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

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 molly.

MDMA stands for Methylene Dioxymethamphetamine.

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 Dioxymethamphetamine,

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 impathogen.

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 achieving incredible early results

in clinical trials for its use as an impathogen

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

of 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.

Well, you will also of course talk about the results

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 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.

So 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.

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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 Shulgen,

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 Shulgen 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 Shulgen 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 mescaline 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 Shulgen

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 PECOL

that stands for P-I-K-H-A-L.

PECOL is the title of the book,

which Shulgen 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.

PECOL 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.

And 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, et cetera.

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 Peacall 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 dioxide, methamphetamine,

but unless you're a chemist,

that's not gonna 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 Vivants,

which basically are either combinations of amphetamines

or single type 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,

it 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 buton, okay,

axon is the wire component of the neuron

that can reach to another site in the brain

and then release the neurotransmitter

or neuromodulator there.

At those axonal butons, 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

or 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 and 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 back up 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 monomine transporter for serotonin.

And in doing so, it leads to a big buildup of serotonin

in the 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 amphetamine

such as Adderall, Vyvance, et cetera,

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 release

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.

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, et cetera.

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 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 prosocial 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, as you can imagine,

could be very beneficial for the treatment of PTSD.

Okay, so hopefully the way I described 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,

and 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 its chemical basis, et cetera.

You can find that like all episodes at hubermanlab.com.

I also did an episode with expert guest,

Dr. Robin Carthardt-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 5-HT2A,

or serotonin, 5-HT just stands for serotonin,

5-HT2A 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-methyldiaspartate 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 anactogen,

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 this serotonergic component

that makes it an empathogen or an anactogen.

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

than the big increases in serotonin

that 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.

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.

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 understand,

but one of the key things that quality MDMA therapy consists

of is not just having a very good rapport

and communication with the therapist

that's guiding the PTSD treatment,

but also rapport and a willingness to engage

in conversations with oneself.

And 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 Conti,

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 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 therapist

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

for 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 they're in to be able to explore new possibilities

to essentially rewire their relationship to that trauma.

So I promised that a little bit later,

we'll talk about 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?

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So in 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 resting 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.

What we're thinking about ourselves,

this may come as no surprise,

but if you're just sitting there on the bus

or 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.

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 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 has taken 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.

There are even studies, believe it or not,

on the effects of MDMA in cephalopods.

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.

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 self-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 playful experiment

just done 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 what I consider very beautiful work

of Harriet DeWitt.

Harriet DeWitt runs the Human Behavioral Pharmacology

Laboratory in the Department of Psychiatry

and Behavioral Neuroscience at the University of Chicago.

And 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 rating 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, et cetera.

So everything from a grin to a smirk to a giant smile,

everything from a sort of, you know,

somebody looking a little bit of scance 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, et cetera,

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 100 kilogram person,

there'll 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.

Somebody 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 one 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 wellbeing or lack of wellbeing

for everything from our skin inward.

Okay, so that's interoception.

You actually can interocept now,

even though you're always interocepting a little bit,

you can interocept 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 interoceptive 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 interoception.

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 interoception and it is distinctly different

from exteroception, 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 exteroception.

The insula is a brain area

that is absolutely critical for interoception,

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 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,

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 interoception,

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.

It 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 10 for that person.

Are you, these things are normalized

for a particular person.

And then after taking MDMA and doing PTSD therapy,

it was five out of 10 or four out of 10.

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 eight out of 10 to seven out of 10

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 PTSD 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 insula,

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

of oh, this brain area is active or less active over time.

And 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% of people out there.

However, it's also important that 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

I did on psilocybin and the guest episode

with Dr. Robin Carthart Harris.

Those episodes, like all other episodes

of the Huberman Lab podcast can be found

at hubermanlab.com.

It's a fully searchable site.

You can put keywords into the search function.

It will take you to specific timestamps.

Every episode is timestamps.

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 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

Carthart 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 dosages 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.

Now translate to English, what that means is that

during the MDMA session, people report feeling

less threatened, more prosocial 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,

prosocial 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 wanna 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 prosocial 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 Prosocial 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 mesolimbic 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 in so far as the effects of MDMA

and which neurochemicals are involved is concerned.

