of dopamine from

neurons after dopamine is released so

for those of you that heard the episode

that I did on drugs to treat ADHD I

discussed the biology and mechanisms of

drugs like Adderall and Vyvanse which

basically are either combinations of

amphetamines or single types of

amphetamines that have either a quick

release or a long release

now MDMA because it has this

methamphetamine component prevents the

reuptake of dopamine and in doing so

creates net increases in dopamine so for

those of you that don't have a

background in neurobiology let me just

briefly explain I'll make this very

simple neurons or nerve cells release

chemicals at their sites of

communication which are called synapses

synapses are little gaps between neurons

and what happens is the neurons spit out

these little spherical balls which we

call vesicles or vesicles depending on

where in the world you live they'll

either be called vesicles or vesicles

and those little vesicles contain

neurotransmitter or what's technically

referred to as a neuromodulator dopamine

is a neuromodulator can modulate the

activity of other neurons it can either

increase or decrease the activity of

other neurons now at the end of the

neuron that what we call the axonal

Bouton okay axon is the wire component

of the neuron that can reach to another

side in the brain and then release the

neurotransmitter or neuromodulator there

at those axonal boutons which are the

sites of release

the vesicles literally fuse with the

edge of the neuron and vomit their

neuromodulator out into the synapse and

then the neuromodulator in this case

dopamine will bind to receptors on the

postsynaptic side that means to another

neuron and then depending on how much

binds and depending on what else is

going on in that local neighborhood of

neuronal connections the neuron will

either increase its neural activity and

itself release neuromodulator and

neurotransmitter someplace else so sort

of a chain reaction or else it will

suppress its activity and the flow of

communication from one neuron to the

next will be stopped okay so MDMA

doesn't prevent the release of dopamine

at the synapse it does quite the

opposite it actually prevents the

sucking up of the dopamine that's been

released and that does not bind to The

receptors so basically what it does is

it blocks these things called dopamine

Transporters and the Transporters are

the things that suck back up the

dopamine that's been released that has

not bound to receptors so because it

blocks that sucking up process

there's more dopamine around in the

synapse to hang out and then bind to

receptors once some become available

okay the other thing that the

methamphetamine component of MDMA does

just like methamphetamine is that it

actually gets into what we call the

presynaptic neuron the neuron that

releases the dopamine and it interferes

with the repackaging of dopamine into

those vesicles now you might think oh it

interferes with the repackaging of

dopamine into vesicles and therefore

less will be released but actually what

happens is as a consequence of that

a bunch of dopamine builds up in the

presynaptic neuron so that when an

electrical impulse comes down that

neuron and dopamine is released a huge

amount of dopamine is released and this

is one of the characteristic properties

of methamphetamine end of MDMA which is

that it leads to enormous increases in

the amount of dopamine released and the

amount of dopamine that hangs around in

the synapse and therefore it increases

what we call dopaminergic Tone or

dopaminergic drive that's just a bunch

of different ways to describe increases

in dopamine okay so that's the main way

that MDMA and by extension

methamphetamine increase dopamine

however MDMA is not just methamphetamine

it's methylene dioxide methamphetamine

and it has another incredible property

which is that it doesn't just lead to

huge increases in dopamine it also leads

to huge increases in serotonin and

that's because there are other neurons

that release serotonin and they have

serotonin transporters which are

sometimes called certs s-e-r-t-s's

serotonin Transporters and they work

very much in the same way that dopamine

Transporters do right they basically

control the sucking backup of Serotonin

that's been released into the synapse

and that has not bound to serotonin

receptors on the other neurons yet and

in doing so allow more serotonin to hang

out and have its effects as those

receptors become available for serotonin

to bind to them the other thing MDMA

does is it also gets into the

presynaptic neuron to impact the

packaging of Serotonin into something

called the vesicle monoamine transporter

for serotonin and in doing so it leads

to a big buildup of serotonin in

presynaptic Terminals and then massive

increases in serotonin release okay so

what we've got with MDMA is a really

interesting compound unlike

methamphetamine or other amphetamines

such as adderall Vyvanse Etc that cause

increases in dopamine by blocking

reuptake and increasing release of

dopamine MDMA does that but it also does

the same thing for serotonin and here's

a really key point

the increases in serotonin that MDMA

creates are at least three times and

maybe as much as eight times greater

than the amount of dopamine released

that MDMA causes but when you put those

two things together what you basically

have is a drug that causes huge

increases in dopamine and even bigger

increases in serotonin

and remember earlier when I said that

MDMA is a purely synthetic compound as

far as we know it does not exist in any

plants or fungus or anything else in

nature well

this is a very unusual circumstance of

having big increases in dopamine and big

increases in serotonin caused by the

same compound and that combination of

big increases in dopamine and big

increases in serotonin are what lead to

these highly unusual and yet what seem

to be potentially clinically very

beneficial effects of having people feel

a lot of mood elevation and a lot of

stimulation from the stimulant

properties of the methamphetamine

component and so that's the dopamine

effect the dopaminergic tone goes way up

so it's a stimulant people feel really

alert they feel like talking a lot they

feel very excited they feel a lot of

positive motivation these are classic

effects of drugs that promote the

release of dopamine including

amphetamine cocaine Etc but ordinarily

that's not such a good thing because

what happens is there's then a crash in

the dopamine levels and then people feel

depressed they feel lethargic they they

don't feel good at all MDMA seems to

cause these increases in dopamine and

all the accompanying effects I just

described but by also causing big

increases in serotonin it activates

neural networks that are associated with

feeling more socially connected in fact

we'll talk about data in a little bit

where people have had their brains

imaged while under the influence of MDMA

and it's very clear that people who have

taken MDMA

look at faces that ordinarily they would

rate as fearful and rate them as less

fearful they see faces that are smiling

and they rate those smiling happy faces

as more positive than they would off the

drug the big increases in serotonin

create what we call a pro-social effect

and that combined with the dopaminergic

increase in mood and the stimulation

effect creates this thing that we call

an empathogen where and this is very

important the empathy isn't just for

other people it's also for oneself and

one's own experiences happening in the

moment as well as empathy for

experiences from the past which so you

can imagine could be very beneficial for

the treatment of PTSD Okay so

hopefully the way I describe the biology

of MDMA makes some sense if you didn't

get anything out of the description I

provided except the understanding that

MDMA is unusual in that it causes big

increases in dopamine and even bigger

increases in serotonin then you have

more in your knowledge base now about

MDMA than you need in order to

understand the rest of our discussion

before we go any further I do want to

separate MDMA out from some other

compounds which are referred to as

psychedelics and I recently did a

podcast episode all about psilocybin and

its therapeutic exploration and it's

chemical basis Etc you can find that

like all episodes at hubermanlab.com I

also did an episode with expert guest Dr

Robin Carhart Harris who's at University

of California San Francisco who's

pioneering a lot of the studies on the

clinical application of psilocybin

psilocybin and LSD

are mainly going to increase serotonin

activation in the brain in fact they

very closely resemble serotonin itself

and they activate What's called the

