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 methylenedioxypyrovalerone feta mean,
that's right. You heard the word methamphetamine in there and
MDMA has properties similar.
ER 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 methylenedioxypyrovalerone fetish
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
Linked from Pure stimulants such as methamphetamine, because MDMA by producing big increases in both dopamine and serotonin acts as what's
called an empath Aegean. 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.
Clinical trials for its use as a name pathogen for the treatment of PTSD in clinical therapeutic
settings. I want to be
very clear that at this point in time, June 20 23, 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. The 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
about the key difference between recreational use and therapeutic use. And the important components of the studies, exploring MDMA in the clinical setting for the treatment of PTSD. So, during today's discussion, we will talk about what MDMA really is, how it works at the level of neurons, which brain circuits, it activates and deactivates and in doing. So you will come to understand why it is so exciting as a treatment for PTSD. Will you also, of course, talk about the results of these clinical trials using MD
A, 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 in the therapeutic use of
May we will also talk about the toxicity of MDMA. This is a very important issue because many of you have, perhaps heard, the MDMA quote, unquote, puts holes in your brain or kill 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
Is about its toxicity, and its long-term
effects. Both after acute use
meaning, just one to three times as well as
chronic use. Meaning people who have taken it many, many times. We'll talk about the spacing between sessions of MDMA. We will talk about dosages. We will
also talk about things that people do in 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
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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 1900's 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 guy named Alexander. Shulgin, who was a bit of a renegade drug chemist.
Who was designing different drugs for the purpose of understanding, their subjective
effects on humans?
So there's a long history of shulgin, Designing
drugs, he was after all a chemist
and then taking those drugs himself, and then if he liked the effects of a particular drug, or rather, if he thought that it had potential clinical utility, he would give it to his wife, then she would give him her notes about those drugs, and then they would share them with their friends. And it was a small group of
friends, who consisted of therapists and Physicians. So, this was a really underground kind of operation. It was technically not illegal when it started because MDMA wasn't illegal when it started. But over the several decades, that Shogun and his wife, and this group were
doing this, kind of exploration,
MDMA did become illegal, and he fell under. Let's just say scrutiny by the DEA. Now, here's the important thing to understand about MDMA and its history first.
All
MDMA is a synthetic compound as far as we know, it does not exist anywhere in nature. So unlike similar compounds such as mescaline because MDMA and masculine are very similar in their chemical properties, and to some extent, their subjective properties unlike mescaline, which can be found in the plant kingdom or LSD, which comes from her got, 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, shulgin 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 Peak
all that stands for p. Ik h. Eh, l p call is the title of the book, which Shogun
Wrote which describes his discovery of MDMA.
I confess it also describes the
synthesis of MDMA and for that reason, was a book that for a long time was not
available, but is now available again. Inaudible form and in
printed form P, call stands for phenol. Ethel
means I have known and loved phenylethylamine. Ziz, 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,
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 1 drug. 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 our 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.
Neurons, and
loss of serotonergic
neurons, is known to impact mood negatively, mood
regulation, negatively Etc. The story of MDMA and its potential. Neurotoxicity comes slam right up against this issue of legality. And what we'll get into a little bit later is that there has been a sort of race in the scientific Community. Consisting of two groups, one set of groups trying to
establish the toxicity of MDMA so that it does not become legal again.
And another group trying to establish the utility and the lack of
toxicity and MDMA. So that it does become legal again for the treatment of PTSD. So,
even though the story Peak all 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 global.
By below 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 34, methylenedioxypyrovalerone
feta mean, but unless you're a chemist,
it's not going to mean much to you, nor should it MDMA has some very interesting properties. The first of, which is
That methamphetamine component which
because it's a
methamphetamine and acts like other
amphetamines what it does. Is it blocks the reuptake of dopamine from neurons
after dopamine is released.
So for those of you that heard the episode that I did on drugs
to treat ADHD, I discussed the biology and mechanisms of drugs like Adderall
and Vyvanse which basically are either combinations of amphetamines or single types
of amphetamines that have either a quick release or a long release.
Now
MDMA because it has this methamphetamine component prevents the reuptake of dopamine and in doing so creates net
increases in dopamine. So for those of you that don't have a background in neurobiology, let me just briefly explain all 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
Spiracle
balls which we call vesicles or vesicles depending on where in the world you live. They'll either be called vesicles or be
signals. And those little vesicles containing neurotransmitter or
what's technically referred to as a neuromodulator dopamine is a neuromodulator can modulate the activity of other neurons. It can either increase or decrease the activity of other neurons. Now, at the end of the neuron, that what we call the axonal Bouton. Okay. Axon is the
wire component of the neuron that can reach to another side in the brain and then release the
Neurotransmitter a neuromodulator there at those axonal Bouton, which are the sites of release. The vesicles, literally fused with the edge of the neuron and vomit their neuromodulator out into the synapse. And then the
neuromodulator 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 a 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 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
Years 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
Two 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 it, just a bunch of different ways to describe increases in dopamine. Okay, so
that's the main way that MDMA
and by extension methamphetamine increased
dopamine. However, MDMA is not just methamphetamine, it's methylenedioxypyrovalerone feta mean 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 Ser, TS has 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 monoamine, transporter, for serotonin and in doing so leads to a
Big build-up 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, Vyvanse, Etc, that cause increases in dopamine by blocking reuptake and increasing release of
dopamine. MDMA does that, but it also does the same thing for serotonin and here's a really key point.
