The Science of MDMA & Its Therapeutic Uses: Benefits & Risks
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Welcome to the huberman lab podcast, where we discuss science and science space tools for everyday life. I'm Andrew huberman and i'm a professor of neutral logy and optimal gy at stanford school of medicine. Today we are discussing m dma, sometimes referred to as ecstasy or mali.

M dma stands for method dioxin method fetching. That's right. You heard the word method fetish in there, and m dma has properties similar to methamphetamine, but also properties that are very distinct from metheny demi.

Just as a side note, method demand is a commonly used drug of abuse, IT is an illicit drug, and IT produces some of the greatest and fastest increases in the neuro delatour dopamine of any available drugs on the street or in the clinic and believe you're not metam fet mine is prescribe bed as the prescription drug in some very limited clinical uses m dma method dioxide mEthane heming has properties similar to metheny timing in that IT powerfully promotes the release of doping and IT is a stimulant, and yet IT also powerfully controls the release of serotonin. And in doing so makes M D M A A distinct category of compound from either classic psychodeviant s like soli van or L D, which larger work on the sirett system and tend to produce mystical experiences. And it's also distinct from pure stimulants such as Matthew federman, because M D M A, by producing big increases in both dopa and serotonin, acts as what's called an impair.

Gen IT actually can increase one sense of social connections, ess and empathy, not just for other people, but for oneself. And in that way, M D, M, A 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 empathetic en for the treatment of ptsd in clinical therapeutic settings. I want to be very clear that at this point in time, june twenty twenty three, m dma is still a schedule one drug that IT is highly illegal to possessed or sell in the united states.

And today, we are going to talk about some of the path legality that's under way. We are also going to talk about the history of N D M. A and why I became illegal.

And we are going to talk about the key difference between recreational use and their apex dic use and the important components of the studies expLoring md ma in the clinical setting for the treatment of ptsd. So during today's discussion, we will talk about what M D M A really is, how IT works at the level of neurons with brain circuits. IT activate and deactivate.

And in doing so, you will come to understand why IT is so exciting as a treatment for P T S D. What you will also, of course, talk about the results of these clinical trials using m dma 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 m dma. 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 recreation on the therapist of M D M A.

We will also talk about the toxicity of M D M A. This is a very important issue because many of you have perhaps heard the m dma quoted, puts holes in your brain or killed serotonin neurons, or kills dopy neurons, and indeed, M D M A, because of its similarity to meet in fetch, which is highly neurotic. Ic m dma can be neurotoxic.

However, there are ways to use M D ma thai ticket that avoid its toxicity, and yet there are still questions about its toxicity and its long term effects, both after a queue use, meaning just one to three times, as well as chronic use, meaning people who have taken IT many, many times. We will talk about the spacing between sessions of M D M A. We will talk about dosages.

We will also talk about things that people do in that can be done to offset some of the potential toxic of M D M. A. So by the end of today's discussion, you have a very understanding of what md.

Ma 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 D. M. A.

That remained to be resolved. Before we begin, i'd like to emphasize that this podcast is separate from my teaching and researchers at stanford. IT is, however, part of my desired 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. Our first sponsor is element. Element is an electoral light drink with everything you need and nothing you don't.

That means plenty of salt, magnesium and patasse, this so called electorate, and no sugar. Now, salt, magnesium and potash are critical to the function of all the cells in your body, in particular to the function of your nerve cells, also called neurons. In fact, in order for your neurons to function properly, all three electrical lights need to be present in the proper ratio.

And we now know that even slight reductions in electronic light concentrations or dehydration of the body lead to deficits. And cognitive and physical performance element contains a science back electorate ratio of one thousand milligrams, that one gram of sodium, two hundred milligrams of potassium and sixty milligrams of magnesium. I typically drink element first in the morning when I wake up in order to hydrates my body and make sure I have enough electoral lites.

And while I do any kind of physical training, and after physical training as well, especially if i've been sweating lot, if you'd like to try element, you can go to drink element that's element dot com slash huberman to claim a free element sample pack with your purchase. Again, that drink element L M T dot com slash e. Today's episode also brought to us by waking up, waking up as a meditation APP that includes hundreds of meditation programs, mindfulness trainings, yoga, eda cessions n sdr, non sleep depressed protocols.

I started using the waking up up a few years ago because even though i've been doing regular meditation since my teens and I started doing yoga ea about a decade ago, my dad mentioned to me that he had found an APP turned out to be the waking up APP, which could teach you meditations of different durations, and that had a lot of different types of meditations to place the bringing body into different states, and that he liked IT very much. So I gave the waking up up a try, and I too found IT to be extremely useful, because sometimes I only have a few minutes to meditate. Other times I have longer to meditate.

And indeed, I love the fact that I can explore different types of meditation to bring about different levels of understanding about consciousness, but also to place my brain body into lots of different kinds of states, depending on which meditation I. I also love that the waking up up has lots of different types of yoga eja sessions. Those you don't know. Yoga edra is a process of lying very still, but keeping an active mind. It's very different than most meditations.

And there is excEllent scientific data to show that yoga ea, and something similar to IT called non sleep deep brer N S D R, can greatly restore levels of cognitive and physical energy even, which is to a short ten minute session, if you'd like to try the waking up up, you can go to waking up dot com slash huberman and access a free thirty day trial. Again, that's waking up dot com slash huberman to access a free thirty day trial. Let's talk about M D M A.

M D M, A, 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 this just briefly start with the history of md ma. Md ma was synthesized by the rug company mark in the early one hundred hundred hundreds, 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 a later rediscovered by a guy named lander shuga, who was a bit of a reneging drug chemist who was designing different drugs for the purpose of understanding their objective effects on humans.

So there's a long history of slogan, designing drugs. He was, after all, a chemist, and then taking those drugs himself. And then if he light the effects of a particular drug, or rather, he thought that I had potential clinical utility, he would give IT to his wife, then he would give him hero tes about those drugs, and then they would share them with their friends.

And he was a small group of friends who consisted of therapies and physicians. So this was a really underground kind of Operation. IT was technically not illegal when I started, because M. D. M. A wasn't illegal when it's started.

But over the several decades, that sugar and his wife in this group, we're doing this kind of exploration, M D M A, did become illegal, and he fell under, let's just say, scrutiny by the dea. Now here's the important thing. Understand about M D M A and its history. First of all, M D M A is a synthetic compound.

As far as we know, he does not exist anywhere in nature, so unlike similar compounds such as masculine, because M D M A and masculine very similar in their chemical properties, and to some extend their subjective properties, unlike maskin, which can be found in the planned kingdom, or L, D, which comes from ergotisms slyvia, which of course, can be found in magic mushrooms, M, D, M A is a unique chemical in that, again, as far as we know, only exists in its synthetic format, is human made. And as we get into the chemical effects and the subjective effects of md M A little bit later in the episode, I think you'll understand why is such a unique into some stand 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, prescription drugs that produce the kinds of effects that m dma does.

And by the way, if you're interested in the story of Alexander yoga and the drug sey sympathised 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 M, D, M, A. Became illegal. There is a wonderful book called the peak haul that stands for P I K H A L.

Pico is the title of the book which slogan wrote, which describes his discovery of M D M A. I confess, IT also describes the synthesis of M D M A. And for that reason was a book that for a long time was not available.

but. Is now available again in auto form and in printed form. P stance for finial means I have known and loved finial means is the category of drug for which M D, M, A belongs to. And it's a long book, but a very interesting one, both from the perspective of understanding the history of M D M A and what M D M A is and the the effects that IT produces.

But is also an interesting book because they will teach you a lot about the history of the pharmacology industry, the war on drugs in the united states in the interaction between illegal drug exploration and drugs for clinical treatment of psychiatric chAllenges. So right now, this is a very important issue because m dma 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 posses unless you are one of the scientists who has been granted permission to study in the clinical setting or the laboratory setting. And right now, we are on the cusp of m dma 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 m dma, its ability potentially to kill neurons and the neurons IT has been hypothesize to kill our neons of the serotonin and dopamine types.

So this is something you would not want to 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 are become locked in to some extent. And IT also has cognitive effects, so you don't want to lose dopy neurons.

And loss of search logic neurons is known to impact mood negatively, mood regulation negatively. eta. The story of M D M A, its potential neurotoxicity comes. I am right up against this issue of legality.

And what will 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 M D. M, A, so that IT does not become illegal again. And another group trying to establish the utility and the lack of toxicity and m dma, so that IT does become legal again for the treatment of ptsd.

So even though the story peco relates to events that took place largely in one thousand nine and seventies, eighties and nineties right now, mda and its toxicity or lack of toxicity, its legality or lack of legality or 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 uh, data on M D M A mayor, may not impact the potential legal status of M D M A.

Okay, so what is M D M A? M D M A is three four methods, oxy mEthane fedex in. But unless you're chemist, it's not going to mean much to you, nor should IT. M dma has some very interesting properties, the first of which is that method fedex y component, which because it's a method fedex and acts like other effet mies, 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 hd, I discuss the biology and mechanisms of drugs like adorable, and which basically are either combinations of infected es or single types of infected es that have either a quicker release or a long release. Now, M, D, M, A, because IT has this method, fedewa component prevents the reuptake of dopamine, and in doing so, create net increases in dupine. So for those of you they don't have a background in neurobiology, let me just briefly explain.

Omit this. Very simple neurons, or nerve cells, release chemicals at their sites of communication, which are called synapses. Ses synapse ses are little gaps between neurons.

And what happened is the neurons spit out these little spherical balls, which we call vehicles or vehicles, depending on where in the world you live, there are either be called vehicles or viscous. And those those vesicles is contain neurotransmitter or what's technically ly refer to as a neuromodulator. Top me is a neuromodulator can module the activity of other neurons that can either increase or decrease the activity of other neurons.

