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

Welcome to the Huberman Lab podcast where we discuss science and science based tools for everyday life. I'm Andrew Huberman and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today we are discussing mdma, sometimes referred to as Ecstasy or Molly. MDMA stands for methylenedioxy methamphetamine. That's right, you heard the word methamphetamine in there. And MDMA has properties similar to methamphetamine, but also properties that are very distinct from methamphetamine. Just as a side note, methamphetamine is a commonly used drug of abuse. It is an illicit drug and it produces some of the greatest and fastest increases in the neuromodulator dopamine of any available drugs on the street or in the clinic. And believe it or not, methamphetamine is prescribed as a prescription drug in some very limited clinical uses. Mdma methylenedioxymethamphetamine has properties similar to methamphetamine in that it powerfully promotes the release of dopamine and it is a stimulant, and yet it also powerfully controls the release of serotonin and in doing so makes MDMA a distinct category of compound from either classic psychedelics like psilocybin or lsd, which largely work on the serotonin system and tend to produce mystical experiences. And it's also distinct from pure stimulants such as methamphetamine, because mdma, by producing big increases in both dopamine and serotonin, acts as what's called an empathogen. It actually can increase one sense of social connectedness and empathy, not just for other people, but for oneself. And in that way, MDMA is commonly used as a recreational drug, but also is now being tested and is achieving incredible early results in clinical trials for its use as an empathogen for the treatment of PTSD in clinical therapeutic settings. I want to be very clear that at this Point in time, June 2023, MDMA is still a Schedule 1 drug. That is it is highly illegal to possess or sell in the United States. And today we are going to talk about some of the path legality that's underway. We are also going to talk about the history of MDMA and why it became illegal. And we are going to talk about the key difference between recreational use and therapeutic use and the important components of the studies exploring MDMA in the clinical setting for the treatment of ptsd. So during today's discussion, we will talk about what MDMA really is how it works at the level of neurons, which brain circuits it activates and deactivates. And in doing so you will come to understand why it is so exciting as a treatment for ptsd. We will also, of course, talk about the results of these clinical trials using MDMA for the treatment of ptsd. They are incredibly exciting. In fact, the field of psychiatry has never before seen the kind of success in treatment of PTSD with any other compound that they are seeing and achieving with the appropriate, safe use of mdma. And when I say appropriate, that means in conjunction with nine therapy sessions. So this is an area that really deserves some time for us to discuss because again, there is a distinct difference between the recreational and the therapeutic use of mdma. We will also talk about the toxicity of mdma. This is a very important issue because many of you have perhaps heard that mdma, quote, unquote, puts holes in your brain or kills serotonin neurons, or kills dopamine neurons. And indeed, mdma, because of its similarity to methamphetamine, which is highly neurotoxic, MDMA can be neurotoxic. However, there are ways to use MDMA therapeutically that avoid its toxicity. And yet there are still questions about its toxicity and its long term effects, both after acute use, meaning just one to three times, as well as chronic use, meaning people who have taken it many, many times. We'll talk about the spacing between sessions of mdma. We will talk about dosages. We will also talk about things that people do and that can be to offset some of the potential toxicity of mdma. So by the end of today's discussion, you will have a thorough understanding of what MDMA is, what it isn't, what is known about what it does, what is known about what it doesn't do, as well as some of the still outstanding questions about MDMA that remain to be resolved. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science related tools to the general public. 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Today's episode is also brought to us by HVMN Ketone iq. Ketone IQ is a ketone supplement that increases blood Ketones. I know most people are familiar with or at least have heard of the so called ketogenic diet. It's used for weight loss, it's used to control epilepsy, it's used for mental health reasons. However, most people, including myself, do not follow a ketogenic diet. Nonetheless, increasing your blood ketones can improve the function of your brain and the function of your body. And that's because ketones are preferred use of fuel for the brain and body. So even though I follow an omnivore diet that is I'm not in a ketogenic state. I use ketone IQ to increase my blood ketones prior to doing preparation for podcasts or writing grants or doing research as well as prior to workouts. Especially if I want to work out fasted. I'll take some ketone IQ to increase my blood ketones, which gives me a lot of energy during workouts or during bouts of cognitive work. Even if I haven't eaten in the preceding hours. It really increases my focus and my energy levels. If you'd like to try Ketone IQ, you can go to hvmn.comhuberman to save 20%. Off again, that's hvmn.comhuberman to save 20%. Let's talk about MDMA. MDMA, or ecstasy, is a fascinating compound, and I say fascinating from the perspective of its chemical structure, which is highly unusual. I say fascinating because it has an incredible set of subjective effects in terms of how it makes people feel, and it has a fascinating history. So let's just briefly start with the history of mdma. MDMA was synthesized by the drug company Merck in the early 1900s, but it actually was never applied to any particular clinical use, and it wasn't really explored much in any laboratory territories at all. And then it was