The increases in serotonin that MDMA creates are at least three times, and maybe as much as eight times greater than the amount of
dopamine 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. N 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 seemed to be potentially clinically very beneficial effects of having people feel a lot of mood elevation and a lot of
Of stimulation from the stimulant properties of the methamphetamine component. A, so, that's the dopamine effect, the dopaminergic tone goes way up. So, it's a, stimulant people feel really alert. They feel like talking a lot. They feel very excited. They feel a lot of positive motivation. These are classic effects of drugs that promote the release of dopamine including amphetamine, cocaine, Etc. But ordinarily. That's not such a good thing because what happens is there's then a crash in the dopamine.
Levels, and then people feel depressed, they feel
far Jack, 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
Taken MDMA. Look at faces, that ordinarily. They
would rate as fearful and rate them as less fearful,
they see faces that are smiling and they rate those smiling, happy faces as
more positive than they would off the
drug. The big increases in serotonin, create what we call a pro-social effect. And that combined with the
dopaminergic increase in mood and the
stimulation effect creates this thing that we
call an empath Aegean where and
Is very important that 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 describe the biology of MDMA, make some sense. If you didn't get anything out of the description, I provided except the understanding that MDMA is unusual in that it causes big increases in dopamine and even bigger increases in,
Serotonin,
then you have more
in your knowledge-based. Now about
MDMA. Then 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 it's therapeutic, exploration, and its chemical basis, etcetera. You can
find that like all episodes of huberman, Lab.com, I also did an episode with expert guest doctor
Robin Card Harris. Who's at University of California? San Francisco. Whose 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
resembled serotonin itself and they activate. What's called the 5-ht to a or serotonin 5hd. Just Dance for serotonin, the 5-htt to
a receptor.
After 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-methyl-d-aspartate receptor. Blocker nmda
receptor blocker, that shouldn't mean anything to most of you, but it is a
Associative and aesthetic, 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,
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 empath Aegean, or sometimes called an inactivation. But as an
empath Aegean or an actor Jason it's creating more affiliation, it's affiliative. Okay, so it's a very distinct compound and I think this is important
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
empathic June with stimulant properties and it also has
this serotonergic component, that makes it a name pathogen or an inactivation.
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 in 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
A segmented 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 empathic in component and for reasons that we still don't understand. It seems
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, the MDMA produces seem to act on different receptors. Then the big increases in serotonin
the LSD and
Or Simon 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 seemed to have a more selective activation of just the so called. Serotonin 2A, receptor abbreviated 5-ht to a and that leads to
more interconnectedness between different brain areas more
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
Gives MDMA, it's 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.
Teasing our sense of motivation and desire for something
and to do something. So the increase in dopamine that's created by MDMA seems to make people
what I call forward Center of mass. You know, they want to do something. They're very motivated
to do something. And the
increases in serotonin acting on the serotonin, 1B
receptor seems to be what creates this
desire to bond or
create trust or to have a
discussion of real things, both things that are positive but
also to explore things that are difficult. And
This, I realize it's 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. Yeah, I think that most of us can relate to the fact that we have experiences. Some of which are
Heard, some of which are great and everything in between trauma, is I believe best defined by the words that former guest on this podcast, who is a world expert in trauma Paul, Conte explained, as
trauma is an event that fundamentally changes the way that our brain
works for the worse. Okay.
So not every bad event
of our past is trauma
but events that change the way that we think our emotional tone or our behavior in ways going forward.
Are not adapted 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 or
things. Because oftentimes, trauma can consist of many events. Not just one event.
And the thought, patterns around that in the context, around that and therein to be able to explore new
possibilities to essentially rewire their relationship to that trauma. So, I promise that a little bit later, we'll talk about the direct application of MDMA for the treatment of PTSD,
but now I'd like to shift off of the chemical changes that MDMA
And some of the subjective changes these increases in trust and pleasure and energy and
emotional warmth, 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
Lee
does in the brain both in the short term while someone is under the influence of the drug
and in the long term, what sorts of neuroplastic or rewiring
changes does MDMA produce and how can those be beneficial or perhaps, not beneficial. I'd like to take a quick break and acknowledge one of our sponsors. Athletic greens, athletic greens.
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vitamin D3 k 2. So in order to
Chan. 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
Connected 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 DM, n is the network that is active in our brains when we aren't really attending to anything specific outside us. And we're not trying to think about anything specific or accomplish
anything specific.