Now, at the end of the neurons, that what we call the x onal bouton OK exon is on the wire component, the neon that can reach to another side in the brain, and then release the neurotransmitter neuromodulator there at those extra book tons, which the sites of release, the vehicles literally fused with the edge of the neuron and vomit their neuro delatour out into the synapse. And then the neural delatour, the case dopa men, will bind to receptors on the post optic IDE that means to another neuron. And then depending on how much bines and depending on what else is going on in that local neighborhood of neural connections, the neuron will either increase its neural activity and itself released neuromodulator, nor transmit some place else, so as of a chain reaction, or else you will suppress its activity, and the flow of communication from wonder on to the next will be stopped.

okay. So m dma doesn't prevent the release of dopa at the synapse. IT does quite the opposite.

IT actually prevents the the sucking up of the dopamine that's been released, and that does not bind to the receptors. So basically what he does is blocks these things called dopamine transporters. And the transporters are the things that suck back up.

The document has been released. That has not bound to receptors. So because IT blocks that sucking up process, there's more dopamine around in the syn naps to hang out and then buying to receptors once some become available. okay.

The other thing that the methamphetamine component of m dma does, just like metheny deming, is that IT actually gets into what we call the prison opting girl, the neuron that releases the dopamine and IT interferes with the retina aging of dopamine into those vehicles. Now you might think, oh, IT interference with the retina aging of dopamine, university als. And therefore less will be released.

But actually what happens is, as a consequence of that, a bunch of dopamine builds up in the prison optic neuron so that when an electrical impulse comes down, that neuron and dopamine released, a huge amount of dopamine is released. And this is one of the characteristic properties of mEthanol demand and of md ma, which is that IT leads to enormous increases in the amount of dopamine released and the amount of dopamine in that hangs around in the synapse. And therefore, IT increases what we call dopamine ergimo one or dopamine ergimo.

That's just a bunch of different ways to describe increases in doping. okay? So that's the main way that M D M A, and by extension, method timing increased opening.

However, M D M A is not just method amine, it's method dioxide metheny omy and IT has another incredible property, which is that IT doesn't just leads 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 search S E R T S S certa y transporters.

And they work very much in the same way that dopamine e transporters do, right? They basically controlled the sucking backup of serotonin that's been released into the synapse. And that has not bound to, sir, tone receptors on the other neurons yet.

And in doing so, allow more sir tony, to hang out and have its effects as those recept tors become available for seton's to buy to them. The other thing M D M A does is IT also gets into the prismatic neuron to impact the packaging of serotonin into something called the vesical monem mean transporter for serotonin. And in doing so, IT leads to a big build up of serotonin in prison optic terminals and then massive increases in certa an release.

okay. So what we've got with m dma is a really interesting compound, unlike method fetish or other infection in such as ador vivants set, that cause increases in doped by blocking reuptake and increasing release of dopamine. M dma does that, but IT also does the same thing for serotonin.

And here's a really key point. The increases in serotonin that M D M A creates are at least three times and maybe as much as eight times greater then the amount of dopamine released that m dma causes. But when you put those two things together, what you basically have is a drug that causes huge increases in dopamine in, and even bigger increases in serotonin.

And remember earlier when I said that M D. M A is a purely synthetic compound. As far as we know, IT doesn't 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, or 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 stimulate properties of the methuselah's component. I said that the dopa mean effect, the dopa energia tone, goes way up. So it's a stimulate.

People feel really alert. They feel like talking a lot. They feel very excited. They feel a lot of positive motivation. Um these are classic effects of drugs that promote the release of diploma in including and femme cocaine. Etta, but or nearly 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 argc, they don't feel good at all.

M, D, M, A seems to cause these increases in dopamine, and all the accompany effects are just described, but by also causing big increases in serotonin IT activites neural networks that are associated with feeling more socially connected. In fact, we talk about data little bit where people have had their brains imaged while under the influence of mtm a. And it's very clear that people who have taken M, D, M, A look at faces that are nearly, 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 ceretani create what we call a prosocial effect. And that, combined with the dopamine, a gic increase in mood and the stimulation effect, creates this thing that we call an impatient en where, and this is very important, the empathy isn't just for other people, is also for oneself and one's own experiences happening in the moment, as well as empathy for experiences from the past.

Which you can imagine could be very beneficial for the treatment of P T S D. okay. So hopefully the way I describe the biology of nd ma makes some sense if you didn't get anything out of the description I provided, except the understanding that mtm a is unusual in that IT causes big increases in dopamine and even bigger increases in ceretani.

Then you have more in your knowledge base now about m dma than you need in order to understand the rest of our discussion. Before we go any further, I do want to separate m dma out from some other compounds, which I referred to as psychiatrically. And I recently did a podcast, epsom, all about suicide ban.

And it's the APEC exploration and its chemical basis. It's ata. You can find that like all episodes at huberman lab dot com, I also did an episode with expert guest doctor Robin carta Harris, who's at university california. Cisco, whose pioneering a lot of the studies on the clinical application of suicide in suicide ban and L, S, D, are mainly going to increase certa an activation in the brain.

In fact, they very closely resemble seaton in itself, and they activate what's called the five ht two a or sera one in five ht justice for seaton in the five ht two a recept to create very mystical type experiences. They are considered classic psychodeviant s and are very introspective. And as I described, 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 kadee. I will do an entire episode all about kadee. Kadee is actually A N method, a Spark receptor blocker, N M D, A recept blocker that ouldn't mean anything to most of you. But IT is a decisive anesthetic. Not unlike pcp, what used to be called the Angel dust on the street, kadee is being used as a treatment for depression.

IT is currently legal, so unlike slice van in lsd, which are granted breakthrough status for the study of depression but are not yet legal, they are still illegal, and of course, as a engineering m dma has breakthrough status but is still illegal. Cademy is being used for the treatment of depression, and he does so, as its name suggests, social anesthetic, by creating a sense association from emotions. Ay, now I raise this distinction between suicide de and analysis, which are mystical in their effects.

Kadee, which is decisive in its effects with M D, M A, which is an impair gen, or sometimes called an inactive, but as an impatience en or an aggam, it's creating more affiliations ation. It's affiloir tive. okay? So it's a very distinct compound.

And this is important, understand? Because when we hear the word psychedelic, a lot of people tend to lump together L, D suicide in in md, ma. If you talk to researchers in these areas, they will tell you that mda really isn't that much of a psychiatric. It's an impair gen with stimulant properties. And he also has a certain erga component that makes IT an impair gen or an an active gen.

So m dma is very different than the other psychiatric s and my hunch is that over the next few years, we will stop talking about md ma as a psychodeviant because he does not tend to produce visual fluctuations or auditories halcyons of the sort that classic psychiatrically do. And in general, IT is more of a mood impacting drug than IT is mystical. Okay, so get into some of the brain networks in which ones are activated while under the influence of M D M A.

But I do think it's very important to segment out M D M A from the other so called classic psychiatrically and also segmented IT out from academy. Thanks to some really terrific c studies, both in animal models and in humans, we now understand a lot of what makes m dma produce these incredibly unique effects. And when I say unique, I mean unique from drugs like Sullivan and lsd and cademy and for 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 ceretani, produces a sense of emotional warmth towards others and towards oneself. That's the impatient en component. And for a reason that we still don't understand, IT seems to increase trust.

And the increases in trust turned out to be vital because as you also learn later, when we look at the clinical trials expLoring m dma for the treatment of ptsd, the major effect of M D M A for the treatment of P T S D is not to cure P T S D, but rather to make the therapy, the talk therapy for P T S D much more effective. This is a very important point, in fact, so important. I'm going to repeat least three times during today's episode.

M, dma, taken on its own, does not cure ptsd. M, D, M, A, can augment or boost the effects of talk therapy for P, T, S, D. And IT does that through the engagement of specific neural circuits.

But before we talk about what those neural circuits are, I want to emphasize that the increases in serotonin, the M D M A, produces, seem to act on different receptors. Then the big increases in ceretani, the L, D and Sullivan, produce. So if you listen to the episode that I did on solar, we haven't done yet one on less.

But the mechanisms are very similar for solicit an and ellis, whereby solicit an in elliston very closely mimic the molecule serotonin itself, but seem to have a more selective activation of just the so called serotonin two a recept, abbreviated five H T two a and that leads to more interconnecting is 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 persists long after the sliced effects have worn off. No M D M A can activate the certa in two a receptor, but IT seems that IT largely activates the serotonin one b recept.

What does that mean? Activation of the serotonin one b recept seems to be what gives M D M A 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 therapy 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, doping, 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 dopa mean that's created by M D M A, seems to make people, what I call forward center of mass, you know, they want to do something, they are very motivated to do something. And the increases in serotonin, acting on the serotonin one b 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 realized, is going to be a little bit of a mind ban for people to to understand. But one of the key things that quality M D M A therapy consists of is not just having a very good report and communication with a therapist guiding the P T S D treatment, but also repair and a willingness to engage in conversations with oneself. Yes, 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 is a world expert in ma paul, explained, as trauma is an event that fundamentally changes the way that our brain works for the worse OK. 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 adapted for us. They don't serve as well either because they are highly distracting or because um they creating this idea or because they disrupt left or any number of different things that are maladaptive consequences that what really defines trauma and went under the influence of empty ma because of those parallel increases in dopamine and serotonin.

People seem far more willing to both trust the therapies that they're talking about that trauma with, but also to trust their own ability to coin code, go internal and think about the chAllenging thing or things because often times training can consist of many events, not just one, and the thought patterns around that and the context around that. And they are in to be able to explore new possibilities to essentially require their relationship to that trauma. So I promise you that a little bit leader will talk about the direct application of M D M A for the treatment of ptsd.