later rediscovered by a guy named Alexander Shulgin, who was a bit of a renegade drug chemist who was designing different drugs for the purpose of understanding their subjective effects on humans. So there's a long history of Shulgin designing drugs. He was, after all, a chemist, and then taking those drugs himself. And then if he liked the effects of a particular drug, or rather if he thought that it had potential clinical utility, he would give it to his wife, then she would give him her notes about those drugs, and then they would share them with their friends. And it was a small group of friends who consisted of therapists and physicians. So this was a really underground kind of operation. It was technically not illegal when it started because MDMA wasn't illegal. When it started. But over the several decades that Shulgin and his wife and this group were doing this kind of exploration, MDMA did become illegal and he fell under, well, let's just say scrutiny by the dea. Now, here's the important thing to understand about MDMA and its history. First of all, MDMA is a synthetic compound. As far as we know, it does not exist anywhere in nature. So unlike similar compounds such as mescaline, because MDMA and mescaline are very similar in their chemical properties and to some extent their subjective properties. Unlike mescaline, which can be found in the plant kingdom, or lsd, which comes from ergot, or psilocybin, which of course can be found in magic mushrooms. MDMA is a unique chemical in that, again, as far as we know, only exists in its synthetic form. It is human made. And as we get into the chemical effects and the subjective effects of MDMA a little bit later in the episode, I think you'll understand why it is such a unique and to some extent exciting compound from the perspective of clinical treatment. Put differently, there's really no other compound that we know of in nature or in the pharmaceutical industry shelf or options of drugs that are prescription drugs that produce the kinds of effects that MDMA does. And by the way, if you're interested in the story of Alexander Shulgin and the drugs he synthesized and the group that he built up to take these drugs and try them, and actually had several members of this group using these drugs in therapy with their patients for a long period of time, both before and after MDMA became illegal. There's a wonderful book called PKAL that stands for P I K H A L P Call is the title of the book which Shulgin wrote, which describes his discovery of mdma. I confess, it also describes the synthesis of mdma and for that reason was a book that for a long time was not available, but is now available again in audible form and in printed form. P CALL stands for phenylethylamines. I have known and loved. Phenylethylamines is the category of drug for which MDMA belongs to. And it's a long book, but a very interesting one, both from the perspective of understanding the history of MDMA and what MDMA is and the effects that it produces. But it's also an interesting book because it will teach you a lot about the history of the pharmaceutical industry, the war on drugs in the United States, and the interaction between illegal drug exploration and drugs for clinical treatment of psychiatric challenges. So right now this is A very important issue because MDMA is currently granted breakthrough status, which means it's now something that scientists and clinicians can study if they have authorization to do that. It is, as I mentioned earlier, still a Schedule 1 drug. So it's illegal to possess unless you are one of these scientists who has been granted permission to study it in the clinical setting or the laboratory setting. And right now we are on the cusp of MDMA becoming legal. But again, it is not yet legal. And this is something I'm going to touch back on a few times during today's episode later, for instance, when we talk about the potential toxicity of mdma, its ability potentially to kill neurons, and the neurons it has been hypothesized to kill are neurons of the serotonin and dopamine type. So this is something you would not want. Let's just recall that killing off of or death of dopamine neurons is the underlying basis for Parkinson's disease, which is a movement disorder where people have difficulty generating smooth movements and in very severe form, they can't move at all. They sort of become locked in to some extent. And it also has cognitive effects. So you don't want to lose dopamine neurons. And loss of serotonergic neurons is known to impact mood negatively, mood regulation negatively, etc. The story of MDMA and its potential neurotoxicity comes slam right up against this issue of legality. And what we'll get into a little bit later is that there has been a sort of race in the scientific community consisting of two groups. One set of groups trying to establish the toxicity of MDMA so that it does not become legal again, and another group trying to establish the utility and the lack of toxicity in MDMA so that it does become legal again for the treatment of ptsd. So even though the story P call relates to events that took place largely in the 1970s, 80s and 90s, right now MDMA and its toxicity, or lack of toxicity, its legality or lack of legality are really key issues. So as you're listening to this, I'm giving you a real time blow by blow of what led up to where we are now. But we will also want to think about how what's happening right now, including the description of these data on mdma, may or may not impact the potential legal status of MDMA. Okay, so what is MDMA? MDMA is 3,4 methylenedioxy methamphetamine. But unless you're a chemist, that's not going to mean much to you, nor should it? MDMA has some very interesting properties, the first of which is that methamphetamine component, which, because it's a methamphetamine and acts like other amphetamines, what it does is it blocks the reuptake of dopamine from neurons after dopamine is released. So for those of you that heard the episode that I did on drugs to treat adhd, I discussed the biology and mechanisms of drugs like Adderall and Vyvanse, which basically are either combinations of amphetamines or single types