- 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 methylenedioxymethamphetamine. That's right, you heard the word methamphetamine in there.

And MDMA has properties similar to methamphetamine, but also properties that are very distinct from methamphetamine. Just as a side note, methamphetamine is a commonly used drug of abuse. It is an illicit drug, and it produces some of the greatest and fastest increases in the neuromodulator dopamine of any available drugs on the street or in the clinic.

And believe it or not, methamphetamine is prescribed as a prescription drug in some very limited clinical uses. MDMA, methylenedioxymethamphetamine, has properties similar to methamphetamine in that it powerfully promotes the release of dopamine, and it is a stimulant. And yet it also powerfully controls the release of serotonin, and in doing so, makes MDMA a distinct category of compound from either classic psychedelics like psilocybin or LSD, which largely work on the serotonin system, and tend to produce mystical experiences.

And it's also distinct from pure stimulants such as methamphetamine, because MDMA, by producing big increases in both dopamine and serotonin, acts as what's called an empathogen. It actually can increase one's sense of social connectedness and empathy, not just for other people, but for oneself. And in that way, MDMA is commonly used as a recreational drug, but also is now being tested and is achieving incredible early results in clinical trials for its use as an empathogen for the treatment of PTSD in clinical therapeutic settings.

I want to be very clear that at this point in time, June, 2023, MDMA is still a schedule one drug. That is, it is highly illegal to possess or sell in the United States. And today we are going to talk about some of the path to legality that's underway.

We are also going to talk about the history of MDMA and why it became illegal. And we are going to talk about the key difference between recreational use and therapeutic use and the important components of the studies exploring MDMA in the clinical setting for the treatment of PTSD. So during today's discussion, we will talk about what MDMA really is, how it works at the level of neurons, which brain circuits it activates and deactivates.

And in doing so, you will come to understand why it is so exciting as a treatment for PTSD. We will also, of course, talk about the results of these clinical trials using MDMA for the treatment of PTSD. They are incredibly exciting. In fact, the field of psychiatry has never before seen the kind of success in treatment of PTSD with any other compound that they are seeing and achieving with the appropriate safe use of MDMA.

And when I say appropriate, that means in conjunction with nine therapy sessions. So this is an area that really deserves some time for us to discuss because again, there is a distinct difference between the recreational and the therapeutic use of MDMA. We will also talk about the toxicity of MDMA.

This is a very important issue because many of you have perhaps heard that MDMA, quote unquote, puts holes in your brain or kills serotonin neurons or kills dopamine neurons. And indeed MDMA, because of its similarity to methamphetamine, which is highly neurotoxic, MDMA can be neurotoxic. However, there are ways to use MDMA therapeutically that avoid its toxicity.

And yet there are still questions about its toxicity and its long-term effects, both after acute use, meaning just one to three times, as well as chronic use, meaning people who have taken it many, many times. We'll talk about the spacing between sessions of MDMA. We will talk about dosages.

We will also talk about things that people do and that can be done to offset some of the potential toxicity of MDMA. So by the end of today's discussion, you will have a thorough understanding of what MDMA is, what it isn't, what is known about what it does, what is known about what it doesn't do, as well as some of the still outstanding questions about MDMA that remain to be resolved.

Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast.

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It really increases my focus and my energy levels. If you'd like to try Ketone IQ, you can go to hvmn.com/huberman to save 20% off. Again, that's hvmn.com/huberman to save 20%. Let's talk about MDMA. MDMA, or ecstasy, is a fascinating compound. And I say fascinating from the perspective of its chemical structure, which is highly unusual.

I say fascinating because it has an incredible set of subjective effects in terms of how it makes people feel, and it has a fascinating history. So let's just briefly start with the history of MDMA. MDMA was synthesized by the drug company Merck in the early 1900s, but it actually was never applied to any particular clinical use, and it wasn't really explored much in any laboratories at all.

And then it was later rediscovered by a guy named Alexander Schulgen, 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 Schulgen 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 Schulgen 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 of all, MDMA is a synthetic compound. As far as we know, it does not exist anywhere in nature. So unlike similar compounds, such as mescaline, because MDMA and mescaline are very similar in their chemical properties, and to some extent, their subjective properties, unlike mescaline, which can be found in the plant kingdom, or LSD, which comes from ergot, or psilocybin, which of course can be found in magic mushrooms, MDMA is a unique chemical in that, again, as far as we know, only exists in its synthetic form.

It is human-made. And as we get into the chemical effects and the subjective effects of MDMA a little bit later in the episode, I think you'll understand why it is such a unique and to some extent exciting compound from the perspective of clinical treatment. Put differently, there's really no other compound that we know of in nature or in the pharmaceutical industry shelf or options of drugs that are prescription drugs that produce the kinds of effects that MDMA does.

And by the way, if you're interested in the story of Alexander 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 PIKAL. That stands for P-I-K-H-A-L. PIKAL is the title of the book which Shulgin wrote, which describes his discovery of MDMA. I confess it also describes the synthesis of MDMA. And for that reason was a book that for a long time was not available, but is now available again in audible form and in printed form.

PIKAL stands for phenylethylamines, I have known and loved. Phenylethylamines is the category of drug for which MDMA belongs to. And it's a long book, but a very interesting one both from the perspective of understanding the history of MDMA and what MDMA is and the effects that it produces. But it's also an interesting book because it will teach you a lot about the history of the pharmaceutical industry, the war on drugs in the United States and the interaction between illegal drug exploration and drugs for clinical treatment of psychiatric challenges.

So right now this is a very important issue because MDMA is currently granted breakthrough status, which means it's now something that scientists and clinicians can study if they have authorization to do that. It is, as I mentioned earlier, still a schedule one 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 are neurons of the serotonin and dopamine type, so this is something you would not want.

Let's just recall that killing off of or death of dopamine neurons is the underlying basis for Parkinson's disease, which is a movement disorder where people have difficulty generating smooth movements and in very severe form, they can't move at all. They sort of become locked in to some extent, and it also has cognitive effects, so you don't want to lose dopamine neurons, and loss of serotonergic neurons is known to impact mood negatively, mood regulation negatively, et cetera.

The story of MDMA and its potential neurotoxicity comes slam right up against this issue of legality, and what we'll get into a little bit later is that there has been a sort of race in the scientific community consisting of two groups, one set of groups trying to establish the toxicity of MDMA so that it does not become legal again, and another group trying to establish the utility and the lack of toxicity in MDMA so that it does become legal again for the treatment of PTSD.

So even though the story, PCAL, relates to events that took place largely in the 1970s, '80s, and '90s, right now MDMA and its toxicity or lack of toxicity, its legality or lack of legality are really key issues. So as you're listening to this, I'm giving you a real-time blow-by-blow of what led up to where we are now, but we will also want to think about how what's happening right now, including the description of these data on MDMA, may or may not impact the potential legal status of MDMA.

Okay, so what is MDMA? MDMA is 3,4-methylenedioxymethamphetamine, but unless you're a chemist, that's not going to mean much to you, nor should it. MDMA has some very interesting properties, the first of which is that methamphetamine component, which, because it's a methamphetamine and acts like other amphetamines, what it does is it blocks the reuptake of dopamine from neurons after dopamine is released.

So for those of you that heard the episode that I did on drugs to treat ADHD, I discussed the biology and mechanisms of drugs like Adderall and Vyvanse, which basically are either combinations of amphetamines or single types of amphetamines that have either a quick release or a long release.

Now, MDMA, because it has this methamphetamine component, prevents the reuptake of dopamine, and in doing so, creates net increases in dopamine. So for those of you that don't have a background in neurobiology, let me just briefly explain. I'll make this very simple. Neurons or nerve cells release chemicals at their sites of communication, which are called synapses.

Synapses are little gaps between neurons, and what happens is the neurons spit out these little spherical balls, which we call vesicles or vesicles, depending on where in the world you live. They'll either be called vesicles or vesicles, and those little vesicles contain neurotransmitter or what's technically referred to as a neuromodulator.

Dopamine is a neuromodulator. It can modulate the activity of other neurons. It can either increase or decrease the activity of other neurons. Now, at the end of the neuron, what we call the axonal bouton, okay? Axon is kind of the wire component of the neuron that can reach to another site in the brain and then release the neurotransmitter or neuromodulator there.

At those axonal boutons, which are the sites of release, the vesicles literally fuse with the edge of the neuron and vomit their neuromodulator out into the synapse, and then the neuromodulator, in this case, dopamine will bind to receptors on the postsynaptic side, that means to another neuron, and then depending on how much binds and depending on what else is going on in that local neighborhood of neuronal connections, the neuron will either increase its neural activity and itself release neuromodulator or neurotransmitter someplace else, so sort of a chain reaction, or else it will suppress its activity and the flow of communication from one neuron to the next will be stopped, okay?

So MDMA doesn't prevent the release of dopamine at the synapse, it does quite the opposite. It actually prevents the sucking up of the dopamine that's been released and that does not bind to the receptors. So basically what it does is it blocks these things called dopamine transporters, and the transporters are the things that suck back up the dopamine that's been released that has not bound to receptors.

So because it blocks that sucking up process, there's more dopamine around in the synapse to hang out and then bind to receptors once some become available, okay? The other thing that the methamphetamine component of MDMA does, just like methamphetamine, is that it actually gets into what we call the presynaptic neuron, the neuron that releases the dopamine, and it interferes with the repackaging of dopamine into those vesicles.

Now you might think, oh, it interferes with the repackaging of dopamine into vesicles and therefore less will be released, but actually what happens is as a consequence of that, a bunch of dopamine builds up in the presynaptic neuron so that when an electrical impulse comes down that neuron and dopamine is released, a huge amount of dopamine is released.

And this is one of the characteristic properties of methamphetamine and of MDMA, which is that it leads to enormous increases in the amount of dopamine released and the amount of dopamine that hangs around in the synapse and therefore it increases what we call dopaminergic tone or dopaminergic drive. That's just a bunch of different ways to describe increases in dopamine.

Okay, so that's the main way that MDMA, and by extension methamphetamine, increase dopamine. However, MDMA is not just methamphetamine, it's methylenedioxymethamphetamine, 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 Serts, S-E-R-T-S, serotonin transporters, and they work very much in the same way that dopamine transporters do, right?

They basically control the sucking back up of serotonin that's been released into the synapse and that has not bound to serotonin receptors on the other neurons yet, and in doing so, allow more serotonin to hang out and have its effects as those receptors become available for serotonin to bind to them.

The other thing MDMA does is it also gets into the presynaptic neuron to impact the packaging of serotonin into something called the vesicle monoamine transporter for serotonin. And in doing so, it leads to a big buildup of serotonin in the presynaptic terminals and then massive increases in serotonin release.

Okay, so what we've got with MDMA is a really interesting compound. Unlike methamphetamine or other amphetamines, such as Adderall, Vyvanse, et cetera, that cause increases in dopamine by blocking reuptake and increasing release of dopamine, MDMA does that, but it also does the same thing for serotonin. And here's a really key point.

The increases in serotonin that MDMA creates are at least three times and maybe as much as eight times greater than the amount of dopamine release that MDMA causes. But when you put those two things together, what you basically have is a drug that causes huge increases in dopamine and even bigger increases in serotonin.