So what they found in this 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 antagonists 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 Vivance 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 wanna learn about mesolimbic 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,

forsake of motivation, et cetera.

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.

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, et cetera.

And what they find is that it really is the activation

of the serotonin 1B receptor in the nucleus accumbens

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 realized 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 gonna get all of that stuff.

In fact, we have to go back to our understanding

that 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, the 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 is very profound.

It dramatically reduces one's tendency

to engage in social interaction.

So this really speaks to the polypharmacology,

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 Phloxatine, Prozac, as well as Zoloft,

and of course, there are many other SSRIs out there,

Citalopram, et cetera,

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 prosocial

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 prosocial, et cetera?

Well, that speaks to the complexity

of all this polypharmacology 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 prosocial

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 at 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 worn off.

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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 neurohormone

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 a 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 neurohormone.

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, et cetera.

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 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 this 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

or 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 endpoint 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, et cetera.

And they looked at how social people felt.

They looked at how insightful people felt.

And the key takeaway from this 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 prosocial 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.

We're 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, et cetera.

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, increased empathy,

or the longstanding changes in neural circuitry

that underlie, for instance, reduced threat detection

or reduced connectivity between threat detection centers

of the brain and interoception.

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 went way up.

It 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, 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 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,

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 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 prososciability and empathy.

I think the bulk of the data really point 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 busts.

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%,

maybe even 80% 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 them 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 small

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 mycer 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.

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, et cetera.

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 illegal as well as people

such as the Sasha Shulgens 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 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 US Congress.

So, you know, there were some connotations

or rather there were some strong suggestions

that there was a political backing

to try 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 publish 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 one 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, 40 times, 200 times, et cetera, et cetera.

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 it on 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 200 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 compounds,

certain drugs, 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,

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,

as 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 60, 60 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,

poorer 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, et cetera,

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, et cetera.

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 and rats and non-human primates,

the retraction of the study in non-human primates

would show that the primates that showed neurodegeneration

were not given MDMA as was thought by the researchers,

but rather as later was acknowledged,

were 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 is 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 and 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.

Talk about sympathomimetics and what that means

in the episode on Adderall and Vivance and ADHD.

But basically it's ramping up the activity

of the sympathetic nervous system

which is your fight-or-flight system.

This is why people who take these drugs get big pupils,

big pupils of the eyes.

This is why they feel agitated, they wanna talk a lot,

they feel like they wanna move a lot.

This is why people take it to dance at raves, et cetera.

But when people take sympathomimetics,

whether that'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 preoptic 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 Huberman Lab Podcast on deliberate cold 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 gonna 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 counterarguments

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 polypharmacology,

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 wanna 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 wanna 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,

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, et cetera.

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 have put out on the internet,

such as, oh, after taking MDMA,

you should take a bunch of five-HTP

or other precursors to serotonin or dopamine,

which come in amino acid form.

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-dopaminergic increase

in prolactin release.

And prolactin is a hormone,

sometimes considered a neurohormone,

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 why drugs like cabragoline, 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, et cetera.

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 cabragoline 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 PTSD.

And this is an area that's starting

to receive some additional attention.

So I just mentioned it briefly here

because for instance, there's a lot of ideas out there

that people should be taking L-triptophan,

they should be taking L-tyrosine,

they should be taking magnesium,

other things, et cetera,

after taking MDMA in order to recover

from the post-MDMA crash more quickly.

But it's really the increase in prolactin,

which speaks most directly

to the subjective effects of the so-called crash.

So by my read of the mechanisms of MDMA,

the neurochemicals it releases,

the neurohormones that it promotes

the release of prolactin in particular,

this P5P suppression of prolactin

is perhaps the one that's most intriguing

and that really has any kind of mechanistic basis.

So I promise that going forward

as the scientists and clinicians that are using MDMA

for the treatment of PTSD and other conditions

such as alcohol use disorder, et cetera,

start to explore the use of post-MDMA session P5P

and other modes of suppressing prolactin

for the hours and days after MDMA,

promise to update you on those findings.

Throughout today's episode,

I've been referring to clinical studies,

that is clinical trials,

exploring the use of MDMA

in order to augment treatment for PTSD.

So let's just take a moment

and talk about what PTSD is.

PTSD is post-traumatic stress disorder.