5ht2a or serotonin 5hd just stands for

serotonin the 5ht 2A receptor to create

very mystical type experiences they are

considered

classic psychedelics and are very

introspective

and as I described in those episodes are

being explored extensively now for the

treatment of major depression a

different compound that's being used for

the treatment of depression is ketamine

I will do an entire episode all about

ketamine ketamine

is actually a n methodaspartate receptor

blocker nmda receptor blocker that

shouldn't mean anything to most of you

but it is a dissociative anesthetic not

unlike PCP what used to be called angel

dust on the street ketamine is being

used as a treatment for depression it is

currently legal so unlike psilocybin and

LSD which are granted breakthrough

status for the study of depression but

are not yet legal they are still illegal

and of course as I mentioned earlier

MDMA has breakthrough status but is

still illegal ketamine is being used for

the treatment of depression and it does

so as its name suggests a dissociative

anesthetic by creating a sense of

dissociation from emotions okay now I

raise this distinction between

psilocybin and LSD which are mystical in

their effects

ketamine which is dissociative in its

effects with MDMA which is an empathogen

or sometimes called an anactogen but as

an empathogen or an enactogen it's

creating more affiliation it's

affiliative okay so it's a very distinct

compound and I think this is important

to understand because when we hear the

word psychedelic a lot of people tend to

lump together LSD psilocybin and MDMA if

you talk to researchers in these areas

they will tell you that MDMA really

isn't that much of a psychedelic it's an

empathogen with stimulant properties and

it also has the serotonergic component

that makes it an empathogen or an

actogen

so MDMA is very different than the other

psychedelics and my hunch is that over

the next few years we will stop talking

about MDMA as a psychedelic because it

does not tend to produce visual

hallucinations or auditory

hallucinations of the sort that classic

psychedelics do and in general it is

more of a mood impacting drug than it is

Mystical okay so we'll get into some of

the brain networks and which ones are

activated while under the influence of

MDMA but I do think it's very important

to segment out MDMA from the other

so-called classic psychedelics and also

segment it out from ketamine thanks to

some really terrific studies both in

animal models and in humans We Now

understand a lot of what makes MDMA

produce these incredibly unique effects

and when I say unique I mean unique from

drugs like psilocybin and LSD and

ketamine and from methamphetamine for

that matter and it's really the

combination of big increases in dopamine

and even bigger increases in serotonin

that create a situation where people

have more energy and yet

despite having more energy they don't

feel irritated

they feel a lot of pleasure they seem to

want to be in the state of having a lot

of energy this will become important as

we talk about anxiety and the anxiety

symptoms of PTSD it also because of the

big increases in serotonin produces a

sense of emotional warmth towards others

and towards oneself that's the

empathogen component and for reasons

that we still don't understand it seems

to increase trust and the increases in

trust turn out to be vital because as

you will you will also learn later when

we look at the clinical trials exploring

MDMA for the treatment of PTSD

the major effect of MDMA for the

treatment of PTSD is not to cure PTSD

but rather to make the therapy the talk

therapy for PTSD much more effective

this is a very important point in fact

so important I'm going to repeat it at

least three times during today's episode

MDMA taken on its own does not cure PTSD

MDMA can augment or boost the effects of

talk therapy for PTSD and it does that

through the engagement of specific

neural circuits but before we talk about

what those neural circuits are

I want to emphasize that the increases

in serotonin that MDMA produces

seem to act on different receptors

then the big increases in serotonin the

LSD and psilocybin produce so if you

listen to the episode that I did on

psilocybin we haven't done yet one on

LSD but the mechanisms are very similar

for psilocybin and LSD

whereby psilocybin and LSD

very closely mimic the molecule

serotonin itself but seem to have a more

selective activation of just the

so-called serotonin 2A receptor

abbreviated 5ht2a and that leads to

more interconnectedness between

different brain areas more consideration

of new possibilities about events from

the past present and future and also the

opening of so-called neuroplasticity of

rewiring of neural connections that

persist long after the psilocybin or LSD

effects have worn off

now MDMA can activate the serotonin 2A

receptor but it seems that it largely

activates the serotonin 1B receptor now

what does that mean activation of the

serotonin 1B receptor seems to be what

gives MDMA its very strong impact on the

neural circuits of the brain that relate

to trust and to social engagement not

just the willingness to engage socially

and to confide in a therapist or another

person but the intense desire to do so

and when I say intense desire that takes

us back to the dopamine system remember

dopamine even though

when increased in the brain can increase

our mood

it is largely responsible for increasing

our sense of motivation and desire for

something and to do something so the

increase in dopamine that's created by

MDMA seems to make people

what I call forward Center of mass you

know they want to do something they're

very motivated to do something and the

increases in serotonin acting on the

serotonin 1B receptor

seems to be what creates this desire to

bond or create trust or to have a

discussion of real things both things

that are positive but also to explore

things that are difficult and this I

realize is going to be a little bit of a

mind Bend for people to to understand

but one of the key things that

quality MDMA therapy consists of is not

just having a very good rapport and

communication with a therapist that's

guiding the PTSD treatment

but also Rapport and a willingness to

engage in conversations with oneself

yeah I think that most of us can relate

to the fact that we have experiences

some of which are hard some of which are

great and everything in between trauma

is I believe best defined by the words

that a former guest on this podcast

who's a world expert in trauma Paul

Conte explained as trauma is an event

that fundamentally changes the way that

our brain works

for the worse okay so not every bad

event of our past is trauma

but events that change the way that we

think our emotional tone or our behavior

in ways going forward that are not

adaptive for us They don't serve us well

either because they are highly

distracting or because

um they create anxiety or because they

disrupt sleep or any number of different

things that are maladaptive consequences

that's what really defines trauma and

when under the influence of MDMA because

of those parallel increases in dopamine

and serotonin people seem far more

willing to both trust the therapists

that they're talking about that trauma

with but also to trust their own ability

to quote unquote go internal and think

about the challenging thing or things

because oftentimes trauma can consist of

many events not just one event and the

thought patterns around that and the

context around that and therein to be

able to explore new possibilities to

essentially rewire their relationship to

that trauma so I promise that a little

bit later we'll talk about the the

direct application of MDMA for the

treatment of PTSD but now I'd like to

shift off of the chemical changes that

MDMA produces and some of the subjective

changes these increases in trust and

pleasure and energy and emotional warmth

to some of the brain circuits that are

activated and Modified by MDMA use and

then we will explore the toxicity issue

and then we will explore the clinical

studies of which I can promise you are

extremely exciting but until we

understand the neural circuit phenomena

and of course until we consider the

neurotoxicity issues I don't think those

clinical findings can be appreciated in

their full value but now I'd like to

talk about what MDMA really does in the

brain both in the short term while

someone is under the influence of the

drug and in the long term what sorts of

neuroplastic or rewiring changes does

MDMA produce and how can those be

beneficial or perhaps not beneficial I'd

like to take a quick break and

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order to understand what MDMA does to