It actually relates to our sense
of imagination and daydreaming it has a lot to do with our self-referencing. You know
what? We're thinking about ourselves, this may come as no surprise, but if you're just sitting there on the bus or, you know, around the dinner table, and you're not paying attention to what's going
on in large part, your brain is
in this default mode
Network and you're thinking
about yourself, okay?
So we can get a sense of what the default mode Network activation is, we can get a sense of which brain areas are more or less active simply by putting.
Ting, 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 a one basic.
Paradigm for exploring the effects of drugs, like MDMA on the brain.
The other way that you can explore the effects of MDMA on the brain is to ask people in the general population. Hey, who out there
is taking MDMA. How many times have you taken it? And come
on into the laboratory and we will image your brain and compare people who have, for instance, taking MDMA 0 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.
Sad faces or images of oneself or even images that recall memories of
traumatic events and so on. So, fortunately, all of those sorts of Studies have been done in humans.
And there are also a large number of studies in animal models, exploring how the social activity of laboratory mice changes when they are under the effects of MDMA,
or even studies believe it or not, on
the effects of MDMA. In cephalopod cephalopods include
octopuses as well.
Well, as
cuddle fish 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. So cell Press Journal. Excellent Journal.
This is from Google Dolan's laboratory
at Johns Hopkins. School of medicine showing that if you give octopuses MDMA, they like to spend
More time with other
octopuses than they do, if they are not on MDMA and that might sound like kind of a
of a playful experiment just done
in order to entertain oneself and the octopus is perhaps.
But actually in that study, they identified in 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 octopus is 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 pulling across a number of different studies, but one of the key sets of studies in this area comes
From the what I consider. Very beautiful work of Harriet, DeWitt. Harriet DeWitt runs the human behavioral pharmacology 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.
Ponce's to social threat and social reward. So what this 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 amygdala, Lloyd 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
White threatening, they tend to rate it as less threatening. In addition they tend to respond to happy faces or even slightly. Happy faces as more kind or more generous or happier than they
would when they are not on MDMA.
Again, the faces that are being shown are not of people on MDMA,
that would be an interesting experiment but that's not what they did here. What's
Happening Here is people are being given MDMA and then
they are raiding in a subjective way
the
Venusaur, the level of threat
that they detect in these facial expressions. And of course, they have
extremes of friendly and threatening, but then they
also grade them, right? They titrate them. So that they also have mildly threatening and mildly happy faces. Etc.
So, everything from a grin to a smirk, to a giant smile, everything from a, from a sort of,
you know, somebody looking a little bit askance at somebody
to really, you know, wide-eyed and
looking angry, like, they're, you know, going to attack you and things of that sort.
So,
It'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.
People different ages, different Sexes, so male and female located in different parts of the world, even some with PTSD, something not with PTSD, Etc. There's been fairly tight dosage control of MDMA in these studies. It's not perfectly matched from study to study, but it's pretty darn close which makes interpreting results across studies. A lot easier for me. And therefore for you, the typical dosages of MDMA used in these neuroimaging studies and in the
Clinical studies of PTSD that we're going to talk about later, range. Anywhere from point 75 milligrams per kilogram of body weight to one point
five milligrams per kilogram of body weight. So for somebody like me I weigh 220 pounds. That's 100
mg one point. Five milligrams per kilogram of body weight would therefore be 150 milligrams
in a single dose okay?
A dosage of 1 milligram per kilogram of body weight would mean
100?
G for my 100 kg. Okay, somebody lighter than
100, kg
would obviously take less MDMA in one of these studies,
but in general, the range of MDMA that's been explored is point seven.
Five to one point five 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 one point five milligrams per kilogram of
body weight. So, again for
100 kg person, that'll be 150 mg 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 point, 75 milligrams per kilogram dosages are used. Why
am I getting so into the details of dosages? Well,
if we are going to talk about toxicity of MDMA, we
absolutely have to talk about dosages because like any drug the toxicity of MDMA does scale with the dosage that's applied. Not just, the frequency of MDMA use, we hear a lot about that, you know, someone has taken MDMA
one time or four times or 200 times. We hear about frequency of use. But rarely do we hear
about the specific dosages that are taken in any one particular
session. So when we talk about the subjective effects or the brain Networks,
Are activated. When people take MDMA
in general, we're talking about dosage is somewhere between point 75 milligrams per kilogram of body weight. And one point five
milligrams per kilogram of body weight. Although typically
you're going to see studies, both clinical, and more research
explorative using anywhere from 1 to 1.5 mg of MDMA per kilogram of body weight. So, that's important to highlight. I
told you about the subjective effects of MDMA.