Trauma is anything that modifies the brain

to function less well going forward.

You can have physical trauma,

you can have emotional trauma.

Typically PTSD is used to refer to emotional trauma

caused by either single events.

So you can imagine car accident, sexual assault.

These can be first-person experiences.

So things that happen to somebody

that leads to trauma and then PTSD.

These can also be third-person events

where someone observes something that is traumatic to them.

Maybe somebody being killed, dismembered,

any number of different things

that could be very traumatic in the immediate and long-term.

And of course, PTSD need not be caused

only by single event traumas,

but by multiple event traumas,

entire relationships, entire childhoods,

wartime experiences,

combinations of different traumas, and on and on.

There are so many different forms of trauma.

If any of you are interested in trauma and its treatment,

I highly recommend the book Trauma by Dr. Paul Conti.

He's an MD, medical doctor, psychiatrist.

He was featured as a guest on this podcast.

He's been on a number of other prominent podcasts.

We will provide a link in our show note captions

to the book Trauma.

I consider that book to be the best book

in terms of describing what trauma is and isn't

and how it leads to PTSD.

It also describes some of Dr. Paul Conti's own experiences

with trauma and his own treatment of trauma

in his patient population,

which is quite wide-ranging men, women, young people,

older people, and a variety of traumatic experiences.

So excellent book for those of you interested in trauma.

Now, the treatment of trauma has been met

with some degree of success through quality talk therapy.

Let's define quality talk therapy

in the way that Dr. Paul Conti did on this episode.

That's talk therapy for which the patient

sometimes referred to as the client,

but more traditionally referred to as the patient

and the therapist.

So a psychologist or psychiatrist has good rapport.

And as a consequence of that rapport,

there is the feeling of support,

that there is a safe place in which to explore the trauma

and what's happening in one's current life

in order to understand how that trauma is fitting in

to adaptive and maladaptive behaviors and emotional states.

Now, in addition to rapport and support being critical,

there's a third component of effective talk therapy

for trauma, which is insight,

where one's ability to come to an understanding

of why one feels the way they do,

and to link that to some larger context

that brings about some degree of relief.

And that's where things start to get a little bit abstract.

And that's also where we start to see that

while trauma therapy in the form of talk therapy

can be very effective,

about half of people that undergo talk therapy

and talk therapy alone for the treatment of PTSD

achieve no long lasting relief of symptoms

and an even smaller number of them

undergo complete remittance of their PTSD.

So their symptoms can lessen,

they can get some improvement,

but that improvement is often slight or is transient.

And for those that do achieve relief,

it's often not complete remission of the PTSD itself.

Now, in addition to talk therapy for PTSD,

there is of course prescription drug therapies.

And most often these fall under the category of SSRI,

selective serotonin reuptake inhibitors.

And it's well known that SSRIs can be

in limited circumstances,

effective for the treatment of PTSD.

It has been shown, for instance, that as many as 40,

maybe as many as 60% of people that take SSRIs

for the treatment of PTSD get some symptom relief.

Now, that is not to say that SSRIs don't have side effects.

They can have side effects.

Some of you are probably familiar with these side effects.

Things like blunting of libido,

blunting of appetite or increases in appetite,

in some cases disruption of sleep wake rhythms,

motivation, et cetera.

So there's often an exploration

for the so-called minimal effective dose

that provides some symptom relief to PTSD,

but that doesn't introduce unwanted side effects.

And of course, there's a third situation

where people are taking SSRIs

and doing talk therapy for PTSD.

And what's very clear is that anytime you add quality

talk therapy to a drug treatment,

you're going to improve the outcomes

for that drug treatment.

The reverse is not always true.

It's not always the case

that adding prescription drug treatment

to talk therapy improves outcomes for talk therapy,

although that has been observed in a number of studies.

Now, the whole idea of exploring the use of MDMA

for the treatment of PTSD stemmed from the fact

that even in people who are getting quality talk therapy,

and again, we can define quality talk therapy

as good rapport between patient and clinician,

as well as feelings of support,

as well as potential insight.

And even when SSRIs are combined

with that quality talk therapy,

there's still a large number of people

who simply do not achieve significant

or long lasting relief from their PTSD,

and even fewer number who go into full remittance

of their PTSD.