the human brain we need to take a step

back and really Define the sorts of

experiments that one could do so for

instance you could take a person who's

never ingested MDMA and put them into an

fmri machine which is functional

magnetic resonance imaging put them into

the fmri machine and just have them sit

there with their eyes closed what we

would call resting functional

connectivity

or arresting State functional

connectivity and simply look at how

interconnected certain brain areas are

which brain areas are active which brain

areas are less active at rest this is an

important thing to do not just to

provide a baseline for understanding

what the drug MDMA will subsequently do

but also because it addresses What's

called the default mode Network the

default mode Network or dmn is the

network that is active in our brains

when we aren't really attending to

anything specific outside us and we're

not trying to think about anything

specific or accomplish anything specific

it actually relates to our sense of

imagination and daydreaming it has a lot

to do with our self-referencing you know

what we're thinking about ourselves this

may come as no surprise but if you're

just sitting there on the bus or you

know around the dinner table and you're

not paying attention to what's going on

in large part your brain is in this

default mode Network and you're thinking

about yourself okay so we can get a

sense of what the default mode Network

activation is we can get a sense of

which brain areas are more or less

active simply by putting somebody into

an fmri machine

then of course you could give somebody

MDMA while they are in the fmri machine

and see how the activation of different

brain networks changes and then of

course you could analyze how the default

mode networks and other brain networks

change in the days and weeks and even

years after the drug has worn off

so-called neuroplasticity effects what

changed in a permanent or pervasive way

okay so that's sort of one basic

Paradigm for exploring the effects of

drugs like MDMA on the brain the other

way that you can explore the effects of

MDMA on the brain is to ask people in

the general population hey who out there

is taking MDMA how many times have you

taken it and come on into the laboratory

and we will image your brain and compare

people who have for instance taken MDMA

zero times to people who have taken MDMA

one time or five times or believe it or

not there's some studies sitting right

here in front of me on my desk of people

who have taken MDMA more than 200 times

and ask the same sorts of questions

which brain areas are more or less

active those Studies have been done as

well and of course one can do studies

where you give people different dosages

of MDMA as well as giving people MDMA

and then giving them specific stimuli

meaning not just asking them to sit

there in the fmri scanner with eyes

closed looking at the resting state

functional connectivity

but also how the brain responds to the

presentation of happy faces or sad faces

or images of oneself or even images that

recall memories of traumatic events and

so on so fortunately all of those sorts

of Studies have been done in humans and

there are also a large number of studies

in animal models exploring how the

social activity of laboratory mice

changes when they are under the effects

of MDMA or even studies believe it or

not on the effects of MDMA encephalopods

cephalopods include octopuses as well as

cuttlefish and other Aquatic animals

that are known for having complex

Behavior some people believe that the

cephalopods are extremely intelligent

you know the obsession with cephalopods

is something that really intrigues me I

actually used to have cuttlefish in my

laboratory we did not put them on MDMA

but there is a study that's been

published in the journal current biology

it's a cell Press Journal excellent

Journal this is from Google Dolan's

laboratory at Johns Hopkins school of

medicine showing that if you give

octopuses MDMA they like to spend more

time with other octopuses than they do

if they are not on MDMA and that might

sound like kind of a um kind of a

playful experiment just done uh in order

to entertain oneself and the octopuses

perhaps but actually in that study they

identified the serotonin transporter in

octopuses and show that it has a lot of

homology similarity to human serotonin

transporter receptors and so what that

really speaks to is the fact that the

pro-social effects of MDMA that are

observed in mice and in humans and in

octopuses all have a common basis which

is the activation of more serotonin

release in particular brain networks

okay so that interesting study on

octopuses aside I think what most of us

are interested in is how MDMA impacts

the brain and so I'm going to spell out

the three major ways in which MDMA

changes the activation of the brain in

the short and long term and here I'm

pooling across a number of different

studies but one of the key sets of

studies in this area comes from the what

I consider very beautiful work of

Harriet DeWitt Harriet DeWitt runs the

human behavioral pharmacology lab in the

department of Psychiatry and behavioral

neuroscience at the University of

Chicago in her laboratory has a long

history of giving people certain drugs

in very specific dosages and then

measuring their effects on the brain

using different types of Imaging

including fmri

and one particular study that I'll

highlight is entitled effects of MDMA on

sociability and neural responses to

social threat and social reward so what

the study looked at is how MDMA impacts

people's perceptions of others emotional

Expressions on their face what they

found is that when people are on MDMA

their response to threatening faces or

other threatening stimuli is reduced and

it's reduced in a very specific way

which is reductions in activity of the

amygdala the amygdala is a structure

that some of you may be familiar with it

is known to be involved in the threat

detection systems or networks of the

brain it is sometimes called the fear

area of the brain although I want to

caution people against assigning any one

particular subjective experience to any

one particular brain area the amygdala

is actually a complex it's actually

called the amygdaloid complex and has a

lot of different sub areas and it's

involved in a lot of things besides fear

and threat detection nonetheless when

people are under the influence of MDMA

and you show them a face that is

grimacing or would otherwise be rated as

quite threatening they tend to rate it

as less threatening in addition they

tend to respond to happy faces or even

slightly happy faces as more

kind or more generous or happier than

they would when they are not on MDMA

again the faces that are being shown are

not of people on MDMA that would be an

interesting experiment but that's not

what they did here what's Happening Here

is people are being given MDMA and then

they are raiding in a subjective way the

friendliness or the level of threat that

they detect in these facial expressions

and of course they have extremes of

friendly and threatening but then they

also grade them right they titrate them

so that they also have mildly

threatening and mildly happy faces Etc

so everything from a grin to a smirk to

a giant smile everything from a from a

sort of a you know somebody looking a

little bit of scans at somebody to

really you know wide-eyed and looking

angry like they're you know gonna attack

you and things of that sort so what's

discovered in the study is that MDMA has

a bi-directional effect on our

perception of others emotions making

people more likely to rate something as

positive if it's initially positive or

even a little bit positive and less

likely to rate a threatening face as

more threatening now one thing I have

not mentioned thus far are the dosages

of MDMA used in this and in other

studies unfortunately despite the

studies that we're going to talk about

using a lot of different types of people

different ages different Sexes so male

and female located in different parts of

the world even some with PTSD some not

with PTSD Etc there's been fairly tight

dosage control of MDMA in these studies

it's not perfectly matched from study to

study but it's pretty darn close which

makes interpreting results across

studies a lot easier for me and

therefore for you

the typical dosages of MDMA used in

these neuroimaging studies and in the

clinical studies of PTSD that we're

going to talk about later

range anywhere from 0.75 milligrams per

kilogram of body weight to 1.5

milligrams per kilogram of body weight

so for somebody like me I weigh 220

pounds that's 100 milligrams

1.5 milligrams per kilogram of body

weight would therefore be 150 milligrams

in a single dose okay

a dosage of one milligram per kilogram

of body weight would mean 100 milligrams

for my 100 kilograms okay somebody

lighter than 100 kilograms would

obviously take less MDMA in one of these

studies but in general the range of MDMA

that's been explored is 0.75 to 1.5

milligrams per kilogram of body weight

the exception being in the clinical

studies that we'll talk about a little

bit later there's a tendency to explore

both an initial dose of 1.5 milligrams

per kilogram of body weight so again for

a hundred kilogram person that would be

150 milligrams or so and then a

so-called booster of half that amount

about 90 minutes to two and a half hours

into the session so another 75

milligrams later and I should point out

that there is not always the inclusion

of the so-called booster and in some

cases lower doses of MDMA such as the

0.75 milligrams per kilogram dosages are

used why am I getting so into the

details of dosages well

if we are going to talk about toxicity

of MDMA we absolutely have to talk about

dosages because

like any drug the toxicity of MDMA does

scale with the dosage that's applied not

just the frequency of MDMA use

we hear a lot about that you know

someone has taken MDMA one time or four

times or 200 times we hear about

frequency of use but rarely do we hear

about the specific dosages that are

taken in any one particular session so