Engaging the
Ponce's 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
Colonel States and our feelings of well-being or lack of well-being, for everything from our skin inward, okay? So that's
interesection you actually can intercept. Now even though you're always interrupting a little bit, you can
intercept now
to a great degree, if you were to, for
instance, close your eyes or simply focus on the contact points between your body and any surface
that you happen to be contacting. So maybe the backs of your legs against a chair or your feet against the floor or the bottoms of your shoes or
sandals. Your
Nervous system is constantly sensing
those contact points
but normally they're not under your conscious awareness unless you direct Your
interoceptive Capacity to them which is just fancy nerd. Speak for saying,
you normally don't notice. What's going on from your skin in word
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 interception and it
Distinctly different from extra reception 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 interception and extra reception.
The insula is a brain area that is absolutely critical for interoception so much so that it has a map of the
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,
then 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, 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 exist 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 one point, five 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 up
Overtime 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 at activated or inactivated or you say okay.
One person at a certain connection between threat centers and the interceptive
centers of the brain was let's say arbitrary units. Let's say was level 8 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 ten or four out of ten
that's a good experiment. But what's far more powerful is to observe that in that
patient or that person
and then to see a change that's perhaps less.
So a shift from eight out of ten 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 all this brain area is active or less active over
time and you know, this person has more or fewer
symptoms of PTSD.
To something that starts to look like a mechanistic and logical framework for
understanding PTSD, as well as the
effects of MDMA. And for understanding, how changes in the
brain underlie relief from
PTSD. Okay? So, again, even if you just could grasp the idea that you have a brain area, the amygdala that's involved in threat detection and it provides inputs to another brain area called the insula,
which is involved in this thing called
interoception, and that reductions in those
connections between the
Ella 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 to 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
Heart Harris. Those episodes like all other episodes of The huberman
Lab podcast can be found at huberman. Lab.com, it's a fully searchable site. You can put keywords into the search function, it will take you to a specific
time stamps, every episode is time stamps.
You can navigate to topics of particular interest to. You
feel free to go there and listen to those episodes about psilocybin. And MDMA by contrast does not seem to produce
long-lasting increases in lateral connectivity between those same brain networks, probably because it impacts a
current 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 Card Harris as the first author. So not only has he done incredible. Work on psilocybin and LSD and DMT and
Ayahuasca in his laboratory, but also on MDMA and the particular
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 it.
Here, the 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, translate to English what that means is that during the MDMA session people, report, feeling, less threatened more pro-social towards others more empathic towards others and themselves.
Elves. And then after the session, they have less of a threat
response to memories that before the session were more troubling and those changes in the brain. Do seem to be pervasive.
So, there are both short term and long term effects of MDMA. All of which point in the direction
of lowered levels of threat
detection. Heightened levels of positivity, pro-social
components of the brain, more active threat detection centers of the brain, less active. Now earlier we talked about MDMA
As a drug that potently increases
dopamine. And even more,
potently increases serotonin largely acting through this serotonin 1B receptor now,
without getting into too many more details before. Moving on to issues of toxicity around MDMA, I do want to touch on what I think is perhaps the finest of the animal model studies of MDMA that explored which brain networks, and which chemical that is serotonin or dopamine is responsible.
For say, the motivational components
of MDMA versus the pro social effects of MDMA. And then it also raises a really important point which I haven't mentioned yet in this episode which is the role of
oxytocin, something that many of you have, perhaps heard
of the paper that I'm going to describe, is from the laboratory of dr.
Robert milenka. 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. No, caption is entitled distinct neural mechanisms for the pro-social and rewarding properties of MDMA. And I'm just going to summarize the major results of this study. It's a
That was done on mice and I realized that a lot of people will hear that and think 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 hypothalamus circuits. These are what are called, knees Olympic circuits. These are all names for circuits that are highly conserved
between mice and
humans and so results in mice. Really do
translate quite well to results in humans at least.
Insofar as the effects of MDMA and which neurochemicals are involved, is
concerned. So what they found in this study using a huge array of beautiful
techniques such as in activation of specific brain areas activation of specific brain areas drug antagonist, to prevent oxytocin function or drug antagonist, to prevent specific receptors involved in the serotonin pathway. Lots and lots of tools in their tool kit. What they found is that MDMA causing the release of dopamine.
Is what really establishes the rewarding effects of an experience. This isn't really a surprise, we've known that MDMA, just like cocaine or Methamphetamine or Adderall for that matter, or Vyvanse for that matter. Creates big increases in dopamine that tend to couple and 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 me. So limbic reward pathway. If you
want to learn about music Olympic reward,
Pathways and dopamine, and how they control everything from your level of motivation, to your tendency, to procrastinate or overcome
procrastination. Done, two episodes about dopamine,
you can simply go to human lab.com, put dopamine into the search function and you'll find at least two episodes on that topic.
And you'll also find a number of different tools related
to how one can better regulate their own patterns of
dopamine release for sake of motivation etcetera.
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
Activation of certain brain areas and again using drug antagonist, Etc. 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 sir tonin to a 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
Forced 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,
And by MDMA on top of the release of dopamine sets in motion to parallel circuits, 14, rewarding something, anything, that's the dopamine component. And then fortunately, because the increase in serotonin caused
by MDMA
increases empathy and social ability for and with others. But also for oneself the motivation, that's reinforced that's wired into the brain. Seems to be a motivation to perceive others as more kind.