That is despite being diligent

and hardworking in their talk therapy,

despite the therapist being very committed,

despite the use of SSRIs in conjunction

with that talk therapy,

those people often still qualify as having PTSD.

And the goal, of course, is for somebody

to receive treatment that allows them

to no longer meet the criteria for having PTSD,

not just in terms of a clinical evaluation,

but that they themselves report feeling much better,

not feeling overwhelmed with the symptomology of PTSD.

Now, the symptomology for PTSD is vast,

and it's far too vast to go into a lot of detail right now.

I think most people are familiar

with the stereotyped example of PTSD.

This is the soldier that comes back from overseas

that has been in gunfights or in battles of different kinds,

has likely seen casualties and severe injuries,

and that upon return to a safe environment,

is still experiencing a lot of anxiety

and sometimes panic attacks that occur seemingly at random,

or that can be sparked by the classic stereotyped example

as a car backfires and then the person

suddenly feels as if they're back in battle.

That sort of thing does happen, certainly,

but there are a whole other category of symptoms of PTSD,

which include dissociative symptoms of PTSD.

People who have PTSD from very intensely traumatic

experiences that are checked out,

they don't feel like they can engage,

they have brain fog, they are distracted,

they go from feeling anxious to feeling exhausted,

they have sleep issues, not surprisingly then,

people with PTSD of either the dissociative type

or other symptomology of PTSD,

and keep in mind that one can have both dissociative

and non-dissociative symptoms of PTSD,

such as anxiety and panic,

are at a far greater risk of substance abuse.

So the current estimates are that people with PTSD,

no matter what type of PTSD, dissociative symptoms

or otherwise, you know, panic attacks or both,

are at a much greater risk of having addictions

to either illicit drugs or prescription drugs or both.

So things like alcohol use disorder is very common

in people with PTSD, opioid use disorder is very common,

stimulant use disorder, and on and on.

So people with PTSD suffer at a number of different levels

and there are all these what are called comorbidities

with PTSD, including addiction,

but also depression, anxiety,

and so you can start to see how PTSD sets up

a whole cascade of things that make

living life extremely problematic

at the level of basic relationships

functioning in the workplace.

And even when mental health appears to be in check,

oftentimes people are holding a lot in,

so they have cardiovascular and cerebral vascular deficits

that cause a lot of problems in their immediate

and long-term physical health.

So PTSD is a very serious issue.

The current estimates are that as many as 8% of people

in the United States have PTSD,

and again, the estimates around comorbidities

range anywhere from, you know, 17 to 46

or as high as 65% of people with PTSD having comorbidities

for other mental health issues and addiction in particular.

So finding lasting relief to PTSD is extremely important

and made even more important by the fact

that many people with PTSD sadly end up committing suicide.

So suicide rates are far greater in people with PTSD.

The exact rates of increase in suicidality

in people with PTSD are a little bit hard to arrive

at in the statistics because of all the comorbidities,

but suffice to say that suicide is far more likely

in people with PTSD along with all the other issues

that PTSD brings about.

Now PTSD creates all the problems that it does

largely through changes in brain circuitry

as well as neural communication between the brain and body.

Many people have perhaps heard of the book

The Body Keeps the Score, which is a very successful

and popular book about the idea that trauma can be

quote unquote stored in the body.

To be clear, traumas can't actually be stored in the body.

You don't actually store memories in the body.

What you store are activation of neural circuits

that include brain and body,

and they all seem to center back into the insula,

that structure that we talked about earlier,

this structure in our brain

that has a map of our body surface.

So contrary to popular belief,

we don't store memories in the body or trauma in the body

in a way that for instance, working out a knot

or a pain in one's lower back will relieve the trauma.

It sometimes can activate a memory of the trauma,

but when one is doing that, what you're really doing

is activating neural circuits that reside within the brain,

within the insula that correspond

to sensations within the body.

Now, I don't want to diminish the role of the body

and the formation and the persistence of PTSD.

And I certainly think the book The Body Keeps the Score

is a pioneering book, it's in fact an important book,

but I want to emphasize that the modern neuroscience

really points to the fact that PTSD is caused

by the exact sorts of brain network activations

that we were discussing earlier.