But now I like to shift off of the chemical changes the M D M A 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 in, modified by m dma 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 phenomenon, 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 m dma 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 neuroplasticity rewiring changes does m dma produce, and how can those be beneficial, or perhaps not beneficial? I'd like to take a quick break and acknowledge one of our sponsors, athletic Greens. Athletic Greens, now called ag one, is a vital mineral probiotic c drink that covers all of your foundation tional nutritional needs.

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Supply of vitamin d three k two. So in order to understand what m dma does to the human brain, we need to take a step back and really define the sort of experiments that one could do. So for instance, you could take a person who's never injured ted, md. Ma, and put them into an F M I machine, which is functional magnetic resonance imaging.

Put them in the F M R machine and just have them sit there with their eyes closed, but we will call resting functional connectivity, or resting state functional connectivity, and simply look at how interconnected certain brain areas are, which in areas are active, which brain is, are less active at rest. This is an important thing to do, not just to provide a baseline for understand what the drug md ma will subsequently do, but also because IT addresses what's called the default mode network. The default mode network, or D M N, is the network that is active in our brains.

When we aren't really attending to anything specific outside us, we're not trying to think about anything specific or accomplishing anything specific that actually relates our sense of imagination and daydreaming. IT has a lot to do with ourselves for referencing, you know, what we're thinking about ourselves. This may come as no surprise, but you're just sitting there on the bus or you know around the dinner table and you're not paying attention what's going on.

In large part, your brain is and this defauts mode network and you're thinking about yourself. okay. So we can get a sense of what the defauts mode network activation is. We can get a sense of which brain areas are more less active, simply be by putting somebody into an FM a machine. Then of course, you could give somebody md ma, while they are in the F, M R I 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 the neuroplasticity effects. What changed in a permanent or pervasive way? That's to one basic paradigm for expLoring the effects of drugs like md ma on the brain.

The other way that you can explore the effects of md ma on the brain is to ask people in the general population, hey, who out there is taking md ma? 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 m dma zero times. Two people who have taken M D M A one time or five times, or believe or not, they're some study's sitting right here in front of me on my desk of people who have taken dma more than two hundred times and asked the same source of questions, which brain areas are more less active.

Those studies have been done as well. And of course, one can do studies where you give people different dosages of md ma, as well as giving people md ma, and then giving them specific stimuli, meaning not just asking them to sit there in the F M. Ize scanner with eyes, clothes, 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, numerous studies in animal models expLoring how the social activity of laboratory mice changes when they are under the effects of m dma. There even studies, believe or not, on the effects of md ma.

In seafloor, ds slopes include octopuses as well as cuddle fish and other aquatic animals that are known for having complex behavior. Some people believe that the several pods are extremely intelligent. The obsession was settled pods as something that really intrigues me.

I actually used to have cut fish in my laboratory. We did not put them on m dma. But there is a study that's been published in the journal current biology of a self press journal, excEllent journal.

This is from good dolans laboratory at john's hopkins school of medicine, showing that if you give octopus S M D M A, they like to spend more time with other octopuses than they do if they are not on M D M A. And that might sound like kind of a kind of a playful experiment just done in order, entertain oneself, and the octopuses perhaps. But actually in that study they identify that the serial and transport in octopus es and show that IT has a lot of homology similarity to human serotonin transporter receptors.

And so what that really speaks to is the fact that the pro social effects of md ma that are observed in mice and in humans and in octopuses all have a common basis, which is the activation of more serotonin release, in particular brain networks. okay. So that interesting study on octopus is aside, I think what most of us are interested in is how M D M A impacts the brain.

And so i'm going to spell out the three major ways in which M D M A changes the activation of the brain in the short and long term. And here i'm pulling across the number of different studies. But one of the key sets of studies in this area comes from the what I consider very beautiful work of harriet do IT do IT runs the human behavioral for macos gy laboratory in the department, psychology, behavioral neuroscience of the university of chicago and her abortion.

Ory has a long history of giving people certain drugs in very specific dosages and then measuring their effects on the brain using different type of imaging, including f mi. And one particular study that all highlight is entitled the effects of md ma on sociability and neural responses to social threat and social reward. So what the study looked at is how m dma impacts people's perceptions of others emotional expressions on their face.

What they found is that when people are on M, D, M, A, their response to threats, faces, rather threatening stimuli is reduced. And it's reduced in a very specific way, which is reductions in activity of the amiga. The amiga 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 objective experience to any one particular brainer, the amiga, as is actually a complex, is 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 edna, you show them a face that is grim, sing, or would otherwise be rated as quite threatening. They attend IT as less threatening.

In addition, they tend to respond to happy faces, or even the slightly happy faces as more kind or more generous or happier than they would when they are not on M, D, M A. Again, the faces that are being shown are not of people on M, D, M. A.

That would be an interesting experiment, but that's not what they did hear. What's happening here is people are being given M, D, M, A, and then they are reading in a subjective way the friendship ss, or the level of threat that they detect in these facial expressions. And of course, they have extremes of friendly and threatened, but then they also grade them, right? They titre them so that they also have mildly threatening and mildly happy faces at set up.

So everything from a grin to a smirk to a giant smile, everything from a, from a sort of somebody looking a little bit of scans at somebody to really, you know, wide, wide and looking angry like that, you know, going to attack you and things of that sort. So what's discovered in the study is that md ma has a by 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 threatened face as more threatening. Now one thing I have not mentioned as far are the dosages of M, D, M A used in this and other studies.

Unfortunately, despite the studies that we're going to talk about using, a lot of different types of people, different ages, different sexes or male and female, located in different parts of the world, even some with P, T S D, not with P T S D set. There's been fairly tight dosage control of M D M A 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 M D M A used in these new imaging studies and in the clinical studies of ptsd, they were going to talk about later range anywhere from point seven five milligrams per kilogram of body weight to one point five milligrams per kilogram of body weight. So for somebody like me, I wait two hundred twenty pounds. That's one hundred.

Milgram, one point five milligrams per kilogram of body weight would therefore be a one hundred and fifty milligrams in a single dose. Okay, a dosage of one milligram per kilogram of body weight would mean one hundred milligrams for my hundred kilograms. Okay, somebody lighter than one hundred kilograms would obviously take less M D M A in one of these studies.

But in general, the range of md may that's been explored is point seven five to one point five milligrams per kilogram of body. The exception being in the clinical states that will talk about a little bit later, there is a tendency to explore both an initial dose of one point five milligrams per kilogram of body weight. So again, for a hundred kilogram person, there will be one hundred and fifty milligrams or so, and then a so called booster of half that amount, about ninety minutes to two and half hours into the session.

So another seventy five 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 m dma, such as the points up in five 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 m dma, we absolutely have to talk about dosages.

Because, like any drug, the toxicity of M D M A does scale with the dosage that applied, not just the frequency of M D M A use. We hear a lot about that. You know, someone has taken M, D, M, A one time or four times or two hundred 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 m dma in general, we're talking about dosages somewhere between point seven five milligrams peculiar um a body way in one point five milligrams per kilogram of body weight, although typically you are going to see studies, both clinical and more research, explore ative using anywhere from one to one point five milligrams of M D M A per kilogram of body weight. So that's important to highlight. I told you about the subjective effects of M D M A 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 a middle of activity.

Now one of the key features, P T S D, seems to be that there is a heighten connectivity between the amiga la. And a brain area called the insula. The insula is a brain area that's very important for something that's called into reception.

Into reception is one's perception of our feelings, both pure sensations, but also our emotional states, and our feelings of well being, or lack of well being, for everything from our skin inward OK. So that's interrex tion you actually can into accept now, even though you're always into accepting a little bit, you can take accept now to a great degree. If you were, 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 bottom 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 interactive 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 into reception.

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 in the reception. And IT is distinctly different from extra reception, which is your ability and tendency to focus on things beyond the confines es of your skin.

So this could be visual attention, auditory attention, IT could be paying attention to um events like birds flying by whether not your uber is showing up these kinds of things. And we are always in baLance, a push pull of interruption and extra action. The inside is a brain area that is absolutely critical for interaction tion, 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 f mi 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 inside of the person will say, oh, you know, I I feel something going on in my god 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 heads. So there's a systematic map of interaction tion in the insula, and there are direct connections between the amygdala and the insular and the amygdala, despite getting this reputation, is 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 hip campus 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 amiga la. And the insula, then is Normally observed in people who do not have ptsd OK. 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 inter reception, which provides a logical explanation for why people with P, T, S, D often will feel the memory, or sense the discomfort, or just feel agitation or even other types of bodily sensations like bad pain, or just perhaps just A 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. Kay, so this is a really interesting brain network that I should mention exist in everybody, but that in people with ptsd seems to have heightened connectivity. And those brain networks can be revealed by putting people with P, T, S, D into functional imaging machines, getting them to recall a traumatic event, or even looking at the resting state of connectivity between the middle in the insula.

So those experiments have been done. And what's also been done is to give people one point five milligrams per kilogram of m dma, and to look at the connectivity between the amygdala and the insult and between the hip campus, the ami della and the insulation. And so what's observed over time in people that have been given M D M A. 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 amiga and the insula, and that scales very directly with the relief of symptoms from ptsd.

This is really exciting because it's one thing to see a brain network and activated or inactivated or you say OK one person, a certain connection between threats centers and the interaction pty centres of the brain was let's a arbitrary units that I was level eight out of ten for that person, are these things are Normal ized for a particular person. And then after taking md, M. A.