But
also to be kinder to
oneself. Now I realize that for some of you who are listening to this, you're probably saying, well, of course,
right. You know, serotonin is pro-social and dopamine is motivation. So you put the two together and people become more
motivated to be social and kinder to themselves, ah, but it didn't necessarily
have to be that way, right? It is
very hard to go from a statement like drug, a produces
effects BC, and D 2.
Neurochemicals b, c, and d, cause motivation, and sociability. And therefore, when you take that drug, you're going to get all of that stuff. In fact, we have to go back to our understanding the MDMA, despite causing a big
increase in serotonin. Also causes
huge increases in dopamine and it does. So, with this molecule that is
methamphetamine,
methamphetamine is not known to be a pro-social drug. In fact, a study, I just referred to as well as some human Studies, have explored.
How the application of methamphetamines and 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 poly pharmacology as it's called of
MDMA. The fact
that serotonin and dopamine is released together has distinctly different effects than if just dopamine
or just serotonin is
Has increased so much so that
it's worth taking a step back and talking about
another class of drugs which dramatically increases serotonin which are the
ssris, The
Selective serotonin reuptake Inhibitors.
Ssris such as fluoxetine Prozac as well as Zoloft. And of course there are many other accessorize out there citalopram Etc. They block the reuptake of Serotonin and thereby lead to
net increases in the amount of Serotonin and yet,
those drugs are not known.
To
create
even close to the same sorts of effects as MDMA. In fact,
there have been human. And animal studies showing that if you give somebody an SSRI, prior
to them taking MDMA, you actually block the pro-social and empathic genetic effects of MDMA. Now,
you might say, why in the world would that be aren't these drugs, just increasing serotonin and
the increasing serotonin is pro-social ETC.
Ah, well, that speaks to the complexity
T of all this poly pharmacology and the fact that it's really the activation of
Serotonin at particular receptors. In this case, the serotonin 1B receptor in particular, brain areas. In this case, the nucleus accumbens a brain area, associated with motivation and reward that largely explains the effects of MDMA in making people and animals, and octopuses included for that matter, more pro-social and more empathic towards themselves.
It's not just an issue of raising the levels of one neurochemical. It's really about raising levels of particular, neurochemical
acting, in particular receptors in particular, brain
areas. And in the case of MDMA, the fact that there's also dopamine increased in those very same brain areas, right? I don't think I mentioned this before but the nucleus accumbens is part of that means Olympic 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 empath
Aegean 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 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 what 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, Etc. In
fact are even data suggesting that
humans can have strong oxytocin.
Oz 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 are 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 here, 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 notes. Captions entitled plasma, oxytocin concentrations following MDMA or intranasal oxytocin in humans. Nowadays oxy,
Listen 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 .75 or one point.
Five milligrams per kilogram of body, weight of MDMA
experienced increases in oxytocin. However, it was only the group that took one point five
milligrams, per kilogram of body weight,
Of MDMA that
experience 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
Only 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 one point five milligrams per kilogram of
MDMA which is eighty three point seven
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 liked the feeling how much they felt. Hi. They measure their heart rate.
Their systolic pressure the diastolic blood pressure Etc 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 pro social effects of MDMA.
And that's also what was found in the animals.
Studies of MDMA, we're in those studies.
Mice were given MDMA at comparable. Doses.
Doses, were a little bit higher than using the human studies but at comparable, doses, big increases in oxytocin were observed increases. In Sochi, ability 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 Social.
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 socio ability, 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 as 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. So, see, ability empathy,
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. So see ability increase empathy
or the long-standing changes in neural circuitry that underlie for instance reduce threat detection or reduce connectivity between
Threat detection centers of the brain and interception. So is the big
increase in oxytocin produced by MDMA completely irrelevant in the context of this discussion, we don't know.
It appears that it's not very relevant, is oxytocin a meaningless
molecule right after all. They gave these people nasal
infusions of oxytocin, oxytocin and went way up. It didn't
observe anything very interesting or significant in the context of sociability, but we do know that oxytocin can
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 it, subjective effects on empathy. So see ability or any of those other factors either.
Either
now, perhaps the one caveat to that is that Harriet do. It'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 Pro sociability 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 illegalities of MDMA and put the drug enforcement agencies on to 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
ports of major MDMA seizures and bus. So again, I want to highlight the fact that MDMA is still illegal to possess
or sell and certainly to
traffic. I also want to highlight the fact that nowadays all recreational drugs but certainly MDMA included are often in fact very often contaminated with fentanyl. And while fentanyl has certain clinical uses, fentanyl is highly deadly. The current estimates are as much as sixty percent, maybe even 80% of
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
smaller 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
City 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 and
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 3 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 point seven five to one point five milligrams per kilogram of
body weight. There is some evidence that in laboratory, mice, or 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 and dopamine big releases and 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 will be reductions in those sorts of proteins, right
after all, a lot of dopamine and serotonin is released and it can
Be depleted, but I should point out depletion of a neuromodulator in the short term is not the same thing as depletion of
that neuromodulator in the
long-term nor is it the same as loss of the neurons that release dopamine and serotonin itself. So, there are data pointing to the fact that repeated administration of MDMA at dosages that are very much within lines with what we're talking about. Today, one point five milligrams per kilogram of body weight can lower total amounts of Serotonin or other proteins.