Things like heightened levels of activation

in the amygdala to insula pathway,

which of course would exacerbate bodily sensations

related to the trauma or heightened activation

of the hippocampus, this memory center in the brain,

to amygdala to insula circuitry.

Now, therefore it should come as no surprise

that if MDMA can reduce the levels of activity

in the hippocampal to amygdala to insula circuitry

and can do so both while someone is under the effects

of MDMA, but then lead to persistent long lasting reductions

in the activation of those brain networks.

Well, then it stands to reason that MDMA could be

a valid therapeutic for the treatment of PTSD.

And of course, this has been explored.

And here we can really give a nod and a large debt

of gratitude to the so-called maps group.

The maps group is a group that's operating mainly

out of Santa Cruz, California, but they have a number

of different satellite laboratories and clinical groups

both in the US and Canada and abroad,

where they've worked with government organizations

to get legal authorization to give MDMA to patients

who have PTSD to also give them talk therapy

and then to compare the effects of talk therapy with MDMA

to talk therapy with placebo alone.

And there are about three to five studies in this area now

that stand as large scale clinical trials

that are showing what can only be described

as remarkable results for the treatment of PTSD.

So rather than going to any one of those studies

in immense detail, I'm going to summarize across those studies.

I will provide links to those in the show note captions.

The two that I think are most interesting

are the study entitled MDMA assisted therapy

for severe PTSD, a randomized double blind placebo controlled

phase three study, as well as the study entitled

the effects of MDMA assisted therapy on alcohol

and substance use in a phase three trial

for the treatment of severe PTSD.

So as the title suggests, both clinical trials

involve giving people talk therapy and MDMA

or talk therapy and placebo.

Talk about exactly how that was done in a moment.

And then to look at relief of PTSD symptoms,

but also relief of some of the addictive symptoms

that are commonly associated with PTSD.

So just to give you an overview of what's happening

with these trials and why there's so much excitement

and why we really are on the cusp of legalization of MDMA

for the treatment of PTSD

in the sorts of clinical context I described.

When people are given just talk therapy alone

or talk therapy with SSRIs, they will often,

as I mentioned earlier, experience reductions

in their severity of PTSD symptoms.

And rarely they will experience complete remittance

of their PTSD.

That is they will no longer qualify for PTSD

after receiving a number of talk therapy sessions.

So let's compare that to what happens

when people do talk therapy in conjunction with MDMA.

And I'll explain exactly what that means in a moment,

but it essentially means taking MDMA while doing talk therapy.

However, this is a very important, however,

the people who are taking MDMA in these trials

have already done talk therapy without MDMA.

Then they're doing talk therapy under the influence of MDMA

and then they are doing sessions of talk therapy,

not under the influence of MDMA.

And the entire time they're doing that

with the same two therapists.

In the placebo group, people are doing talk therapy

with two therapists, but they're not taking MDMA.

So they're doing the same number of therapy sessions,

but they're not taking MDMA.

So to just get to the key numbers first,

the overall rate for clinically effective response

to MDMA assisted therapy is 88%.

That's what's emerging from these trials

versus 60% for the placebo and therapy alone.

So on the face of it, you might say, okay, wow,

88% of people who do talk therapy,

and here I might as well just finally explain

how this is done.

Patients are selected because they have PTSD.

They meet the clinical criteria for PTSD.

They do three 90 minute therapy sessions with two therapists

talking about their PTSD symptoms,

talking about to the extent that they can,

or incidents, the life events that led to that PTSD.

None of that is done under the influence of any drug.

Okay, so everyone in the experiment does that.

Then the group divides into two

where half are taking MDMA.

They take that three times.

During those three times, they are also receiving

therapy sessions with the same therapists

that they were working with before they took MDMA.

The first session, they're taking 80 milligrams of MDMA

and then a 40 milligram booster

about an hour and a half to two hours in.

The second session, they are taking a higher dose of MDMA.

It's 120 milligrams.

And then if they elect to,

they can take a 60 milligram booster

about an hour and a half to two hours into the session.

And then there's a third session where they take,

again, 120 milligrams of MDMA

and have the option to take a 60 milligram booster

about an hour and a half to two hours into the session.

Again, anytime they're on MDMA,

they have therapists there

that they're talking to about their trauma.