when we talk about the subjective

effects or the brain networks that are

activated when people take MDMA in

general we're talking about

dosages somewhere between 0.75

milligrams per kilogram of body weight

and 1.5 milligrams per kilogram of body

weight although typically you're going

to see studies both clinical and more

research explorative using anywhere from

1 to 1.5 milligrams of MDMA per kilogram

of body weight so that's important to

highlight I told you about the

subjective effects of MDMA engaging the

responses of people's faces but I didn't

tell you about the brain areas that are

responsible except for the reduction in

amygdala activity now one of the key

features of PTSD seems to be that there

is a heightened connectivity between the

amygdala and a brain area called the

insula the insula is a brain area that's

very important for something that's

called interoception

interoception is one's perception of our

feelings both pure Sensations but also

our emotional states and our feelings of

well-being or lack of well-being for

everything from our skin inward okay so

that's interoception you actually can

intercept now even though you're always

intercepting a little bit you can

intercept now to a great degree if you

were to for instance close your eyes or

simply focus on the contact points

between your body and any surface that

you happen to be contacting so maybe the

backs of your legs against a chair or

your feet against the floor or the

bottoms of your shoes or sandals your

nervous system is constantly sensing

those contact points but normally

they're not under your conscious

awareness unless you direct Your

interceptive Capacity to them which is

just fancy nerd speak for saying you

normally don't notice what's going on

from your skin inward unless you focus

on it that focus is interception

it can be about the fullness of your gut

it can be about how happy or sad you are

it can be about how tired or alert you

happen to feel but that's interception

and it is distinctly different from

exteriorception which is your ability

and tendency to focus on things beyond

the confines of your skin so this could

be visual attention auditory attention

it could be paying attention to events

like birds flying by whether or not your

Uber is showing up these kinds of things

and we are always in a balance a

push-pull of interoception and extra

reception the insula is a brain area

that is absolutely critical for

interception so much so that it has a

map of the complete body surface

including our internal organs

in other words if you put somebody into

an fmri machine or you were to record

from the insula with electrodes as has

been done in humans many times now

during the course of neurosurgery for

other purposes what you would find is

that if you stimulate neurons in one end

of the insula the person will say oh you

know I I feel something going on in my

gut and on my left side and then as you

were to March that stimulation across

the insula you would find that they

would now be paying attention to their

legs or just to one leg or to their

whole body or to the sensations in their

face or their head so there's a

systematic map of interoception in the

insula and there are direct connections

between the amygdala and the insula and

the amygdala despite getting this

reputation as just being a fear Center

or a threat detection Center is actually

part of a much larger set of networks

that include inputs from the hippocampus

an area of the brain that's involved in

memory formation and Storage

and what is observed is that people who

have PTSD tend to have greater or rather

stronger connections between the

amygdala and the insula than is normally

observed in people who do not have PTSD

okay so there seems to be heightened

input from the threat detection centers

of the brain to this area of the brain

the insula that is responsible for our

sense of interception which provides a

logical explanation for why people with

PTSD often will feel the memory or sense

the discomfort or just feel agitation or

even other types of bodily Sensations

like back pain or just perhaps just a

sense within their body that's more

generalized it doesn't even have to be

pain doesn't even have to be negative

but that's associated with the negative

memory of some traumatic event or series

of events okay so this is a really

interesting brain Network that I should

mention exists in everybody but that in

people with PTSD seems to have

heightened connectivity and those brain

networks can be revealed by putting

people with PTSD into functional Imaging

machines

getting them to recall a traumatic event

or even looking at the resting state of

connectivity between the amygdala and

the insula so those experiments have

been done and what's also been done is

to give people 1.5 milligrams per

kilogram of MDMA and to look at the

connectivity between the amygdala and

the insula and between the hippocampus

the amygdala and the insula and so

what's observed over time in people that

have been given MDMA and this is a very

important

and and have done therapy for PTSD both

before during and after

the drug there's a weakening of

connections between the amygdala and the

insula and that scales very directly

with the relief of symptoms from PTSD so

this is really exciting because it's one

thing to see a brain Network get

activated or inactivated or you say okay

in one person a certain connection

between threat centers and the

interceptive centers of the brain was

let's say arbitrary units let's say it

was level eight out of ten for that

person right these things are normalized

for a particular person and then after

taking MDMA and doing PTSD therapy it

was five out of ten or four out of ten

that's a good experiment but what's far

more powerful is to observe that in that

patient or that person and then to see a

change that's perhaps less dramatic so a

shift from 8 out of 10 to 7 out of ten

in another person and to see less shift

in brain connectivity in the same

network and then perhaps in the person

that went from full-blown PT PSD to full

remission of PTSD something that believe

it or not has been observed in single

sessions with MDMA

if that person demonstrates an even

greater reduction in the connections

between the amygdala and the incilla

well then that gives even more

confidence that this connection between

the amygdala and the insula is actually

perhaps causally related to the

reduction in symptoms of PTSD or even if

it's just correlated with reduction in

symptoms of PTSD the fact that the

degree of reduction of connection of

this circuit scales with the reduction

in clinically relevant symptoms that's a

very powerful finding because it moves

things away from Pure correlation

although this brain area is active or

less active over time and you know this

person has more or fewer symptoms of

PTSD to something that starts to look

like a mechanistic and logical framework

for understanding

PTSD as well as the effects of MDMA and

for understanding how changes in the

brain underlie relief from PTSD okay so

again even if you just could grasp the

idea that you have a brain area the

amygdala that's involved in threat

detection and it provides inputs to

another brain area called the insula

which is involved in this thing called

interoception and that reductions in

those connections between the amygdala

and the insula scale with or correlate

with reductions in PTSD symptoms as a

consequence of people taking MDMA so if

you have that under your mental belt I

promise you you understand far more

about how MDMA impacts the brain in the

short and long term the 99.9 percent of

people out there

however it's also important you

understand a few other things that MDMA

does to the brain as well as what it

doesn't do to the brain first of all

classic psychedelics like psilocybin and

LSD as I mentioned earlier are known to

create more lateral connectivity between

different areas of the so-called

neocortex and these are long-lasting

changes that are thought to underlie

both some of the relief from major

depression but also some of the enhanced

creativity and some of the other things

that have been observed with psilocybin

treatment and again if you're interested

in psilocybin treatments and psilocybin

itself please check out the episode that

I did on psilocybin and the guest

episode with Dr Robin Carhartt Harris

those episodes like all other episodes

of The huberman Lab podcast can be found

at hubermanlab.com it's a fully

searchable site so you can put keywords

into the search function it will take

you to specific time stamps every

episode is time stamps you can navigate

to topics of particular interest to you

feel free to go there and listen to

those episodes about psilocybin MDMA by

contrast does not seem to produce long

lasting increases in lateral

connectivity between those same brain

networks probably because it impacts a

different serotonin receptors it does

however seem to change resting state

functional connectivity Within These

limbic structures like the amygdala and

related structures that are associated

with threat detection now this is

interesting and it actually was

highlighted very nicely in a study I'll

provide a link to in our show note

caption which actually has Dr Robin

Carter Harris as the first author so not

only has he done incredible work on

psilocybin and LSD and DMT in Ayahuasca

in his laboratory but also on MDMA and

the particular study I have in mind here

showed that people who take MDMA

at more or less the dosage that we

talked about earlier

report Mark increases in positive mood

as well as decreased blood flow to the

amygdala and hippocampus so again these

threat detection centers of the brain

and brain areas associated with

memory and those changes are seen both

while under the influence of MDMA and

afterwards when the brain is simply at

rest so it really does appear that MDMA

creates neuroplasticity that changes the

overall level of activation of these

threat detection networks and their

connections to memory systems in a way

that's pervasive over time and that

doesn't require any particular probe

with a negative