And doing ptsd therapy, IT was five out of ten or four out of ten. That's a good experiment. But what's far more powerful is to observe that in that patient or that person, and then to see a change that perhaps less dramatic. So a shift from eight out of ten to seven out of ten in another person and to see less shift in brain connectivity in the same network. And then perhaps in the person that went from full blown ptsd to full remission of ptsd, something that believe or not has been observed in single sessions with m dma, if that person demonstrates an even greater reduction in the connections between the amiga and the insula, well then that gives even more confidence that this connection between the amiga la and the insult is actually perhaps cauSally related to the reduction in symptoms of ptsd, or even if it's just correlated with reduction in symptoms of P T S D.

The fact that the degree of reduction of connection of this circuit scales with the reduction in clinically relevant symptoms, that's a very powerful finding because IT moves things away from pure correlation, although this brainy is active or less active over time, and know this person has more fewer symptoms of ptsd, to something that starts to look like a mechanistic and logical framework for understanding P, T, S D, as well as the effects of M, D, M. A, and for understanding how changes in the brain underly relief from P T S, D. Okay, so again, even if you just could grasp the idea that you have a brain area, the amida er that's involved in threat detection and IT provides inputs to another brain area called the insult, which is involved in this thing called the interception.

And that reductions in those connections between amiga and the insula scale with or corporate with reductions in P, T, S, D symptoms as a consequence of people taking M, D, M A. So if you have that under your mental belt, I promise you, you understand far more about how M D M A impacts the brain in the short, long term, the ninety nine point nine percent of people out there. However, it's also important to understand a few other things that m dma does to the brain as well.

What IT doesn't do to the brain. First of all, classic psychodeviant ics, like solicited and 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 sliced and treatment.

And again, if you're interested in slye and treatments and slice von itself, please check out the epsom that I did on seller van and the guest episode with doctor Robin carhart Harris. Those episodes, like all other episode des of the human in lab podcast, can be found at huberman and labb dot comments of fully searched sites. You can put keywords into the search function.

IT will take you to specific time stamps. Every episode is time stamps. You can navigate the topics of particular interest to you. Feel free to go there and listen to those episodes. Suicide M D M A, by contrast, does not seem to produce long lasting increases in lateral connectivity between those same brain networks, probably because IT impacts different ceretani receptors. IT does, however, seem to change resting state functional connectivity within these olympic structures, like the amiga line related structures that are associated with threat detection.

Now this is interesting, and IT actually was highlighted very nicely in the study or provide a link to in our shoonoo caption, which SHE has doctor Robin cartner Harris, the first author. So not only has he done incredible work on Sullivan and L D and D M, T. Osca in his lavatory, but also on md ma.

And the particular study have in mind here showed that people who take M D M A at more less the dosage that we talked about earlier, report market increases in positive mood as well as decreased blood flow to the amiga 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 M D M A, and afterwards when the brain is simply at rest. So IT really does appear that m dma creates neural plasticity that changes the overall level of activation of these threat detection networks and their connections to memory systems in a way that's pervasive over time, and that doesn't require any particular probe with a negative stimulus.

Now, translate to english. What that means is that during the m dma session, people report feeling less threatened, more pro social towards others, more empathetic towards others, end 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 m dma, all of which point in the direction of lower levels of threat detection heighten levels of positivity. Pro social components of of the brain more active. Threat detection centers of the brain less active. Now earlier, we talked about md ma as a drug that potentially increases dopy and even more potently increases serotonin, largely acting through this serotonin one b recept.

Now without getting into too many more details before moving on to issues of toxic around m dma, I do want to to touch on what I think is perhaps the finest of the animal model studies of M D M A that explored which brain networks and which chemical that is serotonin or dopa is responsible for, say, the motivational components of M D M A versus the pro social effects of M D M A. And then IT also raises a really important point, which I haven't yet in this episode, which is the role of oxytocin, something that many of you perhaps heard of. The paper that i'm going to describe is from the labatt of doctor Robert millikan.

He's a colleague minus stanford sy, school medicine, psychiatry, 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 M, D, M, A, and now additional compounds that can provide therapy tic support in certain conditions. The study, which I will provide a link to in the shower of caption, is entitled distinct neural mechanisms for the pro social rewarding properties of M D M A.

And i'm just going to summarize, the major results of this study is a study that was done on mice. And I realize that a lot of people hear that and think, what relevance does that have to humans? But when thinking about the effects of dopamine and serotonin in the types of circuits that we've been talking about thus far, these circuits that are subcritical as we refer to them.

So these are olympic icc circuits, these are hypothermic circuits, these are what are called these olympics circuses, 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 M, D, M, A, and which no chemicals are involved is concerned. So what they found in this study, using a huge array of beautiful techniques, such as inactivation of specific brainy, is activation of specific brainers drug tagging ist st to prevent oxytocin function, or drug in antagonist to prevent specific receptors involved in the serotonin pathway.

Lots and lots of tools in their tool kit. What they found is that M D, M, A 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 m dma, just like cocaine or method demon, or adorable for that matter, or violence for that matter, creates big increases in dopamine that tend to couple and experience with a sense of reward, and lead to changes in the neural circuitry that make the animal or human more likely to seek out that same experience again. So these are the rewarding, or sometimes called reinforcing, properties of dopamine that take place in the so called missile limited reward pathways.

If you want to learn about musical limit reward pathways and doping, and how they control everything from your level of motivation to your tendency to procrastinate, to overcome procrastination, done two episodes about doping, you can simply go to your room lab, dom, but doped into the search function, and you'll find at least two episodes on 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 at sea. So M, D, M, A is increasing dopamine in to increase reward to a particular experience.

What's the experience? Well, this paper beautifully passes the fact that IT is serotonin release within a structure called the nuclear accumbens 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 block in the activation of a certain brain areas, and again, using drug and tag ones.

That, and what they find is that IT really is the activation of a serotonin one b recept in the nucleus ocular by M D M A that leads to this pro social effect of md ma. So that's really nice to know because there's always been this conundrum of, okay. So sivan analysis are basically like serotonin.

They activate the serotonin to a receptor m. Dma has a huge certain erga component, tons of serotonin released when one takes md ma. 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 md ma is activating the sir otto ent one b recept and not the serotonin to a recept, and is doing so in a completely different set of brain networks, as is elliston and suicide. And so what happens when an animal or a person takes md ma 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 M, D, M A in the clinical therapeutic setting for the treatment of P T S D 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 M D M A 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 ceretani caused by md ma increases empathy and sociability for and with others, but also for oneself, the motivation that's reinforced, that's wired into the brain seems to be a motivation to perceive others as more kind, but also to be kinder to oneself.

Now, I realized that for some of you who are listening to this, you're probably saying, well, of course, right, 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. But IT didn't necessarily have to be that way, right? This is very hard to go from a statement like drug a produces affects B, C and d to neurochemicals B, C and d cause motivation and possibility.

And therefore, when you take that drug, you're gonna all of that stuff. In fact, we have to go back to our understanding. The M D M A, despite causing a big increase in the tony, also causes huge increases in doping. And IT does so with this molecule, that is, method fetchin. Now, method fedex ine 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 method fedex or not M D M A, but pure method federman impacts social interactions, and what IT does the social interactions is very profound. IT dramatically reduces one's tendency to engage in social interaction. So this really speaks to the polyphonic ology, as it's called A M D M A, the fact that serotonin and dopamine a released together has distinctly different effects.

Then if just dopamine or just serotonin is increased so much so that it's worth taking a step back and talking about another classic drugs which dramatically increases salton's, which are the S S R, is the selective serotonin reuptake inhibited S S R S, such as floki project, as well as so off. And of course, there are many other accessorize out. There's a telegram eeta.

They blocked 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 md ma. In fact, there have been human and animal studies showing that if you give somebody A S S R I prior to them taking m dma, you actually block the pro social and impatient ic effects of M D M A.

Now you might say, why in the world would that be? Aren't these drugs just increasing serotonin? And the increase in serotonin is pro social? Ta, uh, well, that speaks to the complexity of all this, Polly pharmacology and the fact that it's really the activation of serotonin, at particular recept tors, in this case the serotonin one bee receptor, in particular brain areas, in this case the nuclear accused of brain area, associated with motivation and reward.

That largely explains the effects of M D M A in making people, any animals, and octopus is included, for that matter, more pro social and more impair ic 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 M D M A, the fact there's also dopa increased in those very same brain areas, right? I don't think I mentioned this before, but the nuclear economies is part of that new olympic reward pathway that is essentially establishing a reward for whatever is happening at the moment.

So the way to conceptualize m dma and its effects on the brain, both subjectively and mechanistically, is that it's an impatient en 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 a long period of time after the drug has worn off. Now, one of the things that's been exploding with the animal literature and the human literature is that m dma doesn't just increase dopy and doesn't just increase serotonin, but IT also profoundly increases levels of oxytocin lease in the brain. Now, oxytocin is considered what's called a neuro hormone because IT access both a neurotransmitter, or, I guess, if we were going to be really specific, we say, a neuromodulator, because IT tends to module the activity of a bunch of other circuits and the hormonal, how can we say it's a hormonal later or transmitter? Well, hormonal effects tend to be effects that act not just locally, but on many sites within the brain and body as well.

And oxytocin is known to do that as well as to work locally. So that's what we call a neuron. Ormond IT activates neurons and is associated with neural networks related to their 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 break up death departure at several, in fact, 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 released in response to their owners.

I think for any dog lovers or dog owners, certain ly include to me, i'm raising my hand. That comes as no surprise anyone that ever had to put down a dog who has lost a dog. And here, no disrespect to the cat owners, but i'm just referred 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. M dma is known to powerfully increase oxytocin release. In fact, there's a really nice study on this done in humans. This is a study or provide a link to in the shown o captions entitled plasma oxytocin concentrations following M D M A or intro oxytocin in humans, nowaday oxytocin is available by nasal and tailor to be also I don't know the legality around IT.