And remember earlier when I said that MDMA is a purely synthetic compound, as far as we know, it does not exist in any plants or fungus or anything else in nature? Well, this is a very unusual circumstance of having big increases in dopamine and big increases in serotonin caused by the same compound.

And that combination of big increases in dopamine and big increases in serotonin are what lead to these highly unusual and yet what seem to be potentially clinically very beneficial effects of having people feel a lot of mood elevation and a lot of stimulation from the stimulant properties of the methamphetamine component, so that's the dopamine effect.

The dopaminergic tone goes way up. So it's a stimulant. People feel really alert. They feel like talking a lot. They feel very excited. They feel a lot of positive motivation. These are classic effects of drugs that promote the release of dopamine, including amphetamine, cocaine, et cetera. But ordinarily that's not such a good thing because what happens is there's then a crash in the dopamine levels and then people feel depressed.

They feel lethargic. They don't feel good at all. MDMA seems to cause these increases in dopamine and all the accompanying effects I just described, but by also causing big increases in serotonin, it activates neural networks that are associated with feeling more socially connected. In fact, we'll talk about data in a little bit where people have had their brains imaged while under the influence of MDMA.

And it's very clear that people who have taken MDMA look at faces that ordinarily they would rate as fearful and rate them as less fearful. They see faces that are smiling and they rate those smiling happy faces as more positive than they would off the drug. The big increases in serotonin create what we call a prosocial effect.

And that combined with the dopaminergic increase in mood and the stimulation effect creates this thing that we call an empathogen where, and this is very important, the empathy isn't just for other people. It's also for oneself and one's own experiences happening in the moment, as well as empathy for experiences from the past, which as you can imagine could be very beneficial for the treatment of PTSD, okay?

So hopefully the way I described the biology of MDMA makes some sense. If you didn't get anything out of the description I provided except the understanding that MDMA is unusual in that it causes big increases in dopamine and even bigger increases in serotonin then you have more in your knowledge base now about MDMA than you need in order to understand the rest of our discussion.

Before we go any further, I do want to separate MDMA out from some other compounds which are referred to as psychedelics. And I recently did a podcast episode all about psilocybin and its therapeutic exploration and its chemical basis, et cetera. You can find that like all episodes at Hubermanlab.com.

I also did an episode with expert guest, Dr. Robin Carthart-Harris, who's at University of California, San Francisco, who's pioneering a lot of the studies on the clinical application of psilocybin. Psilocybin and LSD are mainly going to increase serotonin activation in the brain. In fact, they very closely resemble serotonin itself and they activate what's called the 5-HT2A or serotonin, 5-HT just stands for serotonin, the 5-HT2A receptor to create very mystical type experiences.

They are considered classic psychedelics and are very introspective. And as I described in those episodes are being explored extensively now for the treatment of major depression. A different compound that's being used for the treatment of depression is ketamine. I will do an entire episode all about ketamine. Ketamine is actually a N-methyl-D-aspartate receptor blocker, NMDA receptor blocker, that shouldn't mean anything to most of you, but it is a dissociative anesthetic, not unlike PCP, what used to be called angel dust on the street.

Ketamine is being used as a treatment for depression. It is currently legal. So unlike psilocybin and LSD, which are granted breakthrough status for the study of depression, but are not yet legal, they are still illegal. And of course, as I mentioned earlier, MDMA has breakthrough status, but is still illegal.

Ketamine is being used for the treatment of depression and it does so, as its name suggests, a dissociative anesthetic by creating a sense of dissociation from emotions, okay? Now I raised this distinction between psilocybin and LSD, which are mystical in their effects. Ketamine, which is dissociative in its effects, with MDMA, which is an empathogen or sometimes called an enactogen, but as an empathogen or an enactogen, it's creating more affiliation, it's affiliative, okay?

So it's a very distinct compound. And I think this is important to understand because when we hear the word psychedelic, a lot of people tend to lump together LSD, psilocybin, and MDMA. If you talk to researchers in these areas, they will tell you that MDMA really isn't that much of a psychedelic.

It's an empathogen with stimulant properties and it also has the serotonergic component that makes it an empathogen or an enactogen. So MDMA is very different than the other psychedelics and my hunch is that over the next few years, we will stop talking about MDMA as a psychedelic because it does not tend to produce visual hallucinations or auditory hallucinations of the sort that classic psychedelics do.

And in general, it is more of a mood impacting drug than it is mystical, okay? So we'll get into some of the brain networks and which ones are activated while under the influence of MDMA, but I do think it's very important to segment out MDMA from the other so-called classic psychedelics and also segment it out from ketamine.

Thanks to some really terrific studies, both in animal models and in humans, we now understand a lot of what makes MDMA produce these incredibly unique effects. And when I say unique, I mean unique from drugs like psilocybin and LSD and ketamine and from methamphetamine for that matter. And it's really the combination of big increases in dopamine and even bigger increases in serotonin that create a situation where people have more energy and yet despite having more energy, they don't feel irritated.

They feel a lot of pleasure. They seem to want to be in the state of having a lot of energy. This will become important as we talk about anxiety and the anxiety symptoms of PTSD. It also, because of the big increases in serotonin, produces a sense of emotional warmth towards others and towards oneself.

That's the empathogen component. And for reasons that we still don't understand, it seems to increase trust. And the increases in trust turn out to be vital because as you will also learn later when we look at the clinical trials exploring MDMA for the treatment of PTSD, the major effect of MDMA for the treatment of PTSD is not to cure PTSD, but rather to make the therapy, the talk therapy for PTSD much more effective.

This is a very important point. In fact, so important I'm going to repeat it at least three times during today's episode. MDMA taken on its own does not cure PTSD. MDMA can augment or boost the effects of talk therapy for PTSD. And it does that through the engagement of specific neural circuits.

But before we talk about what those neural circuits are, I want to emphasize that the increases in serotonin that MDMA produces seem to act on different receptors than the big increases in serotonin that LSD and psilocybin produce. So if you listen to the episode that I did on psilocybin, we haven't done yet one on LSD, but the mechanisms are very similar for psilocybin and LSD, whereby psilocybin and LSD very closely mimic the molecule serotonin itself, but seem to have a more selective activation of just the so-called serotonin 2A receptor, abbreviated 5-HT-2A.

And that leads to more interconnectedness between different brain areas, more consideration of new possibilities about events from the past, present, and future, and also the opening of so-called neuroplasticity of rewiring of neural connections that persist long after the psilocybin or LSD effects have worn off. Now, MDMA can activate the serotonin 2A receptor, but it seems that it largely activates the serotonin 1B receptor.

Now, what does that mean? Activation of the serotonin 1B receptor seems to be what gives MDMA its very strong impact on the neural circuits of the brain that relate to trust and to social engagement, not just the willingness to engage socially and to confide in a therapist or another person, but the intense desire to do so.

And when I say intense desire, that takes us back to the dopamine system. Remember, dopamine, even though when increased in the brain, can increase our mood, it is largely responsible for increasing our sense of motivation and desire for something and to do something. So the increase in dopamine that's created by MDMA seems to make people what I call forward center of mass.

They want to do something. They're very motivated to do something. And the increases in serotonin acting on the serotonin 1B receptor seems to be what creates this desire to bond or create trust or to have a discussion of real things, both things that are positive, but also to explore things that are difficult.

And this, I realize, is going to be a little bit of a mind bend for people to understand. But one of the key things that quality MDMA therapy consists of is not just having a very good rapport and communication with a therapist that's guiding the PTSD treatment, but also rapport and a willingness to engage in conversations with oneself.

And I think that most of us can relate to the fact that we have experiences, some of which are hard, some of which are great, and everything in between. Trauma is, I believe, best defined by the words that a former guest on this podcast, who's a world expert in trauma, Paul Conte, explained as trauma is an event that fundamentally changes the way that our brain works for the worse, okay?

So not every bad event of our past is trauma, but events that change the way that we think, our emotional tone, or our behavior, in ways going forward that are not adaptive for us, they don't serve us well, either because they are highly distracting, or because 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, 'cause oftentimes trauma can consist of many events, not just one event, and the thought patterns around that, and the context around that, and therein to be able to explore new possibilities to essentially rewire their relationship to that trauma.

So I promised that a little bit later, we'll talk about the direct application of MDMA for the treatment of PTSD, but now I'd like to shift off of the chemical changes that MDMA produces and some of the subjective changes, these increases in trust and pleasure and energy and emotional warmth, to some of the brain circuits that are activated and modified by MDMA use, and then we will explore the toxicity issue, and then we will explore the clinical studies of which I can promise you are extremely exciting, but until we understand the neural circuit phenomena, and of course, until we consider the neurotoxicity issues, I don't think those clinical findings can be appreciated in their full value.

But now I'd like to talk about what MDMA really does in the brain, both in the short term, while someone is under the influence of the drug, and in the long term, what sorts of neuroplastic or rewiring changes does MDMA produce, and how can those be beneficial or perhaps not beneficial?

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Again, that's athleticgreens.com/huberman to get the five free travel packs and the year's supply of vitamin D3K2. So in order to understand what MDMA does to the human brain, we need to take a step back and really define the sorts of experiments that one could do. So for instance, you could take a person who's never ingested MDMA and put them into an fMRI machine, which is functional magnetic resonance imaging, put them into the fMRI machine, and just have them sit there with their eyes closed, what we would call resting functional connectivity or resting state functional connectivity, and simply look at how interconnected certain brain areas are, which brain areas are active, which brain areas are less active at rest.

This is an important thing to do, not just to provide a baseline for understanding what the drug MDMA will subsequently do, but also because it addresses what's called the default mode network. The default mode network or DMN is the network that is active in our brains when we aren't really attending to anything specific outside us, and we're not trying to think about anything specific or accomplish anything specific.

It actually relates to our sense of imagination and daydreaming. It has a lot to do with our self-referencing, what we're thinking about ourselves. This may come as no surprise, but if you're just sitting there on the bus or around the dinner table and you're not paying attention to what's going on, in large part, your brain is in this default mode network, and you're thinking about yourself, okay?

So we can get a sense of what the default mode network activation is. We can get a sense of which brain areas are more or less active, simply by putting somebody into an fMRI machine. Then of course, you could give somebody MDMA while they are in the fMRI machine and see how the activation of different brain networks changes.

And then of course, you could analyze how the default mode networks and other brain networks change in the days and weeks and even years after the drug has worn off, so-called neuroplasticity effects, what changed in a permanent or pervasive way. Okay, so that's sort of one basic paradigm for exploring the effects of drugs like MDMA on the brain.

The other way that you can explore the effects of MDMA on the brain is to ask people in the general population, hey, who out there has taken MDMA? How many times have you taken it? And come on into the laboratory and we will image your brain and compare people who have, for instance, taken MDMA zero times to people who have taken MDMA one time or five times, or believe it or not, there's some studies sitting right here in front of me on my desk of people who have taken MDMA more than 200 times and ask the same sorts of questions, which brain areas are more or less active?