stimulus I'll translate to English what

that means is that during the MDMA

session

people report feeling less threatened

more pro-social towards others more

empathic towards others and themselves

and then after the session they have

less of a threat response to memories

that before the session were more

troubling and those changes in the brain

do seem to be pervasive so there are

both short-term and long-term effects of

MDMA all of which point in the direction

of lowered levels of threat detection

heightened levels of positivity

pro-social components of the brain more

active threat detection centers of the

brain less active now earlier we talked

about MDMA as a drug that potently

increases dopamine and even more

potently increases serotonin largely

acting through this serotonin 1B

receptor now without getting into too

many more details before moving on to

issues of toxicity around MDMA I do want

to touch on what I think is perhaps the

finest of the animal model studies of

MDMA that explored which brain networks

and

which chemical that is serotonin or

dopamine is responsible for say the

motivational components of MDMA versus

the pro-social effects of MDMA and then

it also raises a really important point

which I haven't mentioned yet in this

episode which is the role of oxytocin

something that many of you have perhaps

heard of

the paper that I'm going to describe is

from the laboratory of Dr Robert malenka

he's a colleague of mine at Stanford

University School of Medicine Psychiatry

and Behavioral Sciences

he is both a Pioneer and luminary in the

field of neuroplasticity of how the

brain wires and forms memories and can

change itself over time in response to

experience as well as the study of drugs

of abuse as well as the study of drugs

like MDMA and now additional compounds

that can provide therapeutic support in

certain conditions the study which I

will provide a link to in the show note

caption is entitled distinct neural

mechanisms for the pro-social and

rewarding properties of MDMA and I'm

just going to summarize the major

results of this study it's a study that

was done on mice and I realized that a

lot of people will hear that and think

ah what relevance does that have to

humans but when thinking about the

effects of dopamine and serotonin in the

types of circuits that we've been

talking about thus far

these circuits that are subcortical as

we refer to them so these are limbic

circuits these are hypothalamic circuits

these are what are called mesolymbic

circuits these are all names for

circuits that are highly conserved

between mice and humans

and so results in mice really do

translate quite well to results in

humans at least insofar as the effects

of MDMA and which neurochemicals are

involved is concerned so what they found

in the study using a huge array of

beautiful techniques such as

inactivation of specific brain areas

activation of specific brain areas drug

antagonists to prevent oxytocin function

or drug antagonist to prevent specific

receptors involved in the serotonin

pathway lots and lots of tools in their

toolkit what they found is that MDMA

causing the release of dopamine

is what really establishes the rewarding

effects of an experience this isn't

really a surprise

we've known that MDMA just like cocaine

or Methamphetamine or Adderall for that

matter or Vyvanse for that matter

creates big increases in dopamine that

tend to couple an experience with a

sense of reward

and lead to changes in the neural

circuitry that make the animal or human

more likely to seek out that same

experience again okay these are the

rewarding or sometimes called

reinforcing properties of dopamine that

take place in the so-called mesolimbic

reward pathway if you want to learn

about mesolimic reward Pathways and

dopamine and how they control everything

from your level of motivation to your

tendency to procrastinate or overcome

procrastination I've done two episodes

about dopamine you can simply go to

hubermanlab.com put dopamine into the

search function and you'll find at least

two episodes on that topic and you'll

also find a number of different tools

related to how one can better regulate

their own patterns of dopamine release

for sake of motivation Etc

so MDMA is increasing dopamine to

increase reward to a particular

experience what's the experience well

this paper beautifully parses

the fact that it is serotonin release

within a structure called the nucleus

accumbens which is part of the reward

pathway which is rewarding the

experience of social interaction now

they do this by putting mice in arenas

where they have the option of either

spending time with other mice or not

spending time with other mice and

blocking the activation of certain brain

areas and again using drug antagonists

Etc and what they find is that it really

is the activation of the serotonin 1B

receptor

in the nucleus of Commons by MDMA that

leads to this pro-social effect of MDMA

so that's really nice to know because

there's always been this conundrum of

okay psilocybin and LSD are basically

like serotonin they activate the

serotonin 2A receptor MDMA has this huge

serotonergic component tons of Serotonin

released when one takes MDMA but very

different effects in the short and long

term

very different subjective effects very

different patterns of change activity in

the brain in the short and long term

well that's because MDMA is activating

the serotonin-1b receptor not the

serotonin 2A receptor and it's doing so

in a completely different set of brain

networks as is LSD and psilocybin so

what happens when an animal or a person

takes MDMA is that social connection is

strongly rewarded and reinforced making

social connection more likely after the

drug wears off

now that's one component of social

connection but in addition

people who take MDMA in the clinical

therapeutic setting for the treatment of

PTSD often report feeling more empathy

and compassion for themselves during the

session but also for long periods of

time maybe even indefinitely after the

session

so it really seems that the addition of

this huge release of Serotonin by MDMA

on top of the release of dopamine sets

in motion two parallel circuits one for

rewarding something anything that's the

dopamine component and then fortunately

because the increase in serotonin caused

by MDMA

increases empathy and sociability for

and with others but also for oneself

the motivation that's reinforced that's

wired into the brain seems to be a

motivation to perceive others as more

kind but also to be kinder to oneself

now I realize that for some of you who

are listening to this you're probably

saying well of course right you know

serotonin is pro-social and dopamine is

motivation so you put the two together

and people become more motivated to be

social and kinder to themselves ah but

it didn't necessarily have to be that

way right it is very hard to go from a

statement like drug a produces effects b

c and d to neurochemicals b c and d

cause motivation and sociability and

therefore when you take that drug you're

going to get all of that stuff in fact

we have to go back to our understanding

the MDMA despite causing a big increase

in serotonin also causes huge increases

in dopamine and it does so with this

molecule that is methamphetamine now

methamphetamine is not known to be a

pro-social drug in fact a study I just

referred to as well as some human

Studies have explored how the

application of methamphetamine so not

MDMA but pure methamphetamine impacts

social interactions and what it does to

social interactions it's very profound

it dramatically reduces one's tendency

to engage in social interaction so this

really speaks to the poly pharmacology

as it's called of MDMA the fact that

serotonin and dopamine are released

together has distinctly different

effects than if just dopamine or just

serotonin is increased so much so that

it's worth taking a step back and

talking about another class of drugs

which dramatically increases serotonin

which are the ssris The Selective

serotonin reuptake Inhibitors ssris such

as fluoxetine Prozac as well as Zoloft

and of course there are many other

accessories out there citalopram Etc

they block the reuptake of Serotonin and

thereby lead to net increases in the

amount of Serotonin and yet those drugs

are not known to create

even close to the same sorts of effects

as MDMA

in fact there have been human and animal

studies showing that if you give

somebody an SSRI prior to them taking

MDMA you actually block the pro-social

and empathogenic effects of MDMA now you

might say why in the world would that be

aren't these drugs just increasing

serotonin and the increase in serotonin

is pro-social ETC ah well that speaks to

the complexity of all this poly

pharmacology and the fact that it's

really the activation of Serotonin at

particular receptors in this case the

serotonin 1B receptor in particular

brain areas in this case the nucleus

accumbens a brain area associated with

motivation and reward

that largely explains the effects of

MDMA in making people and animals and

octopuses included for that matter more

pro-social and more empathic towards

themselves

it's not just an issue of raising the

levels of one neurochemical it's really

about raising levels of a particular

neurochemical acting in particular

receptors in particular brain areas and

in the case of MDMA the fact that

there's also dopamine increased in those

very same brain areas right I don't

think I mentioned this before but the

nucleus accumbens is part of that

mesolimbic reward pathway that is

essentially establishing a reward for

whatever is happening at the moment

so the way to conceptualize MDMA and its

effects on the brain both subjectively

and mechanistically is that it's an

empathogen for which empathy and social

connection is very strongly reinforced

while under the influence of the drug

and in a way so intense and Powerful

that those neural networks get stronger

and persist in being more active for

long periods of time after the drug has

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drink element lmnt.com huberman now one