They are either spending time

with their eyes closed lying down,

sometimes in an eye mask and thinking about the trauma,

thinking about their current state and experience,

also thinking about what happened before,

then they're exiting the eye mask

or talking to the therapist.

Therapist is taking notes, asking questions.

Remember, they've established a strong rapport,

supportive relationship with these therapists

prior to taking MDMA in the therapy session.

And then they also undergo three 90 minute therapy sessions

with the two therapists spaced one week apart

after the final MDMA session.

Now, those that were placed into the placebo condition

do everything exactly the same as I just described.

So three 90 minute sessions as prep,

then three eight hour sessions with those two therapists

and then three 90 minute follow-up sessions one week apart,

but they take a placebo, not MDMA.

So you can see that in these so-called MAPS studies,

these clinical trials for PTSD,

the conditions are very similar

except for the inclusion of the drug MDMA.

So those rates of success with talk therapy and MDMA,

again, overall rate for clinically effective response

to MDMA assisted therapy was 88% compared to 60%

for therapy and placebo.

What's even more impressive, however,

is that 67% of the people in the MDMA

plus therapy treatment group,

no longer met the criteria for PTSD

by the end of the treatment.

So in other words, their PTSD went into remittance.

We could say they are quote unquote cured,

but typically for things like PTSD,

that's not the language that's used.

Rather what's used is statistical evaluation

of how the different symptoms like dissociation

or anxiety or sleep disorders are explored.

So while to some of you,

a difference between 60% success with talk therapy

and placebo versus 88% success with talk therapy

plus MDMA might not seem like that big of a difference.

It is indeed quite an enormous difference.

In fact, to my knowledge,

there is no other example of a treatment

for a psychiatric disorder

that is successful to the same magnitude.

I could be wrong about that.

I'm sure some psychiatrists out there

are gonna jump on me about this.

And please do, I would encourage you

if you are aware of any therapy plus drug treatment

that is effective at rates of greater than 88%

for the treatment of a major psychiatric disorder,

please do put that information in the comments on YouTube

and perhaps a reference to a study would be even better,

but even if not, just put a reference to that.

That would be great for sake of future episodes, et cetera.

But nonetheless, an 88% success rate,

and here I'm referring to success rate

as a significant reduction in clinical symptoms for PTSD

and 67% of those people going into full remittance for PTSD

by the end of the treatment is pretty spectacular,

which is why you're hearing so much these days

about the potential transition of MDMA

from a schedule one drug for which there quote unquote,

no clinical applications to potentially a legal

within the context of clinical use application of MDMA,

which it does appear the legislature

is at least considering for as early as 2024,

maybe even later in 2023, it remains to be seen.

Now, a number of other important results have emerged

from this and other clinical trials.

For instance, remember earlier,

I talked about how many people with PTSD also suffer

from alcohol use disorder.

What's interesting is that for people

that were in the MDMA plus talk therapy group

in this and other studies who also had patterns

of alcohol use disorder

and even some other substance use disorders,

the MDMA plus talk therapy treatment in many cases

resolved their addiction to alcohol

or other symptoms as well.

And perhaps that shouldn't be surprising

if we think about the addictions as stemming directly

from their PTSD, but it is surprising

if you think about the fact that alcohol use disorder

and some other addictive disorders oftentimes will stem

from disruptions in neural circuitry

that are the same disruptions in neural circuitry

that occur in PTSD, but often are the consequence

of entirely other brainwiring phenomenon.

What I'm saying here is that just because addiction

and PTSD are often comorbid with one another,

it was not necessarily the case that treating

and resolving PTSD would resolve the alcohol

or substance abuse disorder.

And yet that seems to be the case often, not always

but often in these successful treatments of PTSD.

So that's very exciting.

Some of the other particularly exciting results

from these clinical trials on MDMA plus talk therapy

is that the dissociative form of PTSD

has traditionally proved to be especially hard to treat.

And that's thought to stem from the fact

that successful treatment of PTSD,

whether or not it's by talk therapy

or talk therapy combined with SSRIs

or talk therapy combined with any drug treatment

or behavioral treatment like EMDR,

eye movement desensitization, reprogramming

or other forms of treatments that are designed

to rewire neural circuitry almost always involve

the patient getting very close to

or at least reporting the traumatic experiences

in a lot of detail.