Those studies have been done as well. And of course, one can do studies where you give people different dosages of MDMA as well as giving people MDMA and then giving them specific stimuli, meaning not just asking them to sit there in the fMRI scanner with eyes closed, looking at the resting state functional connectivity, but also how the brain responds to the presentation of happy faces or sad faces or images of oneself or even images that recall memories of traumatic events and so on.

So fortunately, all of those sorts of studies have been done in humans and there are also a large number of studies in animal models exploring how the social activity of laboratory mice changes when they are under the effects of MDMA. There are even studies, believe it or not, on the effects of MDMA in cephalopods.

Cephalopods include octopuses as well as cuttlefish and other aquatic animals that are known for having complex behavior. Some people believe that the cephalopods are extremely intelligent. The obsession with cephalopods is something that really intrigues me. I actually used to have cuttlefish in my laboratory. We did not put them on MDMA, but there is a study that's been published in the journal Current Biology.

It's a cell press journal, excellent journal. This is from Gould Dolan's laboratory at Johns Hopkins School of Medicine, showing that if you give octopuses MDMA, they like to spend more time with other octopuses than they do if they are not on MDMA. And that might sound like kind of a playful experiment just done in order to entertain oneself and the octopuses, perhaps.

But actually in that study, they identified the serotonin transporter in octopuses and showed 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 prosocial effects of MDMA that are observed in mice and in humans and in octopuses all have a common basis, which is the activation of more serotonin release in particular brain networks.

Okay, so that interesting study on octopuses aside, I think what most of us are interested in is how MDMA impacts the brain. And so I'm going to spell out the three major ways in which MDMA changes the activation of the brain in the short and long-term. And here I'm pooling across a number of different studies.

But one of the key sets of studies in this area comes from what I consider very beautiful work of Harriet DeWitt. Harriet DeWitt runs the Human Behavioral Pharmacology Laboratory in the Department of Psychiatry and Behavioral Neuroscience at the University of Chicago. And her laboratory has a long history of giving people certain drugs in very specific dosages and then measuring their effects on the brain using different types of imaging, including fMRI.

And one particular study that I'll highlight is entitled Effects of MDMA on Sociability and Neural Responses to Social Threat and Social Reward. So what 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 amygdaloid complex and has a lot of different sub areas. And it's involved in a lot of things besides fear and threat detection. Nonetheless, when people are under the influence of MDMA and you show them a face that is grimacing or would otherwise be rated as quite threatening, they tend to rate it as less threatening.

In addition, they tend to respond to happy faces or even slightly happy faces as more kind or more generous or happier than they would when they are not on MDMA. Again, the faces that are being shown are not of people on MDMA. That would be an interesting experiment, but that's not what they did here.

What's happening here is people are being given MDMA and then they are rating in a subjective way the friendliness or the level of threat that they detect in these facial expressions. And of course, they have extremes of friendly and threatening, but then they also grade them, right? They titrate them so that they also have mildly threatening and mildly happy faces, et cetera.

So everything from a grin to a smirk to a giant smile, everything from a sort of somebody looking a little bit askance at somebody to really wide-eyed and looking angry like they're going to attack you and things of that sort. So what's discovered in the study is that MDMA has a bi-directional effect on our perception of others' emotions, making people more likely to rate something as positive if it's initially positive or even a little bit positive and less likely to rate a threatening face as more threatening.

Now, one thing I have not mentioned thus far are the dosages of MDMA used in this and in other studies. And fortunately, despite the studies that we're going to talk about, using a lot of different types of people, different ages, different sexes, so male and female, located in different parts of the world even, some with PTSD, some not with PTSD, et cetera, there's been fairly tight dosage control of MDMA in these studies.

It's not perfectly matched from study to study, but it's pretty darn close, which makes interpreting results across studies a lot easier for me and therefore for you. The typical dosages of MDMA used in these neuroimaging studies and in the clinical studies of PTSD that we're going to talk about later range anywhere from 0.75 milligrams per kilogram of body weight to 1.5 milligrams per kilogram of body weight.

So for somebody like me, I weigh 220 pounds, that's 100 milligrams. 1.5 milligrams per kilogram of body weight would therefore be 150 milligrams in a single dose, okay? A dosage of one milligram per kilogram of body weight would mean 100 milligrams for my 100 kilograms, okay? Somebody lighter than 100 kilograms would obviously take less MDMA in one of these studies.

But in general, the range of MDMA that's been explored is 0.75 to 1.5 milligrams per kilogram of body weight. The exception being in the clinical studies that we'll talk about a little bit later, there's a tendency to explore both an initial dose of 1.5 milligrams per kilogram of body weight.

So again, for a 100 kilogram person, that'd be 150 milligrams or so. And then a so-called booster of half that amount, about 90 minutes to two and a half hours into the session. So another 75 milligrams later. And I should point out that there is not always the inclusion of the so-called booster.

And in some cases, lower doses of MDMA, such as the 0.75 milligrams per kilogram dosages are used. Why am I getting so into the details of dosages? Well, if we are going to talk about toxicity of MDMA, we absolutely have to talk about dosages. Because like any drug, the toxicity of MDMA does scale with the dosage that's applied, not just the frequency of MDMA use.

We hear a lot about that. Someone has taken MDMA one time or four times or 200 times. We hear about frequency of use, but rarely do we hear about the specific dosages that are taken in any one particular session. So when we talk about the subjective effects or the brain networks that are activated when people take MDMA, in general, we're talking about dosages somewhere between 0.75 milligrams per kilogram of body weight and 1.5 milligrams per kilogram of body weight.

Although typically you're going to see studies, both clinical and more research explorative, using anywhere from one to 1.5 milligrams of MDMA per kilogram of body weight. So that's important to highlight. I told you about the subjective effects of MDMA engaging the responses of people's faces, but I didn't tell you about the brain areas that are responsible, except for the reduction in amygdala activity.

Now, one of the key features of PTSD seems to be that there is a heightened connectivity between the amygdala and a brain area called the insula. The insula is a brain area that's very important for something that's called interoception. Interoception is one's perception of our feelings, both pure sensations, but also our emotional states and our feelings of wellbeing or lack of wellbeing for everything from our skin inward, okay?

So that's interoception. You actually can interocept now, even though you're always interocepting a little bit, you can interocept now to a great degree if you were to, for instance, close your eyes or simply focus on the contact points between your body and any surface that you happen to be contacting.

So maybe the backs of your legs against a chair or your feet against the floor or the bottoms of your shoes or sandals. Your nervous system is constantly sensing those contact points, but normally they're not under your conscious awareness unless you direct your interoceptive capacity to them, which is just fancy nerd speak for saying, you normally don't notice what's going on from your skin inward unless you focus on it.

That focus is interoception. It can be about the fullness of your gut. It can be about how happy or sad you are. It can be about how tired or alert you happen to feel, but that's interoception. And it is distinctly different from exteroception, which is your ability and tendency to focus on things beyond the confines of your skin.

So this could be visual attention, auditory attention. It could be paying attention to events like birds flying by, whether or not your Uber is showing up, these kinds of things. And we are always in a balance, a push-pull of interoception and exteroception. The insula is a brain area that is absolutely critical for interoception, so much so that it has a map of the complete body surface, including our internal organs.

In other words, if you put somebody into an fMRI machine or you were to record from the insula with electrodes, as has been done in humans many times now during the course of neurosurgery for other purposes, what you would find is that if you stimulate neurons in one end of the insula, the person will say, "Oh, you know, I feel something going on in my gut and on my left side." And then as you were to march that stimulation across the insula, you would find that they would now be paying attention to their legs or just to one leg or to their whole body or to the sensations in their face or their head.

There's a systematic map of interoception in the insula, and there are direct connections between the amygdala and the insula, and the amygdala, despite getting this reputation as just being a fear center or a threat detection center, is actually part of a much larger set of networks that include inputs from the hippocampus, an area of the brain that's involved in memory formation and storage, and what is observed is that people who have PTSD tend to have greater or rather stronger connections between the amygdala and the insula than is normally observed in people who do not have PTSD, okay?

So there seems to be heightened input from the threat detection centers of the brain to this area of the brain, the insula that is responsible for our sense of 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 exists in everybody, but that in people with PTSD seems to have heightened connectivity, and those brain networks can be revealed by putting people with PTSD into functional imaging machines, getting them to recall a traumatic event, or even looking at the resting state of connectivity between the amygdala and the insula.

So those experiments have been done, and what's also been done is to give people 1.5 milligrams per kilogram of MDMA and to look at the connectivity between the amygdala and the insula and between the hippocampus, the amygdala and the insula. And so what's observed over time in people that have been given MDMA and, this is a very important and, and have done therapy for PTSD, both before, during, and after the drug, there's a weakening of connections between the amygdala and the insula, and that scales very directly with the relief of symptoms from PTSD.

So this is really exciting because it's one thing to see a brain network get activated or inactivated, or you say, okay, in one person, a certain connection between threat centers and the interoceptive centers of the brain was, let's say, arbitrary units. Let's say it was level eight out of 10 for that person, right?

These things are normalized for a particular person. And then after taking MDMA and doing PTSD therapy, it was five out of 10 or four out of 10. That's a good experiment, but what's far more powerful is to observe that in that patient or that person, and then to see a change that's perhaps less dramatic.

So a shift from eight out of 10 to seven out of 10 in another person, and to see less shift in brain connectivity in the same network. And then perhaps in the person that went from full-blown PTSD to full remission of PTSD, something that, believe it or not, has been observed in single sessions with MDMA, if that person demonstrates an even greater reduction in the connections between the amygdala and the insula, well, then that gives even more confidence that this connection between the amygdala and the insula is actually perhaps causally related to the reduction in symptoms of PTSD.

Or even if it's just correlated with reduction in symptoms of PTSD, the fact that the degree of reduction of connection of this circuit scales with the reduction in clinically relevant symptoms, that's a very powerful finding because it moves things away from pure correlation of, oh, this brain area is active or less active over time, and this person has more or fewer symptoms of PTSD, to something that starts to look like a mechanistic and logical framework for understanding PTSD, as well as the effects of MDMA, and for understanding how changes in the brain underlie relief from PTSD.

Okay, so again, even if you just could grasp the idea that you have a brain area, the amygdala, that's involved in threat detection, and it provides inputs to another brain area called the insula, which is involved in this thing called interoception, and that reductions in those connections between the amygdala and the insula scale with or correlate with reductions in PTSD symptoms as a consequence of people taking MDMA.

So if you have that under your mental belt, I promise you, you understand far more about how MDMA impacts the brain in the short and long term than 99.9% of people out there. However, it's also important that you understand a few other things that MDMA does to the brain, as well as what it doesn't do to the brain.

First of all, classic psychedelics like psilocybin and LSD, as I mentioned earlier, are known to create more lateral connectivity between different areas of the so-called neocortex. And these are long-lasting changes that are thought to underlie both some of the relief from major depression, but also some of the enhanced creativity and some of the other things that have been observed with psilocybin treatment.

And again, if you're interested in psilocybin treatments and psilocybin itself, please check out the episode I did on psilocybin and the guest episode with Dr. Robin Carthart-Harris. Those episodes, like all other episodes of the Huberman Lab podcast can be found at hubermanlab.com. It's a fully searchable site. You can put keywords into the search function.