I don't know if it's a Green market or but what i'm about to tell you, we will basically discourage you from wanting to take up because what they found in the study was people given either point seven five or one point five milligrams per kilogram of body weight of m dma experienced increases in oxytocin. However, IT was only the group that took one point five milligrams per kilogram of body weight of m dma that experiences the really big, significant changes in oxytocin. When I say really big, really highly statistically significant, what they observed is that in the placebo group, because of course, they include A A plus bo group, the amount of circulating was eighteen point six pek grams per mill leader, which to you probably means nothing, to me, also sort of means nothing, because those units of ox toon can be directly related to any kind of direct experience of feeling bonded or not bonded.

This just a number, nonetheless provides a baseline to compare to the average levels of oxytocin in the bloodstream of people that we're given one point five milligrams per killer um of md ma which is eighty three point seven Peter grams per mille ader. That equates to nearly a five fold increase in the amount of circulating oxytocin when people are under the influence of m dma. Now this study had a bunch of different conditions, not just m dma of different doses, not just placable.

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 connected this 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 make sure the heart rate, there's systolic pressure, the systolic like pressure at a and they looked at how social people felt. They looked at how insight ful people felt.

And the key take away from the study for sake of our discussion here today is that IT does not, again, IT does not appear that the increases in oxytocin ced by taking M D M A are the source of the pro social effects of M D M A. And that also what was found in the animal studies of M D M A, where in those studies most were given M D M A at comparable doses. This were a little bit higher than using the human studies.

But at comparable doses, big increases in oxytocin were observed, increases in sociability of those mice observed, just as they are in humans that take him dma. But in those mice, they were also given a drug to block the oxytocin recept and loan. Behold, no changes and 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. Oxy tos goes up and levels of sociability do not increase. So what this points to is a situation where M D M A is increasing dopamine in to increase motivation and to reward something.

What gets rewarded? Well, what gets rewarded is the serotonin activation, a particular brain networks associated associated service, and the dramatic increases in oxytocin that are very, very real when people take M D M A, do not appear to underlie any of the known short or long term subjective effects of m dma. Now, a conclusion like that needs to have a covet.

And the caveat is that, as far as we know, the big increases in oxytocin that are produced by M D, M. A aren't doing anything for the sorts of effects that we've been talking about here, sociability, empathy, etcetera. 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 M D M A are not directly related to any of the short and long term effects of m dma that we are most familiar with, namely motivation sociability increase empathy or the lone standing changes in neural circuitry that underlie, for instance, reduce threat detection or reduced connectivity between throw detection centers of the brain and interaction tion. So is the big increase in oxytocin produced by m dma completely irrelevant in the context of the 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 oxide. Oxy tos went way up. I didn't observe anything very interesting or significant in the context of sociability, but we do know that oxytocin play a powerful in airbender and in human, human, human, animal bonding of various kinds from other experiments have been done. So I don't want to minish the incredible power that oxytocin has in our brains and bodies.

But IT doesn't appear that the M D, M, A induced increases in oxytocin, which are enormous, have much to do with anything related to the value of m dma as a treatment for ptsd or for its subjective effects on empathy, sociability or any of those other factors either. Now perhaps the one coffee out to that is that Harry do its slabe atr, which I referred to earlier, has looked at how variations in oxytocin recept genes very between people. So IT turns out that some people have in a leo I, basically a version of the oxytocin recept 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 m dma, they actually experience less of a pro social effect of the drug. Now that spits in the face of everything I just said about oxytocin not being involved in the effects of M D M A and processibility and empathy. I think the bulk of the data really point to the fact that it's the serotonin increases, combined with the dopamine, an increases caused by M D, M A, that lead to most of the understood effects.

And the oxide tosa, if it's playing a role, is going to play a more minor role. Let's talk about the safety and potential neurological icy of M D M A. And here I really want to highlight that our discussion today is couched in a discussion about the application of pure m dma 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 M, D, M. A. In fact, IT was the recreational use of M D M A in the ninety eighties.

But really that took off, even exploded in the one thousand nine hundred nineties, was so called rave culture that created the massive attention on illegality of m dma and put the drug enforcement agencies on to m dma as a drug that they wanted to an indeed do restrict. In fact, just today, in anticipation of this episode, I put md ma into the search function on google and click news, and there were at least two reports of major m dma seizures and bus. So again, I want to highlight the fact that m dma is still illegal to possess or sell, and certainly to traffic.

I also want to highlight the fact that nowaday all recreational drugs, but certainly m dma included are often fact, very often contaminated with fatal. And while fantine nel has certain clinical uses, fanno is highly deadly. The current estimates as much as sixty percent, maybe even eighty percent of drugs that are sold on the grain market are being replaced ed or reformulated with fatal.

And there have been a lot of 4 tunal related deaths， both in kids and adults. So the sourcing of md ma is extremely important, and the safety issues simply cannot be looked. And I say that not to protect to 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 then 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 are buying md ma. The use of M D M A in the laboratory or in the clinical setting with pure M D M A has also been explored for the potential neurotoxicity of M D M A. So how would meet m femme in M D M A be neurotoxic? Well, that's because they increase dopamine in the case of matteh, amine and dopamine and ceretani in the case of M D M A.

And they do so to a very high degree. The big increases in dopamine and her, tony, but in particular, the big increases in dopamine tend to promote electrical activity of other neurons. Remember, these are, after all, neuromodulators.

They module upper down the activity of other neurons, and dopamine intends to the activity of other neurons up. So dopa itself is not neurotically, but when a lot of dopamine is released, IT is neurotoxic. And it's well known that even a single dose of mEthane hideki can be neurotoxic, not just for dopamine e neurons, but for other types of neurons as well, including seattle erga neurons.

Put differently, we know that the brains of people that take method photo mine degenerate to a small or to a large degree, depending on how often they take the drug, how put in the drug is, and whether or not they combining with other drugs. And yes, if you heard that combining caffeine with effet mies can increase the of economy, such as method, that mean that is true. If you heard that taking caffeine within the hours or same day as m dma can increase the toxic of m dma, that does appear to be true based on animal studies.

Now there are not a lot of studies looking at the toxicity of M D, M A in humans, but there are a few. There are also studies looking at the toxic of m dma 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 their scattered in a number of ways.

First of all, some of the animal studies have used dosages of md ma as highs two milligrams per kilogram of body weight, as highs three milligrams per kilogram of body weight, and even in upwards of that. But even for the animal studies that used arrange of dosages from point seven five to one point five milligrams per kilogram of body weight, there is some evidence that in laboratory myer rats there can be some loss of certain ogc tone in the brains of animals that have been administered M D M A. Now notice I said serology c tone.

I didn't say serotonin neurons because of the way that M D. M. A works in encourage or promoting big releases in dopamine, big releases in ceretani. It's not surprising that if the animals that we're given md ma are subsequently sacrificed, say later that day or the next day or maybe even a week or two weeks later, and those brains are stained for proteins that are related to the synthesis or release of salton's, it's not surprising that there will be reductions in those sorts of proteins, right? After all, a lot of documentation, tonia is released and IT can be depleted.

But I should point out, depletion of a modulator in the short term is not the same thing as depletion of that neuromodulator in the long term, nor is the same as a loss of the neurons that released the open mean in itself. So they're all data pointing to the fact that repeated administration of m dma at dosages that are very much within lines with what we're talking about today. One point five milligrams for killing ms.

A body weight can lower total amounts of serotonin or other proteins in the serotonin synthesis pathway or doping, or proteins that are in the dolph ian sthetic is pathway in specific areas of the brain, related to reinforcement, related to mood, to motivation. At seta, however, the primate studies, or I should save the non human primate studies, which are the sorts of animal studies that most closely mimic what one expects, Tracy, in the human brain, because, after all, mice and the effects of these drugs and mice do translate to humans. But I thought that non human primates provide a model that's far more similar to humans there.

The data start to get kind of complicated in a way that suggests the M D, M. A might not be as neurotoxic as I thought, based on the road and studies. And this gets into a whole history of back and forth between different laboratories and governing bodies who are trying to keep mtm a legal as well as people such as the social slogans of the world and people in the therapy community that are excited about the potential for M D.

M. A. Becoming legal for the treatment of P T S D. And IT really centers around one or two studies, both of which were published in very high profile journals.

And the one at all highlight, because the results are now very clear and conclusive, is a study that was published back in two thousand and two, which was entitled severe dopamine c neurotoxic in primates after a common recreational dose regime of mda a or ecstasy. This paper was publishing the journal science, which is one of the three apex journals for publishing scientific research. So there's science, nature and cell.

The top, top journals, most strange journals, to get scientific manuscripts into the paper received a lot of attention because, as you can imagine, based on the titles suggested that even recreational doses of x to see, even if its pure x to see, and IT doesn't have contamination from additional methods, omy or other things in IT is neurotoxi C2Certain mag ic and or dop a ene rgia neu rons. This is largely where M. D, M, I got the reputation for quoting, put, 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 m dma for the treatment of P T S D. As far as I know, there's no direct evidence that that statement is true, but you will actually find that in some of the scientific journals, in fact, I was able to find a an editorial that was published in the biomedical journal in two thousand three, which argued somehow that uh, doctor requited a was accused of, quote, rushing his results into print because of legislation designed to curb eccsand y 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 interpret and so forth. I don't think that ever really got resolved.

What did get resolved, however, is that the very studying in question was retracted. Okay, so the authors themselves publish a letter of attraction that unfortunately is not as well recognized as the paper that stimulated this idea that M D M A is nea toxic in primates. And keep in mind that we are human primates, non on human primates, being the closest model of human primates that we are aware of.