of the things that's been explored in

both the animal literature and the human

literature is that MDMA doesn't just

increase dopamine and doesn't just

increase serotonin but it also

profoundly increases levels of oxytocin

release in the brain now oxytocin is

considered what's called a neuro hormone

because it acts as both a

neurotransmitter or I guess if we were

going to be really specific we'd say a

neuromodulator because it tends to

modulate the activity of a bunch of

other circuits and a hormone how can we

say it's a hormone or a modulator or

transmitter well hormonal effects tend

to be effects that act not just locally

but on many sites within the brain and

body as well and oxytocin is known to do

that as well as to work locally so

that's why we call a neuro hormone it

activates neurons and is associated with

neural networks related to pair bonding

both between parent and child both

mother and child and father and child or

caretaker and child not just biological

parent

as well as bonding between friends

bonding between lovers and it's thought

to actually be involved in the process

that is the painful process of breaking

of bonds when people are no longer

available to us as caretakers or as

partners either by way of breakup death

departure Etc in fact there are even

data suggesting that humans can have

strong oxytocin responses to their pets

in particular dogs and their dogs can

have strong oxytocin

patterns of release in response to their

owners I think for any dog lovers or dog

owners certainly includes me I'm raising

my hand

that comes as no surprise anyone that's

ever had to put down a dog or has lost a

dog and hear no disrespect to the cat

owners but I'm just referring to the

studies that have been done on humans

and dogs

you can certainly relate to the

incredible pain of that loss oxytocin is

thought to be involved in bonding

between people and other creatures as

well as the breaking of those bonds

MDMA is known to powerfully increase

oxytocin release in fact there's a

really nice study on this done in humans

this is a study I'll provide a link to

in the show note captions entitled

plasma oxytocin concentrations following

MDMA or intranasal oxytocin in humans

nowadays oxytocin is available by nasal

inhaler

to be honest I don't know the legality

around it I don't know if it's a gray

Market or but what I'm about to tell you

will basically discourage you from

wanting to take it because what they

found in the study was

people given either 0.75 or 1.5

milligrams per kilogram of body weight

of MDMA experienced increases in

oxytocin however it was only the group

that took 1.5 milligrams per kilogram of

body weight of MDMA that experienced the

really big significant changes in

oxytocin and when I say really big

really highly statistically significant

what they observed is that in the

placebo group

because of course they include a placebo

group the amount of circulating oxytocin

was 18.6 picograms per milliliter which

to you probably means nothing and to me

also sort of means nothing because those

units of oxytocin can't be directly

related to any kind of direct experience

of feeling bonded or not bonded that's

just a number but nonetheless it

provides a baseline to compare to the

average levels of oxytocin in the

bloodstream of people that were given

1.5 milligrams per kilogram of MDMA

which is 83.7 picograms per milliliter

that equates to nearly a five-fold

increase in the amount of circulating

oxytocin when people are under the

influence of MDMA

now this study had a bunch of different

conditions not just MDMA of different

doses not just placebo

they also had people take oxytocin by

nasal spray which we know can change

levels of circulating oxytocin and

indeed when measured in the study it did

change levels of circulating oxytocin

and the end point in the study was to

have people

give subjective ratings of their

feelings of

connectedness to one another as well as

rate and here I'm just drawing directly

from the paper of how much they like the

feeling how much they felt high they

measure their heart rate their systolic

pressure their diastolic blood pressure

Etc and they looked at how

social people felt they looked at how

insightful people felt and the key

takeaway from the study for sake of our

discussion here today is that it does

not again it does not appear that the

increases in oxytocin produced by taking

MDMA

are the source of the pro-social effects

of MDMA

and that's also what was found in the

animal studies of MDMA where in those

studies

mice were given MDMA at comparable doses

the doses were a little bit higher than

used in the human studies but at

comparable doses

big increases in oxytocin were observed

increases in sociability

of those mice were observed just as they

are in humans that take MDMA but in

those mice they were also given a drug

to block the oxytocin receptor and lo

and behold no changes in sociability

were observed

in humans that take oxytocin by nasal

spray

you can see big increases in oxytocin

that's not surprising gets across the

blood-brain barrier oxytocin goes up

and levels of sociability do not

increase

so what this points to is a situation

where MDMA is increasing dopamine to

increase motivation and to reward

something what gets rewarded well what

gets rewarded is the serotonin

activation of particular brain networks

associated with sociability and the

dramatic increases in oxytocin that are

very very real when people take MDMA do

not appear to underlie any of the known

short or long-term subjective effects of

MDMA now a conclusion like that needs to

have a caveat and the caveat is that as

far as we know the big increases in

oxytocin that are produced by MDMA

aren't doing anything for the sorts of

effects that we've been talking about

here sociability empathy Etc but there

could be other effects of oxytocin that

we're just not aware of that said the

data from both animal models and in

humans really point to the fact that the

increases in oxytocin that are produced

by MDMA are not directly related to any

of the short and long-term effects of

MDMA that we are most familiar with

namely motivation sociability increase

empathy or the long-standing changes in

neural circuitry that underlie for

instance reduce threat detection or

reduce connectivity between threats

detection centers of the brain and in

terreception so is the big increase in

oxytocin produced by MDMA completely

irrelevant in the context of this

discussion we don't know it appears that

it's not very relevant is oxytocin a

meaningless molecule right after all

they gave these people nasal infusions

of oxytocin oxytocin and went way up

they didn't observe anything very

interesting or significant in the

context of sociability but we do know

that oxytocin can play a powerful role

in pair bonding and in human human

animal bonding of various kinds from

other experiments that have been done so

I don't want to diminish the incredible

power that oxytocin has in our brains

and bodies but it doesn't appear that

the MDMA induced increases in oxytocin

which are enormous have much to do with

anything related to the value of MDMA as

a treatment for PTSD or for its

subjective effects on empathy

sociability or any of those other

factors either now perhaps the one

caveat to that is that hair Harriet

Dewitt's laboratory which I referred to

earlier has looked at how variations in

oxytocin receptor genes vary between

people so it turns out that some people

have an allele a basically a version of

the oxytocin receptor that is different

from other people that makes oxytocin

work differently and actually less

effectively in activating certain brain

networks and it does appear that when

those people take MDMA they actually it

experience less of a pro-social effect

of the drug now that spits in the face

of everything I just said about oxytocin

not being involved in the effects of

MDMA on pro-sociability and empathy

I think the bulk of the data really

points to the fact that it's the

serotonin increases combined with the

dopamine increases caused by MDMA that

lead to most of the understood effects

and that oxytocin if it's playing a role

is going to play a more minor role let's

talk about the safety and potential

neurotoxicity of MDMA and here I really

want to highlight that our discussion

today is couched in a discussion about

the application of pure MDMA to animals

or humans in the context of laboratory

or clinical studies this is really

important to point out because I would

be remiss if I didn't note that

there is a lot of recreational use of

MDMA in fact it was the recreational use

of MDMA in the 1980s but really that

took off even exploded in the 1990s with

so-called Rave culture that created the

massive attention on illegality of MDMA

and put the drug enforcement agencies

onto MDMA as a drug that they wanted to

and indeed do restrict in fact just

today in anticipation of this episode I

put MDMA into the search function on

Google and clicked news and there were

at least two reports of major MDMA

seizures and bus so again I want to

highlight the fact that MDMA is still

illegal to possess or sell and certainly

to traffic I also want to highlight the

fact that nowadays all recreational

drugs but certainly MDMA included

are often in fact very often

contaminated with fentanyl and while

fentanyl has certain clinical uses

fentanyl is highly deadly the current

estimates are as much as 60 percent

maybe even 80 percent of drugs that are

sold on the gray Market are being

repackaged or reformulated with fentanyl

and there have been a lot of fentanyl

related deaths both in kids and adults

so the sourcing of MDMA is extremely

important and the safety issues simply

cannot be overlooked

and I say that not to protect me I say

that to protect you right the last thing

any of us want is for someone to take a

compound thinking it's one compound and

it contains another compound and I'm

getting hurt or even dying and that is

happening a lot a lot and it is

certainly happening a lot for people

that think that they're buying MDMA

the use of MDMA in the laboratory or in

the clinical setting

with pure MDMA has also been explored

for the potential neurotoxicity of MDMA

so how would methamphetamine and MDMA be

neurotoxic well that's because they

increase dopamine in the case of

methamphetamine and dopamine and

serotonin in the case of MDMA and they

do so to a very high degree

the big increases in dopamine and

serotonin but in particular the big

increases in dopamine tend to promote

electrical activity of other neurons

remember these are after all

neuromodulators they modulate up or down

the activity of other neurons and

dopamine tends to modulate the activity

of other neurons up

so dopamine itself is not neurotoxic but

when a lot of dopamine is released it is

neurotoxic and it's well known that even

a single dose of methamphetamine can be

neurotoxic not just for dopamine neurons