It will take you to specific timestamps. Every episode is timestamped so you can navigate to topics of particular interest to you. Feel free to go there and listen to those episodes about psilocybin. MDMA, by contrast, does not seem to produce long-lasting increases in lateral connectivity between those same brain networks, probably because it impacts different serotonin receptors.

It does, however, seem to change resting state functional connectivity within these limbic structures like the amygdala and related structures that are associated with threat detection. Now, this is interesting, and it actually was highlighted very nicely in a study I'll provide a link to in our show note caption, which actually has Dr.

Robin Carthart-Harris as the first author. So not only has he done incredible work on psilocybin and LSD and DMT and ayahuasca in his laboratory, but also on MDMA. And the particular study I have in mind here showed that people who take MDMA at more or less the dosage that we talked about earlier report marked increases in positive mood, as well as decreased blood flow to the amygdala and hippocampus.

So again, these threat detection centers of the brain and brain areas associated with memory. And those changes are seen both while under the influence of MDMA and afterwards when the brain is simply at rest. So it really does appear that MDMA creates neuroplasticity that changes the overall level of activation of these threat detection networks and their connections to memory systems in a way that's pervasive over time and that doesn't require any particular probe with a negative stimulus.

Translated to English, what that means is that during the MDMA session, people report feeling less threatened, more pro-social towards others, more empathic towards others and themselves. And then after the session, they have less of a threat response to memories that before the session were more troubling. And those changes in the brain do seem to be pervasive.

So there are both short-term and long-term effects of MDMA, all of which point in the direction of lowered levels of threat detection, heightened levels of positivity, pro-social components of the brain, more active threat detection centers of the brain, less active. Now, earlier we talked about MDMA as a drug that potently increases dopamine and even more potently increases serotonin, largely acting through this serotonin 1B receptor.

Now, without getting into too many more details before moving on to issues of toxicity around MDMA, I do want to touch on what I think is perhaps the finest of the animal model studies of MDMA that explored which brain networks and which chemical, that is serotonin or dopamine, is responsible for, say, the motivational components of MDMA versus the pro-social effects of MDMA.

And then it also raises a really important point, which I haven't mentioned yet in this episode, which is the role of oxytocin, something that many of you have perhaps heard of. The paper that I'm going to describe is from the laboratory of Dr. Robert Malanka. He's a colleague of mine at Stanford University School of Medicine, Psychiatry and Behavioral Sciences.

He is both a pioneer and luminary in the field of neuroplasticity, of how the brain wires and forms memories and can change itself over time in response to experience, as well as the study of drugs of abuse, as well as the study of drugs like MDMA and now additional compounds that can provide therapeutic support in certain conditions.

The study, which I will provide a link to in the show note caption, is entitled Distinct Neural Mechanisms for the Pro-Social and Rewarding Properties of MDMA. And I'm just going to summarize the major results of this study. It's a study that was done on mice, and I realize that a lot of people will hear that and think, ah, what relevance does that have to humans?

But when thinking about the effects of dopamine and serotonin in the types of circuits that we've been talking about thus far, these circuits that are subcortical, as we refer to them, so these are limbic circuits, these are hypothalamic circuits, these are what are called mesolimbic circuits, these are all names for circuits that are highly conserved between mice and humans.

And so results in mice really do translate quite well to results in humans, at least in so far as the effects of MDMA and which neurochemicals are involved is concerned. So what they found in this study, using a huge array of beautiful techniques, such as inactivation of specific brain areas, activation of specific brain areas, drug antagonist to prevent oxytocin function, or drug antagonist to prevent specific receptors involved in the serotonin pathway, lots and lots of tools in their toolkit.

What they found is that MDMA causing the release of dopamine is what really establishes the rewarding effects of an experience. This isn't really a surprise. We've known that MDMA, just like cocaine or methamphetamine or Adderall for that matter, or Vyvanse for that matter, creates big increases in dopamine that tend to couple an experience with a sense of reward and lead to changes in the neural circuitry that make the animal or human more likely to seek out that same experience again.

Okay, these are the rewarding or sometimes called reinforcing properties of dopamine that take place in the so-called mesolimbic reward pathway. If you want to learn about mesolimbic reward pathways and dopamine and how they control everything from your level of motivation to your tendency to procrastinate or overcome procrastination, I've done two episodes about dopamine.

You can simply go to hubermanlab.com, put dopamine into the search function, and you'll find at least two episodes on that topic. And you'll also find a number of different tools related to how one can better regulate their own patterns of dopamine release for sake of motivation, et cetera. So MDMA is increasing dopamine to increase reward to a particular experience.

What's the experience? Well, this paper beautifully parses the fact that it is serotonin release within a structure called the nucleus accumbens, which is part of the reward pathway, which is rewarding the experience of social interaction. They do this by putting mice in arenas where they have the option of either spending time with other mice or not spending time with other mice and blocking the activation of certain brain areas, and again, using drug antagonists, et cetera.

And what they find is that it really is the activation of the serotonin 1B receptor in the nucleus accumbens by MDMA that leads to this prosocial effect of MDMA. So that's really nice to know because there's always been this conundrum of, okay, psilocybin and LSD are basically like serotonin.

They activate the serotonin 2A receptor. MDMA has this huge serotonergic component, tons of serotonin released when one takes MDMA, but very different effects in the short and long term, very different subjective effects, very different patterns of change activity in the brain in the short and long term. Well, that's because MDMA is activating the serotonin 1B receptor, not the serotonin 2A receptor, and it's doing so in a completely different set of brain networks as is LSD and psilocybin.

So what happens when an animal or a person takes MDMA is that social connection is strongly rewarded and reinforced, making social connection more likely after the drug wears off. Now, that's one component of social connection, but in addition, people who take MDMA in the clinical therapeutic setting for the treatment of PTSD often report feeling more empathy and compassion for themselves during the session, but also for long periods of time, maybe even indefinitely after the session.

So it really seems that the addition of this huge release of serotonin by MDMA on top of the release of dopamine sets in motion two parallel circuits, one for rewarding something, anything, that's the dopamine component. And then fortunately, because the increase in serotonin caused by MDMA increases empathy and sociability for and with others, but also for oneself, the motivation that's reinforced, that's wired into the brain seems to be a motivation to perceive others as more kind, but also to be kinder to oneself.

Now, I realize that for some of you who are listening to this, you're probably saying, well, of course, right? You know, serotonin is pro-social and dopamine is motivation, so you put the two together and people become more motivated to be social and kinder to themselves. Ah, but it didn't necessarily have to be that way, right?

It is very hard to go from a statement like drug A produces effects B, C, and D to neurochemicals B, C, and D cause motivation and sociability, and therefore, when you take that drug, you're going to get all of that stuff. In fact, we have to go back to our understanding that MDMA, despite causing a big increase in serotonin, also causes huge increases in dopamine, and it does so with this molecule that is methamphetamine.

Now, methamphetamine is not known to be a pro-social drug. In fact, the study I just referred to, as well as some human studies, have explored how the application of methamphetamine, so not MDMA, but pure methamphetamine, impacts social interactions, and what it does to social interactions is very profound. It dramatically reduces one's tendency to engage in social interaction.

So this really speaks to the polypharmacology, as it's called, of MDMA, the fact that serotonin and dopamine are released together has distinctly different effects than if just dopamine or just serotonin is increased, so much so that it's worth taking a step back and talking about another class of drugs which dramatically increases serotonin, which are the SSRIs, the selective serotonin reuptake inhibitors.

SSRIs, such as fluoxetine, Prozac, as well as Zoloft, and of course, there are many other SSRIs out there, citalopram, et cetera, they block the reuptake of serotonin and thereby lead to net increases in the amount of serotonin, and yet those drugs are not known to create even close to the same sorts of effects as MDMA.

In fact, there have been human and animal studies showing that if you give somebody an SSRI prior to them taking MDMA, you actually block the prosocial and empathogenic effects of MDMA. Now, you might say, why in the world would that be? Aren't these drugs just increasing serotonin and the increase in serotonin is prosocial, et cetera?

Ah, well, that speaks to the complexity of all this polypharmacology and the fact that it's really the activation of serotonin at particular receptors, in this case, the serotonin 1B receptor, in particular brain areas. In this case, the nucleus accumbens, a brain area associated with motivation and reward that largely explains the effects of MDMA in making people and animals, and octopuses included for that matter, more prosocial and more empathic towards themselves.

It's not just an issue of raising the levels of one neurochemical. It's really about raising levels of a particular neurochemical acting in particular receptors, in particular brain areas. And in the case of MDMA, the fact that there's also dopamine increased in those very same brain areas, right? I don't think I mentioned this before, but the nucleus accumbens is part of that mesolimbic reward pathway that is essentially establishing a reward for whatever is happening at the moment.

So the way to conceptualize MDMA and its effects on the brain, both subjectively and mechanistically, is that it's an empathogen for which empathy and social connection is very strongly reinforced while under the influence of the drug, and in a way so intense and powerful that those neural networks get stronger and persist in being more active for long periods of time after the drug has worn off.

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Again, that's drinkelementlmnt.com/huberman. Now, one of the things that's been explored in both the animal literature and the human literature is that MDMA doesn't just increase dopamine and doesn't just increase serotonin, but it also profoundly increases levels of oxytocin release in the brain. Now, oxytocin is considered what's called a neurohormone because it acts as both a neurotransmitter, or I guess if we were going to be really specific, we'd say a neuromodulator because it tends to modulate the activity of a bunch of other circuits, and a hormone.

How can we say it's a hormone or a modulator or a transmitter? Well, hormonal effects tend to be effects that act not just locally, but on many sites within the brain and body as well. And oxytocin is known to do that as well as to work locally. So that's 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, et cetera.

In fact, there are even data suggesting that humans can have strong oxytocin responses to their pets, in particular dogs, and their dogs can have strong oxytocin patterns of release in response to their owners. I think for any dog lovers or dog owners, certainly includes me, I'm raising my hand, that comes as no surprise.

Anyone that's ever had to put down a dog or has lost a dog and 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 note captions entitled Plasma Oxytocin Concentrations Following MDMA or Intranasal Oxytocin in Humans. Nowadays, oxytocin is available by nasal inhaler.

To be honest, I don't know the legality around it. I don't know if it's gray market or, but what I'm about to tell you will basically discourage you from wanting to take it, because what they found in this study was people given either 0.75 or 1.5 milligrams per kilogram of body weight of MDMA experienced increases in oxytocin.

However, it was only the group that took 1.5 milligrams per kilogram of body weight of MDMA that experienced the really big significant changes in oxytocin. And when I say really big, really highly statistically significant, what they observed is that in the placebo group, because of course they include a placebo group, the amount of circulating oxytocin was 18.6 picograms per milliliter, which to you probably means nothing.

And to me also sort of means nothing because those units of oxytocin can't be directly related to any kind of direct experience of feeling bonded or not bonded. That's just a number, but nonetheless, it provides a baseline to compare to the average levels of oxytocin in the bloodstream of people that were given 1.5 milligrams per kilogram of MDMA, which is 83.7 picograms per milliliter.