Serotonin synthesis pathway
or dopamine or proteins that are in the dopamine
synthesis pathway in specific areas of the brain related to reinforcements related to mood related to motivation Etc. However
the primate studies or I should say the nonhuman 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 in 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 the MDMA
might not be as neurotoxic as is thought based on the road in studies.
And this gets into a whole history of back and forth between different Laboratories and governing bodies who are trying to keep MDMA legal as well as people such as the Sasha shogun's of the world and people in the therapy community that are excited about the
potential for MDMA.
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.
Science, which is one of the three Apex journals for publishing scientific research. So there's science nature, and
sell 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
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.
Largely where MDMA got the reputation for quote unquote, putting holes in your brain.
However, this study came under a lot of scrutiny for a couple of reasons, first of all, and I'm certainly not saying this, but it was argued that the authors of the study were perhaps trying to
prevent the legalization of MDMA for the treatment of PTSD.
As far as I know, there's no
direct evidence that that statement is true,
but you will actually find that in some of the scientific journals. In fact, I was able to find a
an editorial that was published in the biomedical journal in
2003, which
argued somehow that
dr. Require Tay
was accused of quote, rushing his results in to print because of legislation, designed to curb
ecstasy use before US Congress. So, you know, there was some
connotations or I rather there were some strong suggestions that there was a political backing to trying to get this study done quickly and into print and so forth. I don't think that ever really got resolved. What did
get resolved? However,
Is that
the very study in question was
retracted. Okay. So
the author's 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 the 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 Miss labeling, 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 or neurotoxicity and unfortunately the
neurotoxicity issue is often what's
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
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
I've taken a lot of MDMA anywhere from one to two hundred or sometimes, even in excess of 400 doses of
MDMA and there now are studies that have explored the neurotoxicity and perhaps, even more importantly, the neural cognitive and behavioral effects of taking MDMA either zero times one
time, five times 40 times, 200
times, etc, etc. And one of the, what I would consider Landmark studies in this area
Is a study entitled, residual neurocognitive features of long-term, ecstasy
users with minimal exposure to other drugs.
And those words with minimal exposure, to
other drugs is really key in the context of this conversation. Because as I mentioned before, interactions between drugs. What's called poly Pharmacology 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
The ma 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 talk about the Joe
Rogan podcast, I've talked
about it briefly with a guest on this podcast. Doctor
Nolan Williams, who's a triple board-certified physician psychiatrist and neurologist at Stanford school of
medicine. And it's an interesting study in a little bit controversial because it relied on a population of people who have taken MDMA anywhere from one to two hundred times and who've not taken any other drugs, including caffeine. And the population in mind here is a population of people living in Utah who
self-identify as
Members of the Church of Latter Day Saints, sometimes referred to as Mormons sometimes referred to as LDS or of. The Church of Latter Day
Saints. Church of Latter Day Saints. As I understand does not allow for taking
of certain compounds, certain drugs, certain
certainly, most recreational drugs, alcohol, even caffeine and I'm sure there's some variation on some of those themes depending on where people live in the certain
communities, that they happen to be in. I am
in no way shape or form, declaring that I'm a
Expert on Latter-Day Saints. I have a
couple of friends who are
LDS having to be very nice. People, as far as I know, they were not the people in this
study but this study really emphasized. Ecstasy users, they're called, who have not taken other drugs who self-identify as LDS. And the major takeaway of this study was that for moderate. Meaning, people who have taken ecstasy anywhere from 20 to 250
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 poor
here. I'm quoting from the findings,
poor strategic self-regulation quote possibly reflecting increased impulsivity. However,
When you see a conclusion like that you should immediately be thinking chicken versus egg, right? It could be that people that are more impulsive and that have less strategic self-regulation are more
likely to take ecstasy 450 times. You could
conclude that, or you could conclude that people who have taken ecstasy
75 times or 25 times Etc
are degrading their
levels of self-control and thereby increasing impulsivity the direction of the effect is not known.
These are purely.