But to make a long story short, there are summer sues of labelling of m dma versus other drugs in the laboratory. There were some issues of this labelling, 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 m dma, but rather was met in federman itself.

So what's not often acknowledge 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 and roses showing no toxic of m dma, perhaps even at recreational doses.

But today, at least of my knowledge, there don't seem to be any data in either non human primates or in humans showing toxicity of M D M A at clinically relevant doses, provided IT is pure M D M A. I want to be very clear. I'm not saying that if you can get your M D M A that you should take IT or that IT will not 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 m dma and other compounds and particular caffeine, but also drugs such as cocaine or other stimulants, that some people might experience more toxicity to a given dose of M D, M A compared to somebody else. And there's really no way to detect this acceptability to neurotoxic. Now what we do know is that there are people in the general population that have taken a lot of M, D, M, A anywhere from one to two hundred, or sometimes even the next set of four hundred doses of M D M A.

And there are now how studies that have explored the neurotoxicity, and perhaps even more importantly, the neurocognitive and behavioral effects of taking M D M A either zero times, one time, five times, four times, two hundred times at sea, sea. And one of the what I would consider landmark studies in this area is the study entitled residual neural gnc features of long term excesses, 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 Polly from ecology, can create neurotoxicity.

It's unclear if md ma is neurotoxic, but we know mEthane to my on its own is neurotoxic. We also know that people often will combine M, D M A and meth economy. We also know that a lot of so called M D M A out there is mostly method to me, with only a little bit of M D M A.

So a study of the sort that i'm about to describe where IT is essentially confirmed that people were taking pure M D M A and not taking any other drugs is up immense value. This study has been a little bit controversial. Um in fact, i've talked about IT before.

I talked about on the georgine podcast. I've talked about IT briefly with the guest on this podcast, doctor newlin Williams, whose that triple boards certified physician psychiatry and neurologist at them for school of medicine. And it's an interesting study in a little bit controversial because he relied on a population of people who have taken M D, M.

A anywhere from one to two hundred times, and who've not taken any other drugs, including caffeine. And the population in mind here is a population, people living in the utah who self identify as members of the church of later day sense, sometimes refer to as mormons, sometimes refer to as lds, or of the church of later day sense. The church of latter day science, as I understand, does not allow for taking of certain compound, certain drugs um certain certainly most recreational drugs, alcohol, even caffeine.

And i'm sure they're some variation on some of those themes depending on where people live in the certain communities that they happen to be in. I am in no way shape perform um declaring that i'm an expert on latter day since I have a couple of friends who are L D S. Happened to be very nice people and far as I know, they were not to people in this study.

But this study really emphasized ecstasy users. They're called, who have not taken other drugs, who self identify as lds. And the major takeaway of this study was that for moderate, meaning people who have taken, accessed anywhere from twenty two to fifty times in their lifetime, as well as heavy users of md ma, so these are people who have taken md ma anywhere from sixty six zero to four hundred and fifty times in their lifetime.

There was little evidence of decreased cognitive performance in standard essays for cognitive format. Now there were some effects showing poor. Here am quoting from the findings, poor strategic self regulation quote, possibly reflect increased in cultivation.

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 exercise four hundred and fifty times. You could conclude that, or you could conclude that people were taking x to see seventy five times or twenty five times at sea are degrading their levels, self control, and thereby increasing impulsivity.

The direction of the effect is not known. These are purely correlations, studies. And a few others, like IT really stand as our best evidence. Believe IT or not as to how exercise taken many times.

Because, after all, these people are taken anywhere from twenty two to four hundred hundred and fifty doses of exactly in their lifetime, is producing severe detriments in cogent 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.

And perhaps even looking at levels of serotonin adoption, all things that can be done with positive onic, mission tomography imaging, functional and right and set up hopefull. Those studies will be done in the not too distant future. But if we are, were to just take a step back from all the data, data in mice and rats and nonhuman primates, the retraction of the study in nonhuman primates, which showed that the primates that showed neta generation were not given md.

Ma, as was thought by the researchers, but rather as later was acknowledge, we're actually given math fact mean. And we take into account these moderate and heavy users of md ma, who sfar, 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 m dma are given one or two or three defining doses of pure nd. Ma will talk for those days in moment, think the dish dalt the top countour.

The overall view of those studies is that provided IT as pure m dma and provided the individual is not consuming other drugs, which have the potential to be neurotoxic, and provided that it's been done in a controlled clinical setting, the risk for toxicity seems quite a bit lower then the popular press has promoted, and yet there is still the risk of neurotoxicity of people are taking hyo ses of M D M, A or taking IT very frequently, or certainly if they are taking in conjunction with other drugs, or or I should say, and or taking md ma in settings that can promote neurotoxicity. And the settings are referring to our any settings in which blood pressure or body temperature have the propensity to be greatly increased. Every study in mice and nonhuman primates and in humans in which M D M A is administered, has observed significant increases in blood pressure and heart rate.

M D M A is, after all, a psychostimulant. It's a sympathic medic. Talk about synthetic medics and what that means.

The episode on atter all and vivent hd, but basically ramp ing up the activity of the sympathetic nervous system, which is your fighter flight system OK. This is why people who take these drugs get big pupils. You know, big pupils of the eyes is why they feel agitated.

They want to talk a lot if they feel like they want to move a lot is why you'll take IT to dance at raves at sea. But when people take some athol medics, they're not m dma or in fedex ine or cocaine, 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 is a very little temperature regulation, so people aren't, for instance, drinking enough fluids and electro light very hot in the room, you can get neurotoxicity based on temperature effects.

And that's because so tony and dobbin and also act on the so called media preoptic ticket of the hypothalamus, which is involved in temperature regulation. If you're curious about temperature regulation, I covered a lot of that in the episode of the hubble law podcasts on deliberate cold exposure and deliberate heat exposure. This is an area 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 in in particularly your brain can tolerate decreases in the 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 neurotoxic m dma, the conditions, that is, the environmental conditions, the behavioral conditions under which somebody takes CDMA are vitally important, at least important, I would argue, as any other compound, they might be interesting with m dma. So that's something really serious to sider. So if somebody says M, D, M, A puts holes in your brain, you would be correct, being skeptical, or at least giving them some counter arguments for that statement.

But if somebody says M, D, M A is not toxic, or then you would be equally valid and saying, oh, wait, but we need to think about the conditions in the rich. M D M A is being taken as IT purr. M D M A, or is IT mostly met the effects me, in which case would be very toxic?

Is IT m dma alone or in conjunction with caffeine within the same twenty four hour period? Is IT M D M A while moving around a lot, or being outdoors, or being in an environment, perhaps a rave or dance type environment where temperatures going up? In that case, you could be very neurotoxic.

So pharmacology of m dma counts, but so does Polly pharmacology. The injections of other compounds, not just during the M D M A session, but also in the twenty four hours before and after that M D M A session. And behaviors will certainly impact temperature, which will impact whether not m dma is neurotoxic or and despite my efforts, I couldn't find out whether or not the L, D, S.

Community has officially sanctioned the use of md M A. Certainly, that's one possibility, but I have no evidence for that or rather whether they are not certain people within the L D. S. Community have allowed themselves, give themselves permission to use m dma, and they are not using other drugs. What I do understand to be the case is that people with in 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 well, and self identify as having taken md ma anywhere from twenty two to four hundred and fifty times. But where they got permission for that, whether not is from someone else or from themselves, I do not know. What I do know is that within the acknowledgements of the paper, there is actually a thank you to the person that identify this, quote, unique population for our study.

So I welcome youtube. Take a look at the paper and if any of you know more about if and how a particular sub group within the lds community is allowed to take m dma props. You want to put those in the comment section on youtube before moving to our discussion about what M D M A 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 this data with you. Are you want to touch on something that anyone who's heard about M D M A, or perhaps used md ma is familiar with? And that's the so called crash that people experiences after m dma. There are a lot of myths about the post M D M A crash, and there's a lot of law out there on the internet about how to offset the crash and a lot of law about how to prevent the potential neurotoxic of m dma. Earlier, we talked about some of the major points around offsetting the autopsy.

So certainly making sure that any m dma that one takes is in the legal clinical setting that is therefore pure M D M A, right, that it's not cut with other things, which certainly can increase toxicity, controlling the temperature of one's environment, restricting caffeine, take at least on the day of m dma in gestion. But certainly the day before, in the day after, I would be advantageous as well, simply because of the way that caffeine and activation of the identify receptor, as well as caffeine effects on dopamine receptors, can interact with potential and and potential neurotoxicity of m dma. But the crash that one experiences after M D M A is actually a phenomenon very common to the crush that one experiences after injection tion of any type of stimulant, cocaine and fine seta.

And the crash that we're referring to as a drop in mood, increase in lethargy, of feelings, of lack of motivation. Many people have wrongly assumed that the crash was due to a quote, depletion of serotonin or depletion of the open or maybe even death of certain region and dope energy c neurons. And well, certainly that could be the case.

It's very unlikely that that would be the case in the immediate twenty four or forty eight hours after m dma. And Justin, that said, you will see protocols that people have put out on the internet, such as oh, you know, after taking md, ma should take a bunch of five h tp or other precursors to serotonin or dopamine, which come in a mino acid form. So l trip to fan, for instance, is the a mino acid precor to certa on in its in the serotonin synthetic pathway.

You'll hear that people will take altera acy, which is the amino as precursor to dope me, as a way to try buffer increased dopamine during the so called period of the crash. There is 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 a trip to fan and taking l terracing would actually further deplete sartori and dopamine. And so the logic there um is simply not very good.