That equates to nearly a five-fold increase in the amount of circulating oxytocin when people are under the influence of MDMA. Now, this study had a bunch of different conditions, not just MDMA of different doses, not just placebo. They also had people take oxytocin by nasal spray, which we know can change levels of circulating oxytocin.

And indeed when measured in the study, it did change levels of circulating oxytocin. And the end point in the study was to have people give subjective ratings of their feelings of connectedness to one another, as well as rate. And here I'm just drawing directly from the paper of how much they like the feeling, how much they felt high.

They measure their heart rate, their systolic pressure, their diastolic blood pressure, et cetera. And they looked at how social people felt. They looked at how insightful people felt. And the key takeaway from this study for sake of our discussion here today is that it does not, again, it does not appear that the increases in oxytocin produced by taking MDMA are the source of the prosocial effects of MDMA.

And that's also what was found in the animal studies of MDMA where in those studies, mice were given MDMA at comparable doses. The doses were a little bit higher than used in the human studies. But at comparable doses, big increases in oxytocin were observed, increases in sociability of those mice were observed, just as they are in humans that take MDMA.

But in those mice, they were also given a drug to block the oxytocin receptor. And lo and behold, no changes in sociability were observed. In humans that take oxytocin by nasal spray, you can see big increases in oxytocin. That's not surprising, gets across the blood brain barrier. Oxytocin goes up and levels of sociability do not increase.

So what this points to is a situation where MDMA is increasing dopamine to increase motivation and to reward something, what gets rewarded? Well, what gets rewarded is the serotonin activation of particular brain networks associated with sociability. And the dramatic increases in oxytocin that are very, very real when people take MDMA do not appear to underlie any of the known short or long-term subjective effects of MDMA.

Now, a conclusion like that needs to have a caveat. And the caveat is that as far as we know, the big increases in oxytocin that are produced by MDMA aren't doing anything for the sorts of effects that we've been talking about here, sociability, empathy, et cetera, but there could be other effects of oxytocin that we're just not aware of.

That said, the data from both animal models and in humans really point to the fact that the increases in oxytocin that are produced by MDMA are not directly related to any of the short and long-term effects of MDMA that we are most familiar with, namely motivation, sociability, increased empathy, or the longstanding changes in neural circuitry that underlie, for instance, reduced threat detection or reduced connectivity between threat detection centers of the brain and interoception.

So is the big increase in oxytocin produced by MDMA completely irrelevant in the context of this discussion? We don't know. It appears that it's not very relevant. Is oxytocin a meaningless molecule, right? After all, they gave these people nasal infusions of oxytocin. Oxytocin went way up. It didn't observe anything very interesting or significant in the context of sociability, but we do know that oxytocin can play a powerful role in pair bonding and in human-human-human-animal bonding of various kinds from other experiments that have been done.

So I don't want to diminish the incredible power that oxytocin has in our brains and bodies, but it doesn't appear that the MDMA-induced increases in oxytocin, which are enormous, have much to do with anything related to the value of MDMA as a treatment for PTSD or for its subjective effects on empathy, sociability, or any of those other factors either.

Now, perhaps the one caveat to that is that Harriet DeWitt's laboratory, which I referred to earlier, has looked at how variations in oxytocin receptor genes vary between people. So it turns out that some people have an allele, basically a version of the oxytocin receptor that is different from other people that makes oxytocin work differently and actually less effectively in activating certain brain networks.

And it does appear that when those people take MDMA, they actually experience less of a prosocial 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 prosociability and empathy. I think the bulk of the data really point to the fact that it's the serotonin increases combined with the dopamine increases caused by MDMA that lead to most of the understood effects.

And that oxytocin, if it's playing a role, is going to play a more minor role. Let's talk about the safety and potential neurotoxicity of MDMA. And here, I really want to highlight that our discussion today is couched in a discussion about the application of pure MDMA to animals or humans in the context of laboratory or clinical studies.

This is really important to point out because I would be remiss if I didn't note that there is a lot of recreational use of MDMA. In fact, it was the recreational use of MDMA in the 1980s, but really that took off, even exploded in the 1990s with so-called rave culture that created the massive attention on illegality of MDMA and put the drug enforcement agencies onto MDMA as a drug that they wanted to and indeed do restrict.

In fact, just today, in anticipation of this episode, I put MDMA into the search function on Google and clicked news, and there were at least two reports of major MDMA seizures and busts. So again, I want to highlight the fact that MDMA is still illegal to possess or sell and certainly to traffic.

I also want to highlight the fact that nowadays, all recreational drugs, but certainly MDMA included, are often, in fact, very often contaminated with fentanyl and while fentanyl has certain clinical uses, fentanyl is highly deadly. The current estimates are as much as 60%, maybe even 80% of drugs that are sold on the gray market are being repackaged or reformulated with fentanyl, and there have been a lot of fentanyl-related deaths, both in kids and adults.

So the sourcing of MDMA is extremely important and the safety issues simply cannot be overlooked. And I say that not to protect me, I say that to protect you, right? The last thing any of us want is for someone to take a compound thinking it's one compound and it contains another compound and them getting hurt or even dying, and that is happening a lot, a lot, and it is certainly happening a lot for people that think that they're buying MDMA.

The use of MDMA in the laboratory or in the clinical setting with pure MDMA has also been explored for the potential neurotoxicity of MDMA. So how would methamphetamine and MDMA be neurotoxic? Well, that's because they increase dopamine in the case of methamphetamine and dopamine and serotonin in the case of MDMA, and they do so to a very high degree.

The big increases in dopamine and serotonin, but in particular, the big increases in dopamine tend to promote electrical activity of other neurons. Remember, these are after all neuromodulators, they modulate up or down the activity of other neurons and dopamine tends to modulate the activity of other neurons up. So dopamine itself is not neurotoxic, but when a lot of dopamine is released, it is neurotoxic.

And it's well known that even a single dose of methamphetamine can be neurotoxic, not just for dopamine neurons, but for other types of neurons as well, including serotonergic neurons. Put differently, we know that the brains of people that take methamphetamine degenerate to a small or to a large degree, depending on how often they take the drug, how potent the drug is, and whether or not they combine it with other drugs.

And yes, if you heard that combining caffeine with amphetamines can increase the neurotoxicity of amphetamines, such as methamphetamine, that is true. If you've heard that taking caffeine within the hours or same day as MDMA can increase the toxicity of MDMA, that does appear to be true based on animal studies.

Now, there are not a lot of studies looking at the toxicity of MDMA in humans, but there are a few. There are also studies looking at the toxicity of MDMA in animal models, including non-human primate models. Now, this is a very complex literature, a lot of results, not all over the place, but they're scattered in a number of ways.

First of all, some of the animal studies have used dosages of MDMA as high as two milligrams per kilogram of body weight, as high as three milligrams per kilogram of body weight, and even an upwards of that. But even for the animal studies that used a range of dosages from 0.75 to 1.5 milligrams per kilogram of body weight, there is some evidence that in laboratory 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 in dopamine, big releases in serotonin, it's not surprising that if the animals that were given MDMA are subsequently sacrificed, say later that day or the next day, maybe even a week or two weeks later, and those brains are stained for proteins that are related to the synthesis or release of serotonin, it's not surprising that there would be reductions in those sorts of proteins, right?

After all, a lot of dopamine and serotonin is released and it can be depleted. But I should point out, depletion of a neuromodulator in the short term is not the same thing as depletion of that neuromodulator in the long-term, nor is it the same as loss of the neurons that release dopamine and serotonin itself.

So there are data pointing to the fact that repeated administration of MDMA at dosages that are very much within lines with what we're talking about today, 1.5 milligrams per kilogram of body weight, can lower total amounts of serotonin or other proteins in the serotonin synthesis pathway or dopamine or proteins that are in the dopamine synthesis pathway in specific areas of the brain related to reinforcement, related to mood, related to motivation, et cetera.

However, the primate studies, or I should say the non-human primate studies, which are the sorts of animal studies that most closely mimic what one expects to see in the human brain, because after all, mice and the effects of these drugs 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 that MDMA might not be as neurotoxic as is thought based on the rodent studies. And this gets into a whole history of back and forth between different laboratories and governing bodies who are trying to keep MDMA illegal, as well as people such as the Sasha Shulgans of the world and people in the therapy community that are excited about the potential for MDMA becoming legal for the treatment of PTSD.

And it really centers around one or two studies, both of which were published in very high profile journals. And the one that I'll highlight, because the results are now very clear and conclusive, is a study that was published back in 2002, which was entitled Severe Dopaminergic Neurotoxicity in Primates After a Common Recreational Dose Regimen of MDMA or Ecstasy.

This paper was published in the journal Science, which is one of the three apex journals for publishing scientific research. So there's Science, Nature, and Cell. Those are the top, top journals, the most stringent journals to get scientific manuscripts into. The paper received a lot of attention because as you can imagine, based on the title, it suggested that even recreational doses of ecstasy, even if it's pure ecstasy and it doesn't have contamination from additional methamphetamine or other things in it, is neurotoxic to serotonergic and/or dopaminergic neurons.

This is largely where MDMA got the reputation for "putting holes in your brain." However, this study came under a lot of scrutiny for a couple of reasons. First of all, and I'm certainly not saying this, but it was argued that the authors of the study were perhaps trying to prevent the legalization of MDMA for the treatment of PTSD.

As far as I know, there's no direct evidence that that statement is true, but you will actually find that in some of the scientific journals. In fact, I was able to find an editorial that was published in the Biomedical Journal in 2003, which argued somehow that Dr. Ricarte was accused of "rushing his results into print because of legislation designed to curb ecstasy use before U.S.

Congress." So, you know, there were some connotations, or rather there were some strong suggestions that there was a political backing to trying to get this study done quickly and into print and so forth. I don't think that ever really got resolved. What did get resolved, however, is that the very study in question was retracted, okay?

So the authors themselves published a letter of retraction that unfortunately is not as well recognized as the paper that stimulated this idea that MDMA is neurotoxic in primates. And keep in mind that we are human primates, non-human primates being the closest model to human primates that we are aware of.

But to make a long story short, there were some issues of labeling of MDMA versus other drugs in the laboratory. There were some issues of mislabeling, all of which were eventually acknowledged by the authors of the study. And they concluded, in fact, they verified based on some very detailed analysis that what these monkeys were injected with was not actually MDMA, but rather was methamphetamine itself.

So what's not often acknowledged is the retraction of the paper on neurotoxicity. And unfortunately, the neurotoxicity issue is often what's mentioned. Now, keep in mind, there are studies in rodents showing neurotoxicity of MDMA, perhaps even at recreational doses. But to date, at least to my knowledge, there don't seem to be any data in either non-human primates or in humans showing toxicity of MDMA at clinically relevant doses, provided it is pure MDMA.

I want to be very clear. I'm not saying that if you can get pure MDMA that you should take it or that it won't be neurotoxic. Certainly, we can expect that because of the huge known variation in dopamine receptors, in serotonin receptors, and of course, because of the known interactions between MDMA and other compounds, in particular caffeine, but also drugs such as cocaine or other stimulants, that some people might experience more toxicity to a given dose of MDMA compared to somebody else.