Correlations nonetheless this study and a few others like it really stand as our best evidence believe it or not as to how ecstasy taken many times. Because
after all these people are taking 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,
Brain structures are active, or less active, or perhaps, even looking at levels of
Serotonin or dopamine. All things that can be done
with positron emission,
tomography Imaging, functional MRI Etc. Hopefully, those studies will be done in the not too distant
future. But if we were to
just take a step back from all
the data, the data in mice and rats and non-human primates the retraction
of the study in non-human primates which showed that the primates that showed neurodegeneration. We're not given MDMA
as it was thought by the researchers but rather as later was
Acknowledge we're actually
given methamphetamine. And we take into account these moderate and heavy users of MDMA who as far as we know, are being honest and haven't taken any other drugs. And we look at the clinical studies where people who have never taken MDMA or given one or two or three Define doses of pure MDMA will talk about those stories in a
moment. I think the Gestalt the
top Contour, the overall view of those studies is that provided it as
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 of people are taking
high doses of MDMA or taking it very frequently or
certainly if they are taking in conjunction with
Or
drugs or, or I should say and or taking MDMA in settings that can promote
neurotoxicity. And the
settings, I'm referring to our 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 sympathize mimetic.
Talk about sympathomimetic and what that means, the episode on Adderall and Vyvanse and ADHD.
But basically, it's ramping up the activity
of the sympathetic nervous system which is your fight or flight system, okay? This is why people who take these drugs, get big pupils, you know, big pupils of the eyes is why they feel agitated. They want to
talk a lot. They feel like they want to move. A
lot is why people take it to dance
at Raves, Etc? But when people take some pathan memetics, whether or not to MDMA, or amphetamine or cocaine or even caffeine, there's an increase in blood pressure and heart rate but also
So, 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, the hypothalamus, which is involved in temperature regulation. If you're curious
about temperature regulation, I covered a lot of that in the episodes of the Hebrew and Lab podcast on deliberate, cold exposure and deliver heat exposure. This is an area I used to work on me.
Two years ago, as a research scientist before, moving on to other topics to research in my laboratory.
Big increases in body
temperature are not good, the body and in particular, your brain can tolerate
decreases in body temperature that are pretty
robust, and you can still stay safe, you're not going to kill neurons. But
even an increase of 3 or 4 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
Mets 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 and being
skeptical or, at least giving them some counter Arguments for that statement. But if somebody says, MDMA is not toxic, well, then you would be equally valid and 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 raver dance type environment, where temperature is going up. Well, in that case, it could be very it
neurotoxic. So
pharmacology of MDMA counts, but so does
Polly pharmacology. The ingestion of other compounds, not just during the MDMA session, but also in the 24 hours before
And after that, MDMA session and behaviors will certainly impact temperature, which will impact whether, or not MDMA is neurotoxic or not.
And despite my efforts, I couldn't find out whether or not the LDS Community has
officially sanctioned the use of MDMA. Certainly that's one possibility, but I have no evidence for
that or rather whether or not certain people within the LDS Community have allowed themselves give themselves permission to
use MDMA and they are not using other drugs.
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 n self-identify, as having
taken MDMA anywhere from 20 to 24 hundred fifty times,
but where they got permission for that? Whether or not it's from someone else or from
themselves, I do not know what I do know
is that within the acknowledgements of the paper
There's actually a thank you to the person that identified this quote unique
population, for our study.
So I welcome you to take a look at the paper and if any of you know more about if and how a particular
subgroup within the LDS Community is allowed to take MDMA. Perhaps you want to put those in the comment section on YouTube
before moving to our discussion about what MDMA is
doing and the effects that people are seeing in the clinical studies for the treatment of PTSD.
Which, by the way, are extremely exciting. I can't wait to share these data with you.
I do want to touch on something that anyone who's heard about MDMA, or perhaps used MDMA is familiar with, and that's the so-called
crash that people experience after MDMA.
There are a lot of myths about the post MDMA crash, and there's a lot of lore out there on the internet about how to offset the crash and a lot of lore about how to prevent the potential
neurotoxicity of MDMA earlier. We talked about some of the major points.
Points around offsetting neurotoxicity. So certainly making sure that any MDMA that one takes is in the legal clinical setting that it's there for pure MDMA, right? That it's not cut with other things, which certainly can increase toxicity. Controlling the temperature of one's environment restricting caffeine intake. At least on the
day of MDMA ingestion.
But certainly the day before and the day after would be advantageous as well. See.
Because of the way that caffeine and activation of the adenosine receptor, as well as
caffeine's effects on dopamine receptors can interact with the potential again potential, neurotoxicity of MDMA,
but the crash that one experiences after
MDMA is
actually a phenomenon, very common to the
crash that one experiences. After ingestion of any type of stimulant cocaine amphetamine
Etc and the crash that were referring to as a drop in
mood increase in lethargy feelings of lack of
motivation.
Ocean 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 certain urges 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 are put out on the internet such as oh you know, after taking MDMA should take a bunch of, you know, 58
TP 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 any time, there's a big increase in dopamine. There is going to be a post
dopaminergic, increase in prolog
In 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, letdown and lactating women, it's
involved in setting the refractory period to sexual arousal, and erection, and ejaculation, and males. After ejaculation, it's involved in lots of different functions in the brain and body, including the laying down, a body fat stores,
and it's also associated with
increases in lethargy decreases in dopamine.