And you can imagine why for somebody who's dissociating

from that very experience who's quote unquote checked out

and can't really seem to access the emotional states

and the memories because they're blocked off from them

or because they're unwilling to access those memories

and really think about the full emotional capacity

of those memories that it would be particularly hard

to bring them through any kind of treatment for PTSD.

So it appears that MDMA in providing this pro-social empathic

again empathic for others and empathic for self

chemical and mental environment

as well as the presence of two trusted therapists

which one has a really good rapport

allows patients with PTSD to really get close

to those experiences that were traumatic

to talk about them and to think about them

and in many ways to reframe them in a context

that often involves empathy for others and empathy for self.

Now here we're not necessarily talking about

forgiveness of perpetrators

although that's sometimes the case

that people will forgive the person

that inflicted the trauma on them.

But more often than not it's about tying their feelings

of trauma and their feelings of depression,

anxiety, dissociation, et cetera

to some sort of larger context that allows them

to see themselves in the role of agency

to be in the role of knowing that yes, these things happened

and yet by getting close to the emotional load

of those things and really being in many ways

unafraid to get close to the emotional load of that

and having support around that

that the emotional load seems diminished

and that they experienced the emotional load

of those experiences as diminished

both within the MDMA treatment session

and afterwards for long periods of time.

So essentially what happens is these people feel

that once burdened them, they can still remember

but it no longer burdens them.

It no longer feels like it's in their body

and in their mind or on loop or on repeat

in a way that's invasive and in a way that interferes

with other aspects of normal functioning.

So when one hears about these kinds of results

and when you hear about some of the patient reports

and I invite you to do that, you can go to the map site

which by the way is recruiting subjects

for these clinical trials and you'll also find reports

of individuals who participated in these clinical trials

and of course we will provide links

to these incredible clinical trials

that maps has spearheaded.

What you find is that the combination of MDMA

and talk therapy in many ways is not about the drug

having a particular effect.

It's really about the drug having a particular effect

that allows the motivations and the results

of talk therapy to really be heightened.

And I think that's a really key point to make

because up until now we've really been talking

about the neurochemistry of MDMA,

the potential toxicity or lack thereof of MDMA.

We've been talking about the brain networks, et cetera.

But when one thinks about the valid clinical use of MDMA

for the treatment of PTSD and I should mention

it also had some success in dealing

with not only alcohol use disorders

and other use disorders associated with PTSD

but also relieving the depression associated with PTSD.

So now MDMA is being explored for treatment

of not just PTSD but also for depression,

for alcohol use disorder and for eating disorders as well.

MDMA seems to be a compound that produces

the right kind of subjective and neurochemical milieu

in the brain that allows therapy to be that much more potent

within a limited number of sessions.

And when one thinks about the cost of mental healthcare,

how expensive it is to get therapy over and over

and over again, which in ideal circumstances

people are able to do that either by way of insurance

or by their own finances or I don't wanna say

that the cost of therapy should be reduced

because of course therapists have to survive also.

But the idea here is that people who are suffering

would be able to achieve relief from their PTSD,

their depression, their addiction and to be able to do so

by hopefully persisting in their therapy

over whatever period of time is required.

But also to assume a circumstance in which somebody

only has 10 or 15 or maybe even just three opportunities

to undergo treatment for PTSD and nonetheless

is able to achieve tremendous relief during the session

and after the session.

And it really does seem to be the case

that for reasons that you now understand,

the activation of particular brain networks,

the suppression of other brain networks,

in particular this amygdala to insula pathway

that when people are under the influence of MDMA

in these very safe and therapeutic supportive settings,

they're able to look at traumatic events

and the ways that those traumatic events impact them

in ways that really allow them

to cognitively reframe those events

and somatically reframe those events

to really change the way that it lives in their body and mind

so that it's no longer invasive

and then they can go on and lead productive adaptive lives.

And as a final point related to these clinical studies,

I of course it would be remiss

if I didn't touch on some of the so-called adverse effects

because anytime there's a drug or talk therapy

for a mental health issue,

adverse events have to be considered.