And there's really no way to detect that susceptibility to neurotoxicity. Now, what we do know is that there are people in the general population that have taken a lot of MDMA, anywhere from one to 200 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 neurocognitive and behavioral effects of taking MDMA either zero times, one time, five times, 40 times, 200 times, et cetera, et cetera.

And one of the, what I would consider landmark studies in this area is a study entitled residual neurocognitive features of long-term ecstasy users with minimal exposure to other drugs. And those words with minimal exposure to other drugs is really key in the context of this conversation. Because as I mentioned before, interactions between drugs, what's called polypharmacology, can create neurotoxicity.

It's unclear if MDMA is neurotoxic, but we know methamphetamine on its own is neurotoxic. We also know that people often will combine MDMA and methamphetamine. We also know that a lot of so-called MDMA out there is mostly methamphetamine with only a little bit of MDMA. So a study of the sort that I'm about to describe where it is essentially confirmed that people were taking pure MDMA and not taking any other drugs is of immense value.

This study has been a little bit controversial. In fact, I've talked about it before. I talked about it on the Joe Rogan podcast. I've talked about it briefly with a guest on this podcast, Dr. Nolan Williams, who's a triple board certified physician, psychiatrist and neurologist at Stanford School of Medicine.

And it's an interesting study and a little bit controversial because it relied on a population of people who have taken MDMA anywhere from one to 200 times and who've not taken any other drugs, including caffeine. And the population in mind here is a population of people living in Utah who self-identify as members of the Church of Latter-day Saints, sometimes referred to as Mormons, sometimes referred to as LDS or of the Church of Latter-day Saints.

The Church of Latter-day Saints, as I understand, does not allow for taking of certain compounds, certain drugs, certainly most recreational drugs, alcohol, even caffeine. And I'm sure there's some variation on some of those themes, depending on where people live and the certain communities that they happen to be in.

I am in no way, shape or form declaring that I'm an expert on Latter-day Saints. I have a couple of friends who are LDS. I happen to be very nice people. As far as I know, they were not the people in this study, but this study really emphasized ecstasy users, as they're called, who have not taken other drugs, who self-identify as LDS.

And the major takeaway of this study was that for moderate, meaning people who have taken ecstasy anywhere from 22 to 50 times in their lifetime, as well as heavy users of MDMA, so these are people who have taken MDMA anywhere from 60 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, et cetera, are degrading their levels of self-control and thereby increasing impulsivity.

The direction of the effect is not known, these are purely correlations. Nonetheless, this study and a few others like it really stand as our best evidence, believe it or not, as to how ecstasy taken many times, because after all these people are taken anywhere from 22 to 450 doses of ecstasy in their lifetime, is producing severe detriments in cognitive performance and that simply does not appear to be the case.

Now, unfortunately, there are no data looking at the brains of these individuals, looking at, for instance, which brain structures are active or less active, or perhaps even looking at levels of serotonin or dopamine, all things that can be done with positron emission tomography imaging, functional MRI, et cetera. Hopefully those studies will be done in the not too distant future.

But if we were to just take a step back from all the data, the data in mice, in rats, in non-human primates, the retraction of the study in non-human primates, which showed that the primates that showed neurodegeneration were not given MDMA as it was thought by the researchers, but rather as later was acknowledged, were actually given methamphetamine.

And we take into account these moderate and heavy users of MDMA who, as far as we know, are being honest and haven't taken any other drugs. And we look at the clinical studies where people who have never taken MDMA are given one or two or three defined doses of pure MDMA.

We'll talk about those studies in a moment. I think the gestalt, the top contour, the overall view of those studies is that provided it is pure MDMA and provided the individual is not consuming other drugs which have the potential to be neurotoxic and provided that it's being done in a controlled clinical setting, the risk for toxicity seems quite a bit lower than the popular press has promoted.

And yet there is still the risk of neurotoxicity if people are taking high doses of MDMA or taking it very frequently, or certainly if they are taking it in conjunction with other drugs or, or I should say, and/or taking MDMA in settings that can promote neurotoxicity. And the settings I'm referring to are any settings in which blood pressure or body temperature have the propensity to be greatly increased.

Every study in mice and non-human primates and in humans in which MDMA is administered has observed significant increases in blood pressure and heart rate. MDMA is after all a psychostimulant. It's a sympathomimetic. Talk about sympathomimetics and what that means in the episode on Adderall and 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. This is why they feel agitated, they want to talk a lot. They feel like they want to move a lot. This is why people take it to dance at raves, et cetera.

But when people take sympathomimetics, whether or not it's MDMA or amphetamine or cocaine or even caffeine, there's an increase in blood pressure and heart rate, but also body temperature. And if that's done in an environment in which there's very little temperature regulation, so people aren't, for instance, drinking enough fluids and electrolytes, it's very hot in the room, you can get neurotoxicity based on temperature effects.

And that's because serotonin and dopamine also act on the so-called medial pre-optic area of the hypothalamus, which is involved in temperature regulation. If you're curious about temperature regulation, I covered a lot of that in the episodes of the Huberman Lab Podcast on deliberate cold exposure and deliberate heat exposure.

This is an area I used to work on many years ago as a research scientist before moving on to other topics to research in my laboratory. Big increases in body temperature are not good. The body, and in particular your brain, can tolerate decreases in body temperature that are pretty robust and you can still stay safe.

You're not going to kill neurons, but even an increase of three or four degrees in body temperature can start to kill off neurons. So when thinking about the potential neurotoxicity of MDMA, the conditions, that is the environmental conditions, the behavioral conditions under which somebody takes MDMA are vitally important, at least important, I would argue, as any other compounds they might be ingesting with MDMA.

So that's something really serious to consider. So if somebody says MDMA puts holes in your brain, you would be correct in being skeptical or at least giving them some counterarguments for that statement. But if somebody says MDMA is not toxic, well then you would be equally valid in saying, ah, wait, but we need to think about the conditions under which MDMA is being taken.

Is it pure MDMA or is it mostly methamphetamine? In which case it would be very toxic. Is it MDMA alone or in conjunction with caffeine within that same 24 hour period? Is it MDMA while moving around a lot or being outdoors or being in an environment, perhaps a rave or dance type environment where temperature is going up?

Well, in that case, it could be very neurotoxic. So pharmacology of MDMA counts, but so does polypharmacology, the ingestion of other compounds, not just during the MDMA session, but also in the 24 hours before and after that MDMA session. And behaviors will certainly impact temperature, which will impact whether or not MDMA is neurotoxic or not.

And despite my efforts, I couldn't find out whether or not the LDS community has officially sanctioned the use of MDMA. Certainly that's one possibility, but I have no evidence for that. Or rather whether or not certain people within the LDS community have allowed themselves, given themselves permission to use MDMA and they are not using other drugs.

What I do understand to be the case is that people within the LDS community are discouraged from using drugs like caffeine or cocaine or alcohol. And this particular population of people that was explored in this study self-identify as LDS and self-identify as having taken MDMA anywhere from 22 to 450 times.

But where they got permission for that, whether or not it was from someone else or from themselves, I do not know. What I do know is that within the acknowledgements of the paper, there's actually a thank you to the person that identified this "unique population" for our study. So I welcome you to take a look at the paper.

And if any of you know more about if and how a particular subgroup within the LDS community is allowed to take MDMA, perhaps you want to put those in the comment section on YouTube. Before moving to our discussion about what MDMA is doing and the effects that people are seeing in the clinical studies for the treatment of PTSD, which by the way, are extremely exciting.

I can't wait to share these data with you. I do want to touch on something that anyone who's heard about MDMA or perhaps used MDMA is familiar with. And that's the so-called crash that people experience after MDMA. There are a lot of myths about the post MDMA crash. And there's a lot of lore out there on the internet about how to offset the crash and a lot of lore about how to prevent the potential neurotoxicity of MDMA.

Earlier, we talked about some of the major points around offsetting neurotoxicity. So certainly making sure that any MDMA that one takes is in the legal clinical setting, that it's therefore pure MDMA, right? That it's not cut with other things, which certainly can increase toxicity, controlling the temperature of one's environment, restricting caffeine intake, at least on the day of MDMA ingestion, but certainly the day before and the day after would be advantageous as well, simply because of the way that caffeine and activation of the adenosine receptor, as well as caffeine's effects on dopamine receptors can interact with the potential, again, potential neurotoxicity of MDMA.

But the crash that one experiences after MDMA is actually a phenomenon very common to the crash that one experiences after ingestion of any type of stimulant, cocaine, amphetamine, et cetera. And the crash that we're referring to is a drop in mood, increase in lethargy, feelings of lack of motivation.

Many people have wrongly assumed that the crash was due to quote unquote, depletion of serotonin or depletion of dopamine, or maybe even death of serotonergic and dopaminergic neurons. And while certainly that could be the case, it's very unlikely that that would be the case in the immediate 24 or 48 hours after MDMA ingestion.

That said, you will see protocols that people have put out on the internet such as, oh, you know, after taking MDMA, you should take a bunch of, you know, 5-HTP or other precursors to serotonin or dopamine, which come in amino acid form. So L-tryptophan, for instance, is the amino acid precursor to serotonin, it's in the serotonin synthesis pathway.

You'll hear that people will take L-tyrosine, which is the amino acid precursor to dopamine as a way to try and buffer or increase dopamine during the so-called period of the crash. There's really no evidence that any of those things can be beneficial. And there is actually some reason to believe that it might be detrimental because if anything, taking L-tryptophan and taking L-tyrosine would actually further deplete serotonin and dopamine.

So the logic there is simply not very good. What is clear, however, is that MDMA can cause not just profound increases in dopamine, serotonin, and oxytocin, but that anytime there's a big increase in dopamine, there is going to be a post dopaminergic increase in prolactin release. And prolactin is a hormone, sometimes considered a neurohormone, but it's really a hormone that's involved in a lot of things, milk let down in lactating women.

It's involved in setting the refractory period to sexual arousal and erection and ejaculation in males after ejaculation. It's involved in lots of different functions in the brain and body, including the laying down of body fat stores. And it's also associated with increases in lethargy, decreases in dopamine. This is why drugs that increase dopamine are known to decrease prolactin, at least in the short term.

This is why drugs like cabergoline, for instance, that increase dopamine are used as ways to suppress prolactin. Now, MDMA ingestion is known to dramatically increase prolactin, and people are starting to realize that it perhaps is the increase in prolactin that occurs both during and for some period of time, probably hours or days after ingestion of MDMA that leads to at least some components of the so-called crash, that feeling of lethargy and lack of motivation, maybe diminished mood, et cetera.

And for that reason, some people have started to explore the use of things like P5P, which is essentially a metabolite of vitamin B6, which is known to suppress prolactin as a way to try and buffer some of that crash. To my knowledge, there are no human data yet exploring the use of P5P or other vitamin B6 derivatives or cabergoline or things of that sort to reduce prolactin in a controlled, standardized clinical trial kind of manner.

But I've spoken to some of the clinicians that are using MDMA legally within the context of the treatment of PTSD. And this is an area that's starting to receive some additional attention. So I just mention 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 L-tyrosine, they should be taking magnesium, other things, et cetera, after taking MDMA in order to recover from the post-MDMA crash more quickly.