What is clear, however, is that m dma can cause not just profound increases in dopamine, serotonin and oxytocin, but that anytime there's a big increase in dopamine in there is going to be a post dopo energies increase in proactive release. And proactive is a hormone, sometimes considered a neuro hormone, that's really hormone. It's involved in a lot of things, milk, collect down in electing women.

It's involved in setting the reactor period to sexual arousal and erection and ejaculation and males after event lation. It's involved in lots of different functions in the brain and body, including the line down of body fat stores. And it's also associated with increases in letter gy, decreases in dopamine.

This is why drugs that increase doping are known to decrease proactive, at least in the short term. This is wise drugs like cabe golan, for instance, that increased dopamine e are used as ways to suppress proactive. Now, M, D, M, A injustice is known to dramatically increase proactive.

And people are starting to realize that IT, perhaps, is the increase in proactive that occurs both during in for some period of time, the hours or days after injustice of M D M. A, that leads to at least some components of the so called crash. That feeling of letter gy and lack of motivation may be diminished mood at seta.

And for that reason, some people have started to explore the use of things like p five p, which is essentially a taboo of vitamin b six, which is known to suppress, proactive as a way to try and buffer some of that crash. To my knowledge, there are no human data yet expLoring the use of p5 p or other vitamin in b six derivative or capable golding or things of that sort to reduce pro action in a controlled， standardize clinical trial kind of manner. But i've spoken to some of the clinicians that are using M D M A legally within the context of the treatment of ptsd.

And this is an area that starting to receive some additional attention. So I just mentioned IT briefly here because, for instance, is a lot of ideas out there that people should be taking a trip to fan, they should be taking all terraces, they should be taking magnesium, other things that that are after taking md ma in order to recover from the post md ma crash more quickly. But it's really the increase in proactive, which speaks most directly to the subjective effects of the so called crash.

So by my read of the mechanisms of M D M A, that their chemicals that releases the are a hormones that IT promotes the release of production. In particular, this p5 p suppression of proactive 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 clinton that are using M D M A for the treatment of ptsd and other conditions such as alcohol, a use disorder is that start to explore the use of post M D M A session p5 p and other modes of suppressing pro acting for the hours and days after M D M A 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 M D M A in order to augment treatment for P T S D. Let's just take a moment and talk about what P T S D is. P T S D is post traumatic stress disorder.

Trauma is anything that modifies the brain to function less well going forward. Can have physical trauma. You can have emotional trauma.

Typically, P, T S D is used to refer to emotional trauma caused by either single events. So you can imagine your car accident, sexual assault. These can 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, with somebody being killed, dismembered, any number of different things that could be very traumatic in the immediate and long term. And of course, ptsd need not be used 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 doctor paul county. 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 podcast. We will provide a link in our shown 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 P T S D.

That also describes some of doctor paul count y'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 in 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 counted on this episode. That's talk therapy for which the patient sometimes refer to as the client, but more traditionally refer to as the patient and the therapy of a psychologist or psychiatry. Rist has good repair, and as a consequence of that repair, there is a 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 more adaptive behaviors and emotional states.

Now, in addition to report and support being critical, there's a third component of effective talk therapy for trauma, which is insight, or once 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 started get a little bit abstract. And that's also where we start to see that.

Well, trauma therapy in the form of talk therapy can be very effective. About half of people that undergo talk therapy. And talk therapy, one for the treatment of ptsd, achieve no long lasting relief of symptoms, and an even smaller number of them undergo complete remitted of their P T, S D.

Okay, so their symptoms can lesson, 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 P T S D itself.

Now in addition to talk therapy for P T S D, there is of course, prescription drug therapies. And most often these fall under the category of sss selective serotonin react taken hibor. And it's well known that s saris can be in limited circumstances affected for the treatment of ptsd.

IT has been shown, for instance, ince, that as many as forty, maybe as many as sixty percent of people that take exercise for the treatment of P, T, S, D get some symptom relief. Now that is not to say that S R S 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, weak rythm motivation, IT set up up. So there's often an exploration for the so called minimal effective dose that provides some symptom relief to P, T, S D, but that doesn't introduce unwanted side effects. And of course, there's a third situation where people are taking accessorize and doing talk to people for P T S D.

And what's very clear that any time 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 erp y improves outcomes for talk therapy, although that has been observed in a number of now.

The whole idea of expLoring the use of M D M A for the treatment of P T S D stem from the fact that even in people who are getting quality talk therapy, and again, we can define quality talk therapy as good report between patient and clinton, as well as feelings of support as well as potential insight. And even when S R S are combined with that quality talk therapy, they're 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 remitted of their ptsd. That is, despite being diligent and hard working in their talk therapy is by the therapies being very committed despite the use of a zing conjunction with the talk therapy, those people often still qualify as having P, T, S, D.

On the goal, of course, is for somebody to receive treatment that allows them to no longer meet the criteria for having ptsd, not just in terms of a clinical evaluation, but that they themselves report feeling much Better, not feeling overwhelmed with the symptom logy of ptsd. Now the symptom logy for P T, S. D. 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 stereotype example of ptsd.

This is the soldier that comes back from overseas that um has been in gun fights or in battles of different kinds as 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 random that can be Sparked by know the classics are typed. Example is know a car backfires and then the person suddenly feels as if they're back in battle that sort of thing does happen certainly but there are a whole other category of symptoms of P T S D, which include associative symptoms of ptsd. People who have P T S D from very intensely traumatic experiences that um 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 P T S D of either the associated type or other symptom logy of P T S D. And keep in mind that one can have both associated and non associated systems of P T S D, such as anxiety and panic, are at a four greater risk of substance abuse.

So the current estimates are that people with P T S D, no matter what type of P T S D associated 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. O P, O, I use disorder is very common stimulant use disorder and on and on.

So people with P T S D suffer at a number of different levels. And there are all these water called commodity ties with P, T, S, D, including addiction, but also depression, anxious. And so you can start to see our P, T, S, D.

He sets up a focal, 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, often times as people are holding a lot in. So they have cardiovascular and the very vascular deficits that caused a lot of problems in their immediate and long term physical health.

So P, T, S, D is a very serious issue. The current estimates are that as many as eight percent of people in the united states have P T S T. And again, the estimates around commodity ties range anywhere from seventeen to forty six is hides sixty five percent of people with ptsd having commodities 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 P T, S, D, sadly end up committing suicide. So suicide rates are far greater in people with ptsd. The exact rates of increase in suicide and people with P, T, S, D.

A little bit hard to arrive at in the statistics because of all the commodity ties. But suffice to say that suicide is far more likely in people with ptsd, along with all the other issues that P T S D brings about. Now P T S D 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 perhaps heard of the book the body keeps the score, which is A A very successful and popular book about the idea that trauma can be constant in the body. To be clear, mas can actually be stored in the body. You don't actually store memories in the body.

What you store, our activation of neural circuits that include brain and body. And they all seem to center back into the insula, that structure that we talk about earlier, this structure, our brain that has a map of our body, this. So contrary to popular belief, we don't store memories in the body, or trauma, the body, in a way that, for instance, you working out of not, or a painting once 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 insular, 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, is fact an important book? But I want to emphasize that the modern neuroscience really points to the fact that P T S D is caused by the exact sorts of brain network activation that we were discussing earlier, things like heighten levels of activation in the ami dala to insulate pathway, which of course would exacerbate bodily sensations related to the trauma, or height activation of the hip campus, this memory center in the brain, to a middle a to insulate circuitry.

Now, therefore, IT should come as no surprise that if m dma can reduce the levels of activity in the hip camp to a mig, to insula circuitry, and can do so both while someone is under the effects of m dma, but then the to persistent, long lasting reductions in the activation of those brain networks. Well then IT stands to reason that md ma could be a valid theraputics for the treatment of P T S D. And of course, this has been explored, and here we can really give a nod and large, that of gratitude to the so called maps group.

The maps group is a group that's Operating mainly out of santa s. California, but they have a number of different satellite laboratories and clinical groups, both in the us, in canada and abroad, where we've worked with government organizations to get legal authorization to give mtm a to patients who have P, T, S D, to also give them talk therapy and then to compare the effects of talk therapy with M, D, ma, 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 P, T, S D.

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 shown out captions, the two that I think are most interesting, or the study entitled md ma assistant therapy for severe ptsd irani ized double blind placable controlled LED phase three study, as well as the study entitled the effects of M D M A assist therapy on alcohol and substance use in a face free trial for the treatment of sea P T S D. So as the title suggests, both clinical trials involve giving people talk therapy N M D M A, 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 P T S D. 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 in the cup of legalization of m dma for the treatment of ptsd in the source of clinical context I described. When people are given just talk therapy alone or talk therapy with accessorize, they will often, as I mention earlier, experience reductions in their severity of ptsd symptoms.

And rarely, they will experience complete remitting of their ptsd, that is, they will no longer qualify for P T, S, D after receiving a number of talk therapy sessions. So let's compare that to what happens when people do talk therapy in conjunction with M D M A. And i'll explain exactly what that means in the moment.

But IT essentially means taking M D, M A while doing talk therapy. However, this is a very important. However, the people who are taking md ma in these trials have already done talk therapy without md ma.

Then they're doing talk therapy under the influence of M D M A. And then they are doing sessions of talk therapy, not under the influence of M, D, M, A. And the entire time they are doing that with the same two therapies.

Okay, I in the placebo group, people are doing talk therapy with two therapies, but they're not taking M, D, M, A OK. So they are in the same number therapy sessions, but they're not taking M D M A. So to just get to the key numbers first, the overall rate for clinically effective response to M D, M, A assisted therapy is eighty eight percent.