but for other types of neurons as well

including serotonergic neurons

put differently we know that the brains

of people that take methamphetamine

degenerate to a smaller or to a large

degree depending on how often they take

the drug how potent the drug is and

whether or not they combine it with

other drugs and yes

if you heard that combining caffeine

with amphetamines can increase the

neurotoxicity of amphetamines such as

methamphetamine that is true if you've

heard that taking caffeine within the

hours or same day as MDMA can increase

the toxicity of MDMA that does appear to

be true based on animal studies now

there are not a lot of studies looking

at the toxicity of MDMA in humans but

there are a few

there are also studies looking at the

toxicity of MDMA in animal models

including non-human primate models now

this is a very complex literature a lot

of results not all over the place but

they're scattered in a number of ways

first of all some of the animal Studies

have used dosages of MDMA as high as two

milligrams per kilogram of body weight

as high as three milligrams per kilogram

of body weight and even in upwards of

that

but even for the animal studies that

used a range of dosages from 0.75 to 1.5

milligrams per kilogram of body weight

there is some evidence that in

laboratory Miser rats there can be some

loss of serotonergic tone in the brains

of animals that have been administered

MDMA now notice I said serotonergic tone

I didn't say serotonin neurons

because of the way that MDMA Works in

encouraging or promoting big releases in

dopamine big releases in serotonin it's

not surprising that if the animals that

were given MDMA are subsequently

sacrificed say later that day or the

next day or maybe even a week or two

weeks later and those brains are stained

for proteins that are related to the

synthesis or release of Serotonin it's

not surprising that there would be

reductions in those sorts of proteins

right after all a lot of dopamine and

serotonin is released and it can be

depleted but I should point out

depletion of a neuromodulator in the

short term is not the same thing as

depletion of that neuromodulator in the

long term nor is it the same as loss of

the neurons that release dopamine and

serotonin itself

so there are data pointing to the fact

that repeated administration of MDMA

at dosages that are very much within

lines with what we're talking about

today 1.5 milligrams per kilogram of

body weight

can lower total amounts of Serotonin or

other proteins in the serotonin

synthesis pathway or dopamine or

proteins that are in the dopamine

synthesis pathway in specific areas of

the brain related to reinforcement

related to mood related to motivation

Etc however

the primate studies or I should say the

non-human primate studies which are the

sorts of animal studies that most

closely mimic what one expects to see in

the human brain because after all mice

and the effects of these drugs and mice

do translate to humans but it's thought

that non-human primates provide a model

that's far more similar to humans

there the data start to get kind of

complicated in a way that suggests that

MDMA might not be as neurotoxic as is

thought based on the rodent studies and

this gets into a whole history of back

and forth between different Laboratories

and governing bodies who are trying to

keep MDMA legal as well as people such

as the Sasha Shoguns of the world and

people in the therapy community that are

excited about the potential for MDMA

becoming legal for the treatment of PTSD

and it really centers around one or two

studies

both of which were published in very

high profile journals and the one that

I'll highlight because the results are

now very clear and conclusive is a study

that was published back in 2002 which

was entitled severe dopaminergic

neurotoxicity in primates after a common

recreational dose regimen of MDMA

or ecstasy

this paper was published in the journal

science which is one of the three Apex

journals for publishing scientific

research so there's science nature and

cell those are the top top journals most

stringent journals to get scientific

manuscripts into

the paper received a lot of attention

because as you can imagine based on the

title it suggested that even

recreational doses of ecstasy even if

it's pure ecstasy and it doesn't have

contamination from additional

methamphetamine or other things in it is

neurotoxic to serotonergic and or

dopaminergic neurons this is largely

where MDMA got the reputation for quote

unquote putting holes in your brain

however

this study came under a lot of scrutiny

for a couple of reasons first of all and

I'm certainly not saying this but it was

argued that the authors of the study

were perhaps trying to prevent the

legalization of MDMA for the treatment

of PTSD as far as I know there's no

direct evidence that that statement is

true but you will actually find that in

some of the scientific journals in fact

I was able to find a an editorial that

was published in the biomedical journal

in 2003 which argued

somehow that Dr riccarte was accused of

quote rushing his results into print

because of legislation designed to curb

ecstasy use before U.S Congress so you

know there were some uh connotations or

I'd rather there were some strong

suggestions that there was a political

backing to trying to get this study done

quickly and into print and so forth I

don't think that ever really got

resolved what did get resolved however

is that

the very study in question was retracted

okay so the authors themselves published

a letter of retraction

that unfortunately is not as well

recognized as the paper that stimulated

this idea that MDMA is neurotoxic in

primates and keep in mind that we are

human primates non-human primates being

the closest model to human primates that

we are aware of but to make a long story

short

there were some issues of labeling of

MDMA versus other drugs in the

laboratory there were some issues of

mislabeling all of which were eventually

acknowledged by the authors of the study

and they concluded in fact they verified

based on some very detailed analysis

that what these monkeys were injected

with was not actually MDMA but rather

was methamphetamine itself

so what's not often acknowledged is the

retraction of the paper on neurotoxicity

and unfortunately the neurotoxicity

issue is often what's mentioned now keep

in mind there are studies in rodents

showing neurotoxicity of MDMA perhaps

even at recreational doses but to date

at least to my knowledge

there don't seem to be any data in

either non-human primates or in humans

showing toxicity of MDMA at clinically

relevant doses provided it is pure MDMA

I want to be very clear I'm not saying

that if you can get pure MDMA that you

should take it or that it won't be

neurotoxic certainly we can expect that

because of the huge known variation in

dopamine receptors in serotonin

receptors and of course because of the

known interactions between MDMA and

other compounds in particular caffeine

but also drugs such as cocaine or other

stimulants

that some people might experience more

toxicity to a given dose of MDMA

compared to somebody else and there's

really no way to detect that

susceptibility to neurotoxicity now what

we do know is that there are people in

the general population that have taken a

lot of MDMA anywhere from 1 to 200 or

sometimes even in excess of 400 doses of

MDMA and they're now our studies that

have explored

the neurotoxicity and perhaps even more

importantly the neurocognitive and

behavioral effects of

taking MDMA either zero times one time

five times forty times 200 times etc etc

and one of the what I would consider

Landmark studies in this area is a study

entitled residual neurocognitive

features of long-term ecstasy users with

minimal exposure to other drugs and

those words with minimal exposure to

other drugs is really key in the context

of this conversation

because as I mentioned before

interactions between drugs what's called

polypharmacology can create

neurotoxicity it's unclear if MDMA is

neurotoxic but we know methamphetamine

on its own is neurotoxic we also know

that people often will combine MDMA and

methamphetamine we also know that a lot

of so-called MDMA out there is mostly

methamphetamine with only a little bit

of MDMA so a study of the sort that I'm

about to describe where it is

essentially confirmed that people were

taking pure MDMA and not taking any

other drugs is of immense value this

study

has been a little bit controversial in

fact I've talked about it before I

talked about the Joe Rogan podcast I've

talked about it briefly with a guest on

this podcast Dr Nolan Williams who's a

triple board certified physician

psychiatrist and neurologist at Stanford

School of Medicine

and it's an interesting study and a

little bit controversial because it

relied on a population of people who

have taken MDMA anywhere from one to two

hundred times and who've not taken any

other drugs including caffeine and the

population in mind here is a population

of people living in Utah who

self-identify as members of the Church

of Latter-day Saints sometimes referred

to as Mormons sometimes referred to as

LDS or of the Church of Latter-day

Saints

the Church of Latter-day Saints as I

understand does not allow for

taking of certain compound certain drugs

certain certainly most recreational

drugs alcohol even caffeine and I'm sure

there's some variation on some of those

themes depending on where people live

and the certain communities that they

happen to be in I am in no way shape or

form

um declaring that I'm an expert on

Latter-Day Saints I have a couple of

friends who are LDS

happen to be very nice people as far as

I know they were not the people in this

study but this study really emphasized

ecstasy users they're called who have

not taken other drugs who self-identify

as LDS

and the major takeaway of this study was

that for moderate meaning people who

have taken ecstasy anywhere from 22 to

50 times

in their lifetime as well as heavy users

of MDMA so these are people who have

taken MDMA anywhere from 660 to 450

times in their lifetime

there was little evidence of decreased

cognitive performance in standard assays

for cognitive performance now there were

some effects showing poorer here I'm

quoting from the findings poor strategic

self-regulation

quote possibly reflecting increased

impulsivity however when you see a

conclusion like that you should

immediately be thinking chicken versus

egg right it could be that people that

are more impulsive and that have

less strategic self-regulation are more

likely to take ecstasy 450 times you

could conclude that or you could

conclude that people who have taken

ecstasy 75 times or 25 times Etc

are degrading their levels of

self-control and thereby increasing

impulsivity the direction of the effect

is not known these are purely

correlations nonetheless this study and