But it's really the increase in prolactin, which speaks most directly to the subjective effects of the so-called crash. So by my read of the mechanisms of MDMA, the neurochemicals it releases, the neurohormones that it promotes the release of, prolactin in particular, this P5P suppression of prolactin is perhaps the one that's most intriguing and that really has any kind of mechanistic basis.

So I promise that going forward, as the scientists and clinicians that are using MDMA for the treatment of PTSD and other conditions, such as alcohol use disorder, et cetera, start to explore the use of post-MDMA session P5P and other modes of suppressing prolactin for the hours and days after MDMA, promise to update you on those findings.

Throughout today's episode, I've been referring to clinical studies, that is clinical trials, exploring the use of MDMA in order to augment treatment for PTSD. So let's just take a moment and talk about what PTSD is. PTSD is post-traumatic stress disorder. Trauma is anything that modifies the brain to function less well going forward.

You can have physical trauma, you can have emotional trauma. Typically PTSD is used to refer to emotional trauma caused by either single events. So you can imagine car accident, sexual assault. These could be first person experiences. So things that happened 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 longterm. And of course, PTSD need not be caused only by single event traumas, but by multiple event traumas, entire relationships, entire childhoods, wartime experiences, combinations of different traumas and on and on.

There are so many different forms of trauma. If any of you are interested in trauma and its treatment, I highly recommend the book "Trauma" by Dr. Paul Conte. 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 Conte's own experiences with trauma and his own treatment of trauma in his patient population, which is quite wide ranging men, women, young people, older people, and a variety of traumatic experiences.

So excellent book for those of you interested in trauma. Now, the treatment of trauma has been met with some degree of success through quality talk therapy. Let's define quality talk therapy in the way that Dr. Paul 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, so a psychologist or psychiatrist, has good rapport.

And as a consequence of that rapport, there is the feeling of support, that there is a safe place in which to explore the trauma and what's happening in one's current life in order to understand how that trauma is fitting into adaptive and maladaptive behaviors and emotional states. Now, in addition to rapport and support being critical, there's a third component of effective talk therapy for trauma, which is insight, where one's ability to come to an understanding of why one feels the way they do and to link that to some larger context, that brings about some degree of relief.

And that's where things start to get a little bit abstract. And that's also where we start to see that while trauma therapy in the form of talk therapy can be very effective, about half of people that undergo talk therapy and talk therapy alone for the treatment of PTSD achieve no long lasting relief of symptoms, and an even smaller number of them undergo complete remittance of their PTSD, 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. Things like blunting of libido, blunting of appetite, or increases in appetite in some cases, disruption of sleep-wake rhythms, motivation, et cetera. So there's often an exploration for the so-called minimal effective dose that provides some symptom relief to PTSD, but that doesn't introduce unwanted side effects.

And of course, there's a third situation where people are taking SSRIs and doing talk therapy for PTSD. And what's very clear is that anytime you add quality talk therapy to a drug treatment, you're going to improve the outcomes for that drug treatment. The reverse is not always true. It's not always the case that adding prescription drug treatment to talk therapy improves outcomes for talk therapy, although that has been observed in a number of studies.

Now, the whole idea of exploring the use of MDMA for the treatment of PTSD stemmed from the fact that even in people who are getting quality talk therapy, and again, we can define quality talk therapy as good rapport between patient and clinician, as well as feelings of support, as well as potential insight.

And even when SSRIs are combined with that quality talk therapy, there's still a large number of people who simply do not achieve significant or long-lasting relief from their PTSD, and an even fewer number who go into full remittance of their PTSD. That is despite being diligent and hardworking in their talk therapy, despite the therapist being very committed, despite the use of SSRIs in conjunction with that talk therapy, those people often still qualify as having PTSD.

And the goal of course is for somebody to receive treatment that allows them to no longer meet the criteria for having PTSD, not just in terms of a clinical evaluation, but that they themselves report feeling much better, not feeling overwhelmed with the symptomology of PTSD. Now, the symptomology for PTSD is vast, and it's far too vast to go into into a lot of detail right now.

I think most people are familiar with the stereotyped example of PTSD. This is the soldier that comes back from overseas that has been in gunfights or in battles of different kinds, has likely seen casualties and severe injuries, and that upon return to a safe environment is still experiencing a lot of anxiety, and sometimes panic attacks that occur seemingly at random, or that can be sparked by the classic stereotyped example is a car backfires, and then the person suddenly feels as if they're back in battle.

That sort of thing does happen, certainly, but there are a whole other category of symptoms of PTSD, which include dissociative symptoms of PTSD, people who have PTSD from very intensely traumatic experiences that are checked out. They don't feel like they can engage. They have brain fog. They are distracted.

They go from feeling anxious to feeling exhausted. They have sleep issues. Not surprisingly then, people with PTSD of either the dissociative type or other symptomology of PTSD, and keep in mind that one can have both dissociative and non-dissociative symptoms of PTSD, such as anxiety and panic, are at a far greater risk of substance abuse.

So the current estimates are that people with PTSD, no matter what type of PTSD, dissociative symptoms, or otherwise, you know, panic attacks or both, are at a much greater risk of having addictions to either illicit drugs or prescription drugs or both. So things like alcohol use disorder is very common in people with PTSD.

Opioid use disorder is very common. Stimulant use disorder, and on and on. So people with PTSD suffer at a number of different levels, and there are all these what are called comorbidities with PTSD, including addiction, but also depression, anxiety. And so you can start to see how PTSD sets up a whole cascade of things that make living life extremely problematic at the level of basic relationships, functioning in the workplace.

And even when mental health appears to be in check, oftentimes people are holding a lot in, so they have cardiovascular and cerebral vascular deficits that cause a lot of problems in their immediate and long-term physical health. So PTSD is a very serious issue. The current estimates are that as many as 8% of people in the United States have PTSD.

And again, the estimates around comorbidities range anywhere from 17 to 46 or as high as 65% of people with PTSD having comorbidities for other mental health issues and addiction in particular. So finding lasting relief to PTSD is extremely important and made even more important by the fact that many people with PTSD sadly end up committing suicide.

So suicide rates are far greater in people with PTSD. The exact rates of increase in suicidality in people with PTSD are a little bit hard to arrive at in the statistics because of all the comorbidities, but suffice to say that suicide is far more likely in people with PTSD, along with all the other issues that PTSD brings about.

Now, PTSD creates all the problems that it does, largely through changes in brain circuitry, as well as neural communication between the brain and body. Many people have perhaps heard of the book, "The Body Keeps the Score," which is a very successful and popular book about the idea that trauma can be, quote unquote, "Stored in the body." To be clear, traumas can't actually be stored in the body.

You don't actually store memories in the body. What you store are activation of neural circuits that include brain and body, and they all seem to center back into the insula, that structure that we talked about earlier, this structure in our brain that has a map of our body surface.

So contrary to popular belief, we don't store memories in the body or trauma in the body in a way that, for instance, working out a knot or a pain in one's lower back will relieve the trauma. It sometimes can activate a memory of the trauma, but when one is doing that, what you're really doing is activating neural circuits that reside within the brain, within the insula, that correspond to sensations within the body.

Now, I don't want to diminish the role of the body in the formation and the persistence of PTSD, and I certainly think the book, "The Body Keeps the Score" is a pioneering book. It's, in fact, an important book, but I want to emphasize that the modern neuroscience really points to the fact that PTSD is caused by the exact sorts of brain network activations that we were discussing earlier, things like heightened levels of activation in the amygdala to insula pathway, which, of course, would exacerbate bodily sensations related to the trauma, or heightened activation of the hippocampus, this memory center in the brain, to amygdala to insula circuitry.

Now, therefore, it should come as no surprise that if MDMA can reduce the levels of activity in the hippocampal to amygdala to insula circuitry, and can do so both while someone is under the effects of MDMA, but then lead to persistent, long-lasting reductions in the activation of those brain networks, well, then it stands to reason that MDMA could be a valid therapeutic for the treatment of PTSD, and, of course, this has been explored, and here we can really give a nod and a large debt of gratitude to the so-called MAPS group.

The MAPS group is a group that's operating mainly out of Santa Cruz, California, but they have a number of different satellite laboratories and clinical groups, both in the US, in Canada, and abroad, where they've worked with government organizations to get legal authorization to give MDMA to patients who have PTSD, to also give them talk therapy, and then to compare the effects of talk therapy with MDMA to talk therapy with placebo alone, and there are about three to five studies in this area now that stand as large-scale clinical trials that are showing what can only be described as remarkable results for the treatment of PTSD, so rather than going to any one of those studies in immense detail, I'm going to summarize across those studies.

I will provide links to those in the show note captions. The two that I think are most interesting are the study entitled "MDMA-Assisted Therapy for Severe PTSD, a Randomized, Double-Blind, Placebo-Controlled Phase 3 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 addictive symptoms that are commonly associated with PTSD. So just to give you an overview of what's happening with these trials and why there's so much excitement and why we really are on the cusp of legalization of MDMA for the treatment of PTSD in the sorts of clinical context I described, when people are given just talk therapy alone or talk therapy with SSRIs, they will often, as I mentioned earlier, experience reductions in their severity of PTSD symptoms, and rarely they will experience complete remittance of their PTSD.

That is, they will no longer qualify for PTSD after receiving a number of talk therapy sessions. So let's compare that to what happens when people do talk therapy in conjunction with MDMA. And I'll explain exactly what that means in a moment, but it essentially means taking MDMA while doing talk therapy.

However, this is a very important however, the people who are taking MDMA in these trials have already done talk therapy without MDMA, then they're doing talk therapy under the influence of MDMA, and then they are doing sessions of talk therapy not under the influence of MDMA, and the entire time they're doing that with the same two therapists, okay?

In the placebo group, people are doing talk therapy with two therapists, but they're not taking MDMA, okay? So they're doing the same number of therapy sessions, but they're not taking MDMA. So to just get to the key numbers first, the overall rate for clinically effective response to MDMA assisted therapy is 88%.

That's what's emerging from these trials, versus 60% for the placebo and therapy alone. So on the face of it, you might say, okay, wow, 88% of people who do talk therapy, and here I might as well just finally explain how this is done. Patients are selected because they have PTSD.

They meet the clinical criteria for PTSD. They do three 90 minute therapy sessions with two therapists talking about their PTSD symptoms, talking about to the extent that they can, the incident or incidents, the life events that led to that PTSD. None of that is done under the influence of any drug, okay?

So everyone in the experiment does that. Then the group divides into two, where half are taking MDMA. They take that three times. During those three times, they are also receiving therapy sessions with the same therapists that they were working with before they took MDMA. The first session, they're taking 80 milligrams of MDMA and then a 40 milligram booster about an hour and a half to two hours in.

The second session, they are taking a higher dose of MDMA. It's 120 milligrams. And then if they elect to, they can take a 60 milligram booster about an hour and a half to two hours into the session. And then there's a third session where they take, again, 120 milligrams of MDMA and have the option to take a 60 milligram booster about an hour and a half to two hours into the session.

Again, anytime they're on MDMA, they have therapists there that they're talking to about their trauma. They are either spending time with their eyes closed, lying down, sometimes in an eye mask and thinking about the trauma, thinking about their current state and experience, also thinking about what happened before. Then they're exiting the eye mask or talking to the therapist.