This is why drugs
that increase dopamine are known
to decrease prolactin at least in the short term. This is wise drugs like Caper go lean. 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 the 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, may be diminished mood at cetera.
And for that reason, some people have started to explore the use of things, like P 5. P, 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
Of P 5 P or other vitamin B6 derivatives or Caper go lean 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
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-tryptophan. They should be taking
Tyrosine. They should be taking magnesium, other things that set. Our 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 neural, chemicals. It releases the neurohormones that it promotes, the release
of prolactin in
particular. This P 5 P, 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 Etc.
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
To augment treatment for PTSD. 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 in a 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
Alt these could 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
Epps, 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.
In the way that dr. Paul Conte 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 or 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 into adaptive and maladaptive, behaviors, and emotions,
All states.
Now, in addition to Rapport and support being critical, there's a third component of effective talk therapy for trauma, which is in sight or 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.
P. 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. Okay, 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 ssris, 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 and it's like blunting of libido. Blunting of appetite or increases in appetite, in some cases, disruption of sleep, wake rhythms motivation etcetera. 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 is 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
PTSD and, 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. On 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 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, as
likely seeing casualties and severe injuries, and that
upon return to a safe environment is still
And seeing a lot of anxiety and sometimes panic attacks that occur seemingly at random, or they can be sparked
by, you know, the classic stereotyped example is, you know, 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
symptomatology 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 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 pts tea 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 cerebrovascular deficits that.
That caused 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 eight percent of people in the United States have PTSD. And again, the estimates around comorbidities range anywhere from 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.
The
fact that many people with PTSD,
sadly end up committing suicides and suicide rates are far greater in people, with PTSD, the exact rates of increase in suicidality. And 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 surgery.
Circuitry, as well as mineral 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 seemed to
Center back into the insula, that's
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 painting ones. 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.
Ian 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
Action 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.
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 is large-scale, clinical trials, that are showing what can only be described as
remarkable results for the treatment of PTSD.
So, rather than go into 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. No captions. The two that I think are most interesting or
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 3 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
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
We 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 and 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 to therapist, okay? In the placebo group, people are doing talk therapy with two therapists but they're not taking MDMA.
So 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 percent for the placebo and therapy alone. So, on the face of it, you might say, okay, wow, eighty eight percent 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 the incident that 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 therapist that they were
working with. Before they took MDMA,
the first session, they're taking 80 milligrams of
MDMA and then a 40 mg 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 mg 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 mg 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 you 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 therapist.
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 38 hour sessions with those two therapists and then three 90-minute, follow-up sessions, one week apart, but they
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 percent compared to 60% for
therapy and placebo.
What's even more impressive? However, is that 67 percent 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
80 or Sleep Disorders are explored. So,
while to some of you a difference between 60
percent success, with talk therapy and Placebo, versus 88 percent 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.
Going to 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 percent 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,
Etc. 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 percent of those people going to 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 their quote unquote, No clinical applications to potentially a legal within the context of clinical use application of MDMA, which it
does appear the legislators at least considering for as early as 2020 for 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
A-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 subsystems as well and
perhaps that shouldn't be surprising. If
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
often times 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 brain wiring phenomenon. What
I'm saying here is that just because addiction and PTSD are often
comorbid with one another. It was
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 whose
Put a quote 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
Sense of to trusted
therapist, 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 sometimes the case that people will forgive the person that inflicted the
trauma on them, but more often,
Not it's about tying their feelings of trauma and their feelings of depression, anxiety, dissociation, Etc, 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.
I'll load seems diminished
and that they experience 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 what once burden 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 in a way that interferes with other aspects of normal functioning. So when one hears about these kinds of results,
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
Fact, 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 that brain networks, Etc, 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 the limited number of sessions. And when one thinks about the cost of mental health care, you know, 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,
you know, I don't want to say that the cost of therapy should be reduced because, of course, therapist have to
Survived 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
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 support of settings, they are 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 least to my knowledge, there was no actual suicide attempt or successful suicide and 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
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 augmented 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 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 we're only associated with their recreational uses. And therefore,
we're 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. You know, a lot of issues and problems associated with these compounds and yet, we're now seeing from these clinical trials, when used
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.
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
Orders. 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 pro-social 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 wear 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 and humans and non-human primates point to the
That at reasonable Doses and we talked
earlier about what those are at reasonable
doses. When not combined with other
drugs, it 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 sympathy, mimetic. They, of course, can be neurotoxic anything with methamphetamine and it has the potential to be neurotoxic. But of course, dosage matters, context matters. We talked about
Out that and of course the purity of drug matters. And again I just want to re-emphasize the fentanyl contamination of MDMA that sold on the street and that is being used, recreational is a 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. No
captions. And I think in general we should acknowledge that we are a very interesting and important time in human
history for the
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 neuromodulator systems, are involved.
What we're really talking about are ways to access
neuroplasticity, the nervous systems 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
Ali. 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. If
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