a few others like it really stand as our

best evidence believe it or not as to

how ecstasy taken many times because

after all these people are taken

anywhere from 22 to 450 doses of ecstasy

in their lifetime

is producing severe detriments in

cognitive performance and that simply

does not appear to be the case now

unfortunately there are no data looking

at the brains of these individuals

looking at for instance which brain

structures are active or less active or

perhaps even looking at levels of

Serotonin or dopamine all things that

can be done with positron emission

tomography Imaging functional MRI

Etc hopefully those studies will be done

in the not too distant future but if we

were to just take a step back from all

the data the data in mice in rats and

non-human primates the retraction of the

study in non-human primates which showed

that

the primates that showed

neurodegeneration were not given MDMA as

it was thought by the researchers but

rather as later was acknowledged we're

actually given methamphetamine and we

take into account these moderate and

heavy users of MDMA who as far as we

know are being honest and haven't taken

any other drugs

and we look at the clinical studies

where people who have never taken MDMA

are given one or two or three defined

doses of pure MDMA we'll talk about

those studies in a moment I think the

Gestalt the top Contour the overall view

of those studies is that provided it as

pure MDMA

and provided the individual is not

consuming other drugs which have the

potential to be neurotoxic

and provided that it's being done in a

controlled clinical setting the risk for

toxicity seems quite a bit lower than

the popular press has promoted and yet

there is still the risk of neurotoxicity

if people are taking high doses of MDMA

or taking it very frequently or

certainly if they are taking it in

conjunction with other drugs or or I

should say and or taking MDMA in

settings that can promote neurotoxicity

and the settings I'm referring to are

any settings in which blood pressure or

body temperature have the propensity to

be greatly increased every study in mice

in non-human primates and in humans in

which MDMA is administered has observed

significant increases in blood pressure

and heart rate MDMA is after all a

psychostimulant it's a sympathomimetic

talked about sympathomimetics and what

that means in the episode on Adderall

and Vyvanse and ADHD but basically it's

ramping up the activity of the

sympathetic nervous system which is your

fight or flight system okay this is why

people who take these drugs get big

pupils you know big pupils of the eyes

that's why they feel agitated they want

to talk a lot they feel like they want

to move a lot that's why people take it

to dance at Raves Etc but when people

take sympathomimetics whether or not

it's MDMA or amphetamine or cocaine or

even caffeine there's an increase in

blood pressure and heart rate but also

body temperature and if that's done in

an environment in which there's very

little temperature regulation so people

aren't for instance drinking enough

fluids and electrolytes it's very hot in

the room

you can get neurotoxicity based on

temperature effects and that's because

serotonin and dopamine also act on the

so-called medial pre-optic area of the

hypothalamus which is involved in

temperature regulation if you're curious

about temperature regulation I covered a

lot of that in the episodes of the

Hebrew and Lab podcast on deliberate

coal exposure and deliberate heat

exposure this is an area I used to work

on many years ago as a research

scientist before moving on to other

topics to research in my laboratory

big increases in body temperature are

not good the body and in particular your

brain can tolerate

decreases in body temperature that are

pretty robust and you can still stay

safe

you're not going to kill neurons but

even an increase of three or four

degrees in body temperature can start to

kill off neurons so when thinking about

the potential neurotoxicity of MDMA the

conditions that is the environmental

conditions the behavioral conditions

under which somebody takes MDMA are

vitally important at least important I

would argue as any other compounds they

might be ingesting with MDMA so that's

something really serious to consider so

if somebody says MDMA puts holes in your

brain you would be correct in being

skeptical or at least giving them some

counter Arguments for that statement but

if somebody says MDMA is not toxic well

then you would be equally valid in

saying ah wait but we need to think

about the conditions under which MDMA is

being taken is it pure MDMA or is it

mostly methamphetamine in which case it

would be very toxic is it MDMA alone or

in conjunction with caffeine within that

same 24-hour period is it MDMA while

moving around a lot or being outdoors or

being in an environment perhaps a rave

or dance type environment where

temperature is going up well in that

case it could be very neurotoxic so

pharmacology of MDMA counts but so does

poly pharmacology the ingestion of other

compounds

not just during the MDMA session but

also in the 24 hours before and after

that MDMA session and behaviors will

certainly impact temperature which will

impact whether or not MDMA is neurotoxic

or not and despite my efforts I couldn't

find out whether or not the LDS

Community has officially sanctioned the

use of MDMA certainly that's one

possibility but I have no evidence for

that or rather whether or not certain

people within the LDS Community have

allowed themselves given themselves

permission to use MDMA and they are not

using other drugs what I do understand

to be the case is that people within the

LDS Community are discouraged from using

drugs like caffeine or cocaine or

alcohol and this particular population

of people that was explored in this

study

self-identify as LDS and self-identify

as having taken MDMA anywhere from 22 to

450 times but where they got permission

for that whether or not it was from

someone else or from themselves I do not

know what I do know is that within the

acknowledgments of the paper there's

actually a thank you to the person that

identified this quote unique population

for our study

so I welcome you to take a look at the

paper and if any of you know more about

if and how a particular subgroup within

the LDS Community is allowed to take

MDMA perhaps you want to put those in

the comment section on YouTube before

moving to our discussion about what MDMA

is doing and the effects that people are

seeing in the clinical studies for the

treatment of PTSD which by the way are

extremely exciting I can't wait to share

these data with you I do want to touch

on something that anyone who's heard

about MDMA or perhaps used MDMA

is familiar with and that's the

so-called crash that people experience

after MDMA there are a lot of myths

about the post-mdma crash and there's a

lot of lore out there on the internet

about how to offset the crash and a lot

of lore about how to prevent the

potential neurotoxicity of MDMA earlier

we talked about some of the major points

around offsetting neurotoxicity so

certainly making sure that any MDMA that

one takes is in the legal clinical

setting that it's therefore pure MDMA

right that it's not cut with other

things which certainly can increase

toxicity controlling the temperature of

one's environment restricting caffeine

intake

at least on the day of MDMA ingestion

but certainly the day before and the day

after would be advantageous well simply

because of the way that caffeine and

activation of the adenosine receptor as

well as caffeine's effects on dopamine

receptors can interact with the

potential again potential neurotoxicity

of MDMA but the crash that one

experiences after MDMA is actually a

phenomenon very common to the crash that

one experiences after ingestion of any

type of stimulant cocaine amphetamine

Etc

and the crash that we're referring to is

a drop in mood increase in lethargy

feelings of lack of motivation many

people have wrongly assumed that the

crash was due to quote unquote depletion

of Serotonin or depletion of dopamine or

maybe even death of serotonergic and

dopaminergic neurons and while certainly

that could be the case it's very

unlikely that that would be the case in

the immediate 24 or 48 hours after MDMA

ingestion

that said you will see protocols that

people put out on the internet such as

oh you know after taking MDMA you should

take a bunch of you know 5-HTP or other

precursors to serotonin or dopamine

which come in amino acid forms so

L-tryptophan for instance is the

amino acid precursor to serotonin it's

in the serotonin synthesis pathway

you'll hear that people will take

l-tyrosine which is the amino acid

precursor to dopamine as a way to try

and buffer or increase dopamine during

the so-called period of the crash

there's really no evidence that any of

those things can be beneficial and there

is actually some reason to believe that

it might be detrimental because if

anything taking L-tryptophan and taking

l-tyrosine would actually further

deplete serotonin and dopamine so the

logic there is simply not very good what

is clear however is that MDMA can cause

not just profound increases in dopamine

serotonin and oxytocin but that anytime

there's a big increase in dopamine there

is going to be a post-dopominergic

increase in prolactin release and

prolactin is a hormone sometimes

considered a neural hormone but it's

really a hormone that's involved in a

lot of things milk let down in lactating

women it's involved in setting the

refractory period to sexual arousal

and erection and ejaculation in males

after ejaculation it's involved in lots

of different functions in the brain and

body including the laying down of body

fat stores and it's also associated with

increases in lethargy decreases in

dopamine this is why drugs that increase

dopamine are known to decrease prolactin

at least in the short term this is wise

drugs like cabergoline for instance that

increase dopamine are used as ways to

suppress prolactin now MDMA ingestion is

known to dramatically increase prolactin

and people are starting to realize that

it perhaps is the increase in prolactin

that occurs both during and for some

period of time probably hours or days

after ingestion of MDMA that leads to at

least some components of the so-called

crash that feeling of lethargy and lack

of motivation maybe diminished mood Etc

and for that reason some people have

started to explore the use of things

like p5p which is essentially a

metabolite of vitamin B6 which is known

to suppress prolactin

as a way to try and buffer some of that

crash to my knowledge there are no human

data yet exploring the use of p5p or

other vitamin B6 derivatives or

capergoline or things of that sort to

reduce prolactin in a controlled

standardized clinical trial kind of

manner but I've spoken to some of the

clinicians that are using MDMA legally

within the context of the treatment of