The therapist is taking notes, asking questions. Remember, they've established a strong rapport, supportive relationship with these therapists prior to taking MDMA in the therapy session. And then they also undergo three 90-minute therapy sessions with the two therapists spaced one week apart after the final MDMA session. Now, those that were placed into the placebo condition do everything exactly the same as I just described.

So three 90-minute sessions as prep, then three eight-hour sessions with those two therapists, and then three 90-minute follow-up sessions one week apart, but they take a placebo, not MDMA. So you can see that in these so-called MAPS studies, these clinical trials for PTSD, the conditions are very similar except for the inclusion of the drug MDMA.

So those rates of success with talk therapy and MDMA, again, overall rate for clinically effective response to MDMA-assisted therapy was 88% compared to 60% for therapy and placebo. What's even more impressive, however, is that 67% of the people in the MDMA plus therapy treatment group no longer met the criteria for PTSD by the end of the treatment.

So in other words, their PTSD went into remittance. Now, we could say they are quote-unquote cured, but typically for things like PTSD, that's not the language that's used. Rather, what's used is statistical evaluation of how the different symptoms like dissociation or anxiety or sleep disorders are explored. So while to some of you, a difference between 60% success with talk therapy and placebo versus 88% success with talk therapy plus MDMA might not seem like that big of a difference.

It is indeed quite an enormous difference. In fact, to my knowledge, there is no other example of a treatment for a psychiatric disorder that is successful to the same magnitude. I could be wrong about that. I'm sure some psychiatrists out there are 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% for the treatment of a major psychiatric disorder, please do put that information in the comments on YouTube, and perhaps a reference to a study would be even better, but even if not, just put a reference to that.

That would be great for sake of future episodes, et cetera. But nonetheless, an 88% success rate, and here I'm referring to success rate as a significant reduction in clinical symptoms for PTSD, and 67% of those people going into full remittance for PTSD by the end of the treatment is pretty spectacular, which is why you're hearing so much these days about the potential transition of MDMA from a schedule one drug for which there are, quote unquote, no clinical applications to potentially a legal within the context of clinical use application of MDMA, which it does appear the legislature is at least considering for as early as 2024, maybe even later in 2023.

It remains to be seen. Now, a number of other important results have emerged from this and other clinical trials. For instance, remember earlier, I talked about how many people with PTSD also suffer from alcohol use disorder. What's interesting is that for people that were in the MDMA plus talk therapy group in this and other studies who also had patterns of alcohol use disorder and even some other substance use disorders, the MDMA plus talk therapy treatment in many cases resolved their addiction to alcohol or other symptoms as well, and perhaps that shouldn't be surprising if we think about the addictions as stemming directly from their PTSD, but it is surprising if you think about the fact that alcohol use disorder and some other addictive disorders oftentimes will stem from disruptions in neural circuitry that are the same disruptions in neural circuitry that occur in PTSD, but often are the consequence of entirely other brain wiring phenomenon.

What I'm saying here is that just because addiction and PTSD are often comorbid with one another, it was not necessarily the case that treating and resolving PTSD would resolve the alcohol or substance abuse disorder, and yet that seems to be the case often, not always, but often in these successful treatments of PTSD.

So that's very exciting. Some of the other particularly exciting results from these clinical trials on MDMA plus talk therapy is that the dissociative form of PTSD has traditionally proved to be especially hard to treat, and that's thought to stem from the fact that successful treatment of PTSD, whether or not it's by talk therapy or talk therapy combined with SSRIs or talk therapy combined with any drug treatment or behavioral treatment like EMDR, eye movement desensitization reprogramming, or other forms of treatments that are designed to rewire neural circuitry almost always involve the patient getting very close to, or at least reporting the traumatic experiences in a lot of detail.

And you can imagine why for somebody who's dissociating from that very experience, who's "checked out" and can't really seem to access the emotional states and the memories because they're blocked off from them or because they're unwilling to access those memories and really think about the full emotional capacity of those memories, that it would be particularly hard to bring them through any kind of treatment for PTSD.

So it appears that MDMA in providing this pro-social empathic, again, empathic for others and empathic for self, chemical and mental environment, as well as the presence of two trusted therapists, which one has a really good rapport, allows patients with PTSD to really get close to those experiences that were traumatic, to talk about them and to think about them, and in many ways to reframe them in a context that often involves empathy for others and empathy for self.

Now here, we're not necessarily talking about forgiveness of perpetrators, although that's sometimes the case, that people will forgive the person that inflicted the trauma on them, but more often than not, it's about tying their feelings of trauma and their feelings of depression, anxiety, dissociation, et cetera, to some sort of larger context that allows them to see themselves in the role of agency, to be in the role of knowing that, yes, these things happened, and yet by getting close to the emotional load of those things and really being, in many ways, unafraid to get close to the emotional load of that and having support around that, that the emotional load seems diminished and that they 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 once burdened them, they can still remember, but it no longer burdens them. It no longer feels like it's in their body and in their mind or on loop or on repeat in a way that's invasive, in a way that interferes with other aspects of normal functioning.

So when one hears about these kinds of results, and when you hear about some of the patient reports, and I invite you to do that, you can go to the MAPS site, which by the way is recruiting subjects for these clinical trials. And you'll also find reports of individuals who participated in these clinical trials.

And of course, we will provide links to these incredible clinical trials that MAPS has spearheaded. What you find is that the combination of MDMA and talk therapy in many ways is not about the drug having a particular effect. It's really about the drug having a particular effect that allows the motivations and the results of talk therapy to really be heightened.

And I think that's a really key point to make because up until now, we've really been talking about the neurochemistry of MDMA, the potential toxicity or lack thereof of MDMA. We've been talking about the brain networks, et cetera. But when one thinks about the valid clinical use of MDMA for the treatment of PTSD, and I should mention it also had some success in dealing with not only alcohol use disorders and other use disorders associated with PTSD, but also relieving the depression associated with PTSD.

So now MDMA is being explored for treatment of not just PTSD, but also for depression, for alcohol use disorder and for eating disorders as well. MDMA seems to be a compound that produces the right kind of subjective and neurochemical milieu in the brain that allows therapy to be that much more potent within a limited number of sessions.

And when one thinks about the cost of mental health care, how expensive it is to get therapy over and over and over again, which in ideal circumstances, people are able to do that either by way of insurance or by their own finances, or I don't want to say that the cost of therapy should be reduced because of course, therapists have to survive also.

But the idea here is that people who are suffering would be able to achieve relief from their PTSD, their depression, their addiction, and to be able to do so by hopefully persisting in their therapy over whatever period of time is required, but also to assume a circumstance in which somebody only has 10 or 15, or maybe even just three opportunities to undergo treatment for PTSD, and nonetheless is able to achieve tremendous relief during the session and after the session.

And it really does seem to be the case that for reasons that you now understand, the activation of particular brain networks, the suppression of other brain networks, in particular this amygdala to insula pathway, that when people are under the influence of MDMA in these very safe and therapeutic supportive settings, they're able to look at traumatic events and the ways that those traumatic events impact them in ways that really allow them to cognitively reframe those events and somatically reframe those events, to really change the way that it lives in their body and mind so that it's no longer invasive, and then they can go on and lead productive, adaptive lives.

And as a final point related to these clinical studies, I of course would be remiss if I didn't touch on some of the so-called adverse effects, because anytime there's a drug or talk therapy for a mental health issue, adverse events have to be considered. And I think it's quite reassuring that in the case of MDMA therapy, there were no increases in the number of suicide attempts or suicidality or obsession with suicide.

Contrast that with the group that received placebo, where there were a certain number of baseline and predicted obsessions with suicide. Fortunately, at least to my knowledge, there was no actual suicide attempt or successful suicide, thankfully. But the point being that the addition of MDMA drug therapy to PTSD talk therapy does not seem to increase the quote unquote side effects that are sometimes associated with PTSD talk therapy, because indeed there can be side effects to exploring PTSD and trauma as one would expect.

So overall, I would say it's very exciting times for the exploration of MDMA as an augment to talk therapy for the treatment of PTSD and these other conditions. Again, I think the MAPS group has done a remarkable job of keeping this within the realm of legal and trying to move things forward in terms of legislation to make sure that MDMA isn't simply made legal and then abused recreationally.

I know people out there have different views on whether or not drugs like MDMA should be legal or not, that's not what this episode is about. What I am very excited about, as you can probably tell, and what I think a lot of people in the psychology and psychiatry community are very excited about, you say the mental health community at large, is that these compounds that for many years were only associated with their recreational uses and therefore were not well understood because they were often contaminated or taken in combination with other things or by people that never should have been taking them in the first place, taken by young kids, which is a whole other matter, 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 a miracle cure, it is by no means perfect, and time will tell what problems if any arise from the short or long-term use of MDMA in this context.

But I think it's remarkable that anywhere from two to three sessions with MDMA and talk therapy have been shown to significantly reduce PTSD symptoms, and in some cases completely eliminate PTSD symptoms in such a wide range of patients and in patients that have experienced both PTSD and these other comorbid disorders.

I think it's really remarkable. It's very exciting. And I look forward to seeing what the next round of data produce. So as is often the case on this podcast, today we went into a lot of detail about a subject. MDMA is this incredible compound synthesized, as far as we know, first by humans, not by plants, not by aliens, but by humans.

And that produces big increases in dopamine and serotonin to create these highly motivated 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 where other forms of drug therapy or combination drug and talk therapy had failed before.

We talked about some of the potential neurotoxicity issues. I don't think that is a resolved issue just yet, although the bulk of data in humans and non-human primates point to the fact that at reasonable doses, and we talked earlier about what those are, at reasonable doses, when not combined with other drugs, does not appear that MDMA is exceedingly neurotoxic and it may not be neurotoxic at all.

Of course, one needs to be exceedingly cautious when thinking about the use of any sympathomimetic. They, of course, can be neurotoxic. Anything with methamphetamine in it has the potential to be neurotoxic. But of course, dosage matters, context matters, we talked about that. And of course, the purity of drug matters.

And again, I just want to reemphasize the fentanyl contamination of MDMA that's sold on the street and that is being used recreational is of very serious, potentially lethal concern. I also expect that there will be a lot of interest in these clinical trials that MAPS is doing. So again, you can find links to that in the show note captions.

And I think in general, we should acknowledge that we are a very interesting and important time in human history for the treatment of psychiatric disorders and for neuroscience generally, because whether or not we're talking about psilocybin or LSD or ayahuasca or ketamine or today's topic of MDMA, regardless of what drug and neurotransmitter and neuromodulator systems are involved, what we're really talking about are ways to access neuroplasticity, the nervous system's incredible ability to modify itself in response to experience.

Ideally to be modified in adaptive ways that make it function better. So that's really the crux of what talk therapy and drug therapies are about. That's what the goal of using MDMA as a clinical tool is all about. And in that sense, I find MDMA to be an incredibly interesting and important topic.

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Thank you again for joining me for today's discussion, all about MDMA. And last, but certainly not least, thank you for your interest in science. (guitar strumming)