And I think it's quite reassuring

that in the case of MDMA therapy,

there were no increases in the number of suicide attempts

or suicidality or obsession with suicide.

Contrast that with the group that received placebo

where there were a certain number of baseline

and predicted obsessions with suicide.

Fortunately, at least to my knowledge,

there was no actual suicide attempt

or successful suicide, thankfully.

But the point being that the addition of MDMA drug therapy

to PTSD talk therapy does not seem to increase

the quote unquote side effects

that are sometimes associated with PTSD talk therapy

because indeed there can be side effects

to exploring PTSD and trauma as one would expect.

So overall, I would say it's very exciting times

for the exploration of MDMA as an augment to talk therapy

for the treatment of PTSD and these other conditions.

Again, I think the maps group has done a remarkable job

of keeping this within the realm of legal

and trying to move things forward in terms of legislation

to make sure that MDMA isn't simply made legal

and then abused recreationally.

I know people out there have different views

on whether or not drugs like MDMA should be legal or not.

That's not what this episode is about.

What I am very excited about, as you can probably tell

and what I think a lot of people in the psychology

and psychiatry community are very excited about,

you say the mental health community at large

is that these compounds that for many years

were only associated with their recreational uses

and therefore were not well understood

because they were often contaminated

or taken in combination with other things

or by people that never should have been taking them

in the first place, taken by young kids

which is a whole other matter.

A lot of issues and problems associated with these compounds

and yet we're now seeing from these clinical trials

when used, let's say properly

because really when safety protocols are obeyed,

when there's clinical support,

it is very clear that when MDMA is combined

with quality talk therapy

that the outcomes are looking tremendously positive.

It's by no means a miracle cure,

it is by no means perfect and time will tell

what problems if any arise

from the short or long-term use of MDMA in this context

but I think it's remarkable that anywhere

from two to three sessions with MDMA and talk therapy

have been shown to significantly reduce PTSD symptoms

and in some cases completely eliminate PTSD symptoms

in such a wide range of patients

and in patients that have experienced both PTSD

and these other comorbid disorders.

I think it's really remarkable, it's very exciting

and I look forward to seeing

what the next round of data produce.

So as is often the case on this podcast,

today we went into a lot of detail about a subject.

MDMA is this incredible compound synthesized

as far as we know, first by humans, not by plants,

not by aliens but by humans

and that produces big increases in dopamine and serotonin

to create these highly motivated prosocial empathic states

meaning both empathy for others and for self

and that when applied in the context

of psychiatric challenges like PTSD and addiction

is proving to create a lot of relief

for a lot of people where other forms of drug therapy

or combination drug and talk therapy had failed before.

We talked about some of the potential neurotoxicity issues.

I don't think that is a resolved issue just yet

although the bulk of data in humans

and non-human primates point to the fact

that at reasonable doses

and we talked earlier about what those are

at reasonable doses when not combined with other drugs

does not appear that MDMA is exceedingly neurotoxic

and it may not be neurotoxic at all.

Of course, one needs to be exceedingly cautious

when thinking about the use of any sympathetic,

they of course can be neurotoxic,

anything with methamphetamine in it

has the potential to be neurotoxic

but of course dosage matters, context matters,

we talked about that and of course

the purity of drug matters.

And again, I just wanna reemphasize

the fentanyl contamination of MDMA that's sold on the street

and that is being used recreational

is of very serious potentially lethal concern.

I also expect that there will be a lot of interest

in these clinical trials that MAPS is doing.

So again, you can find links to that

in the show note captions.

And I think in general, we should acknowledge

that we are a very interesting and important time

in human history for the treatment of psychiatric disorders

and for neuroscience generally

because whether or not we're talking about psilocybin

or LSD or ayahuasca or ketamine

or today's topic of MDMA,

regardless of what drug and neurotransmitter

and modulator systems are involved,

what we're really talking about

are ways to access neuroplasticity,

the nervous system's incredible ability

to modify itself in response to experience,

ideally to be modified in adaptive ways

that make it function better.

So that's really the crux of what talk therapy

and drug therapies are about.

That's what the goal of using MDMA

as a clinical tool is all about.

And in that sense, I find MDMA to be

an incredibly interesting and important topic.

And I hope you did as well.

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Machine-generated transcript that may contain inaccuracies.