That's what emerging from these trials versus sixty percent for the placebo and therapy alone. So on the face of IT, you might say, okay, wow, eighty eight percent of people who do talk therapy. And here I miss, well, just finally explain this is done.

Patients are selected because they have ptsd. They meet the clinical criteria for ptsd. They do three ninety minute therapy sessions with two therapies, talking about their P T S D symptoms, talking about, to the extent that they can, the incident, that or incidents, the life events that LED to that ptsd.

None of that is done under the influence of any drug OK. So everyone in the experiment does that. Then the group divides into two, where half are taking M, D, M, A.

They take that three times. During those three times, they're also receiving therapy sessions with the same therapies that they were working with before they took A M dma. The first session, they're taking eighty milligrams of md ma.

And then a forty milligram booster about an hour and half to two hours. In the second session, they are taking a hie dose of m dma. It's one hundred and twenty milligrams.

And then if they elect to, they can take a sixty miligram booster about an hour and a half to two hours into the session. And then there's a third session where they take again, one hundred and twenty milligrams of m dma and have the option to take a sixty milligram booster. But and now and half to two hours into the session, again, anytime they're on M D M, A, they have therapies there that they're talking to about their trauma.

They are either spending time with their eyes closed, lying down, sometimes in I mask, and thinking about the trauma, thinking about their current state and experience, also thinking about what happened before. Then they're exciting. The I ask or talking to the therapist therapy is taking note to asking questions.

Remember, they've established a strong report supportive relationship with these therapies prior to taking m dma in the therapy session. And then they also undergo three ninety minute therapy sessions with the two therapies space one week apart after the final m dma session. Now those that were placed into the placebo condition do everything exactly the same as I just described.

So three nine minute sessions as prep than three eight hour sessions with those two therapies, and then three, ninety minute followed sessions one week apart. But they take a placable, not M D M A. So you can see that in these so called maps studies, these clinical trials for ptst, the conditions are very similar, except for the inclusion of the drug mtm a.

So those rates of success with talk therapy and M D M A, again, overall rate for clinically effective response to M D M A assisted therapy was eighty eight percent compared to sixty percent for therapy and placebo. What even more impressive, however, is that sixty seven percent of the people in the M D M A plus therapy treatment group no longer meet the criteria for ptsd by the end of the treatment. So in other words, their ptsd went into reminds.

Now we could say they are quite what cured, but typically um for things like ptsd that's not the language that's used rather what you use is statistical evaluation of how the different symptoms like association or anxiety or sleep disorders are explored. So well to some of you, a difference between sixty percent success with talk therapy implications o versus eighty eight percent success with talk therapy plus M D M A 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 magnus de, I could be wrong about that. I'm sure some psychiatrists out there are gna 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 eighty eight percent for the treatment of a major psychiatric disorder. Please do put that information in the comments on youtube. And perhaps a reference to a study would be even Better. But even if not just put a reference to that, that would be great for the sake of future episode is eta, but nonetheless eighty eight percent success rate. And here i'm referred to success rate as a significant reduction in clinical systems for a ptsd.

And sixty seven percent of those people going to full limitations 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 m dma from a schedule one drug for which there quote no clinical applications to potentially a legal within the context of clinical use application of m dma, which he does appear the legislature is at least considering for as early as twenty twenty four, maybe even later in twenty twenty three. 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 P, T, S, D. Also suffer from alcohol use disorder. What interesting is that for people that were in the m dma 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 M D M A 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, often times we will stem from disruptions in neural circuitry that are the same, disruptions in neural circuitry that occur ptsd, but often are the consequences entirely other brain wiring phenomenon. What i'm saying here is that just because addiction and P T S D are often call murban with one another, IT was not necessarily the case that treating resolving P T S D 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 P T S D. So that's very exciting.

Some of the other particularly exciting results from these clinical trials on m dma plus talk therapy is that the associated former P T S D has traditionally proved to be especially hard to treat and that thought to stem from the fact that successful treatment of ptsd, whether not by talk therapy, or talk therapy combined with accessorize, or talk therapy combined with any drug treatment or behavioral treatment like em D R I movement, this sensation reprogramme or other forms of treatments that are designed to required neurosis cut ry, almost always involve the patient getting very close to at least reporting the traumatic experiences in a lot of detail. And you can imagine why for somebody who's associating from that very experience, who's ticket 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 P, T, S, D. So IT appears that M, D, M, A, in providing this pro social apathy, again, impair ic for others and impair ic for self, chemical and mental environment, as well as the presence of two trusted therapies.

Which one has A A really good report? Allows patients with ptsd to really get close to those experiences that were traumatic, to talk about them and to think about them, and in many ways, to reframe them in a context that often involves empathy for others and empathy for self. Now here we're not necessarily talking about forgiveness of perpetrators, although that sometimes the case that people will forgive the person that inflicted the trauma on them, but more often than not, it's about tying their feelings of trauma and their feelings of depression.

Anxiety association said a 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 a support around that, that the emotional load seems diminished and that they experience the emotional load of those experiences as diminished, both within the M D M A treatment session and afterwards for long periods of time. So essentially what happens is these people feel that what once burned them, they can still remember.

But I no longer burdens them and 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 when here's about these kinds of results and when you hear about some of the patient report, and I invite you to do that, you can go to the map site, which, by the way, is recruiting subjects for these clinical trials. And you'll also find reports of individuals who participated in these clinical trials.

And of course, we will provide links to these incredible clinical trials that maps has spearheaded. What you find is that the combination of M D M A 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 m dma, the potential toxicity or lack there of m dma. We've been talking about the brain networks at sea, but when one thinks about the valid clinical use of M D M A for the treatment of P T S D, 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. And now md ma is being explored for treatment of not just ptsd, but also for depression, for alcohol use disorder and for eating disorders as well.

M D M A seems to be a compound that produces the right kind of subjective and neurochemical meu 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, you know how expensive IT is to get therapy over and over and over again, which in the ideal circumstances, people are able to do that either by way of insurance or by their own finances or no, I I don't want to say that, that the cost of therapy should be reduced because, of course, therapies 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 circumstances in which somebody only has ten or fifteen, 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 particularly brain networks, the suppression of other brain networks in particular, there's a middle late to insula pathway that when people are under the influence of M D M A in these very safe and thai uc supportive settings, they are able to look at traumatic events in the ways that those traumatic events impact them, in ways that really allow them to cognitive ly refrain those events and dramatically 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, I would be remiss if I didn't touch on some of the so called a diverse effects as 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 M, D, M A therapy, there were no increases in the number of suicide attempts or suicide obsession with suicide. Contrast that with the group that received placebo, where there were a certain number of baseline and predicted obsessions with suicide. Unfortunately, least to my knowledge, there was no actual suicide attempt to a successful suicide, thankfully. But the point being that the addition of m dma drug therapy to P T S D talk therapy does not seem to increase the court side effects sometimes associated with P T S D talk therapy because indeed there can be side effects to expLoring P T S D and trauma as one would expect.

So overall, I would say it's very exciting times for the exploration of M D M A as an augment to talk therapy for the treatment of P T S D in these other then 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 mb ma isn't simply made legal and then abused recreationally. I know people out there have different views on whether or not drugs like m dma should be legal or not. It's not what this episode is about, what I am very excited about.

As you can probably tell what I think a lot of people in the psychology and psychiatry community are very excited about. The mental health community at large is that these compounds that for many years were only associate with their recreational uses and therefore were not well understood because they were often contaminated or taking accommodation with other things or by people that never should have been taking them in the first place um taken by Young kids, which is a whole other matter. You know lot of issues and problems associated with these compound.

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 m dma is combined with quality talk therapy that the outcomes are looking tremendously positive is by no means a miracle cure IT is by no means perfect and time we'll tell uh, what problems of any arise from the short or long term use of M D M A in this context. But I think it's remarkable that anywhere from two to three sessions with them, dma and talk therapy have been shown to significantly reduce ptsd symptoms and in some cases, completely eliminate P T, S, D symptoms in such a wide range of patients and in patients that have experienced both p tsc and these other commode disorders. I think it's really remarkable, is very exciting.

And I look forward to seeing what the next round of data produce. So as is often in the case on this podcast today, we went into a lot of detail about a subject. m. Dma is this incredible compound synthesized, as far as we know, first, by humans, not by plants, not by aliens, but by humans. And that produces big increases in dopamine and serotonin to create these highly motivated prosocial and pathetic 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 on human primates point to the fact that at reasonable doses, and we talked earlier about what that was, are at reasonable doses, when not combined with other drugs, IT does not appear that m dma is exceedingly neurotoxic, and IT may not be neurotoxic at all.

Of course, one needs to be succeedin ly cautious when thinking about the use of any sympathy atic. They, of course, I can be neurotoxic anything with metheny demon in IT as a potential to be neurotic ic, but of course, IT dosage matters, context matters. We talked about that.

And of course, the purity of drug matters. And again, I just want to reemphasize the final contamination of m dma that sold on the street and that is being used recreational is a very serious, potentially lethal concern. I also expect that there will be a lot of interest in these clinical trials that maps is doing. So again, you can find links to that in the shower ote 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 neusatz generally because whether or not we're talking about silicide in our lsd or IO, osca or kadee or today's topic of m dma, regardless of what drug in your transmitter and your modulator systems are involved, what were really talking about our ways to access neural plasticity, the other systems, incredible ability to modify itself in response to experience, ideally to be modified in adaptive ways that make IT function Better. So that's really the cracks of what talk therapy and drug therapies are about. That's what the goal of using m dma as a clinical tool is all about.

And in that sense, I find m dma to be an incredibly interesting, an important topic, and I hope you did as well. If you're learning from and or enjoying this podcast, please subscribed our youtube channel. That's a terrific zero cost way to support us.

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