of amphetamines that have either a quick release or a long release. Now, mdma, because it has this methamphetamine component, prevents the reuptake of dopamine, and in doing so, creates net increases in dopamine. So for those of you that don't have a background in neurobiology, let me just briefly explain. I'll make this very simple. Neurons, or nerve cells release chemicals at their sites of communication, which are called synapses. Synapses are little gaps between neurons. And what happens is the neurons spit out these little spherical balls, which we call vesicles or vesicles, depending on where in the world you live, they'll either be called vesicles or vesicles. And those little vesicles contain neurotransmitter, or what's technically referred to as a neuromodulator. Dopamine is a neuromodulator. It can modulate the activity of other neurons. It can either increase or decrease the activity of other neurons. Now, at the end of the neuron, what we call the axonal boutonna, okay, Axon is kind of the wire component of the neuron that can reach to another site in the brain and then release the neurotransmitter and neuromodulator there. At those axonal boutons, which are the sites of release, the vesicles literally fuse with the edge of the neuron and vomit their neuromodulator out into the synapse. And then the neuromodulator, in this case dopamine, will bind to receptors on the postsynaptic side, that means to another neuron. And then, depending on how much binds and depending on what else is going on in that local neighborhood of neuronal connections, the neuron will either increase its neural activity and itself release neuromodulator or neurotransmitter someplace else. So sort of a chain reaction, or else it will suppress its activity and the flow of communication. From one neuron to the next will be stopped. Okay, so MDMA doesn't prevent the release of dopamine at the synapse. It does quite the opposite. It actually prevents the sucking up of the dopamine that's been released and that does not bind to the receptors. So basically what it does is it blocks these things called dopamine transporters. And the transporters are the things that suck back up the dopamine that's been released that has not bound to receptors. So because it blocks that sucking up process, there's more dopamine around in the synapse to hang out and then bind to receptors once some become available. Okay. The other thing that the methamphetamine component of MDMA does, just like methamphetamine, is that it actually gets into what we call the presynaptic neuron, the neuron that releases the dopamine, and it interferes with the repackaging of dopamine into those vesicles. Now, you might think, oh, it interferes with the repackaging of dopamine into vesicles and therefore less will be released. But actually what happens is, as a consequence of that, a bunch of dopamine builds up in the presynaptic neuron, so that when an electrical impulse comes down that neuron and dopamine is released, a huge amount of dopamine is released. And this is one of the characteristic properties of methamphetamine and of mdma, which is that it leads to enormous increases in the amount of dopamine released and the amount of dopamine that hangs around in the synapse. And therefore it increases what we call dopaminergic tone or dopaminergic drive. That's just a bunch of different ways to describe it increases in dopamine. Okay, so that's the main way that MDMA and by extension methamphetamine increase dopamine. However, MDMA is not just methamphetamine, it's methylenedioxy methamphetamine. And it has another incredible property, which is that it doesn't just lead to huge increases in dopamine, it also leads to huge increases in serotonin. And that's because there are other neurons that release serotonin, and. And they have serotonin transporters, which are sometimes called CERTs, S E R T S serotonin transporters. And they work very much in the same way that dopamine transporters do. Right. They basically control the sucking backup of serotonin. That's been released into the synapse, and that has not bound to serotonin receptors on the other neurons yet. And in doing so, allow more serotonin to hang out and have its effects as those receptors become available for serotonin to bind to them. The other thing MDMA does is it also gets into the presynaptic neuron to impact the packaging of serotonin into something called the vesicle monoamine transporter for serotonin. And in doing so, it leads to a big buildup of serotonin in presynaptic terminals and then massive increases in serotonin release. Okay, so what we've got with MDMA is a really interesting compound. Unlike methamphetamine or other amphetamines such as Adderall, Vyvanse, etc. That cause increases in dopamine by blocking reuptake and increasing release of dopamine, MDMA does that, but it also does the same thing for serotonin. And here's a really key point. The increases in serotonin that MDMA creates are at least three times and maybe as much as eight times greater than the amount of dopamine release that MDMA causes. But when you put those two things together, what you basically have is a drug that causes huge increases in dopamine and even bigger increases in serotonin. And remember earlier when I said that MDMA is a purely synthetic compound. As far as we know, it does not exist in any plants or fungus or anything else in nature. Well, this is a very unusual circumstance of having big increases in dopamine and big increases in serotonin caused by the same compound. And that combination of big increases in dopamine and big increases in serotonin are what lead to these highly unusual and yet what seem to be potentially clinically very beneficial effects of having people feel a lot of mood elevation and a lot of stimulation from the stimulant properties of the methamphetamine components component. So that's the dopamine effect. The dopaminergic tone goes way up. So it's a stimulant. People feel really alert. They feel like talking a lot. They feel very excited, they feel a lot of positive motivation. These are classic effects of drugs that promote the release of dopamine, including amphetamine, cocaine, et cetera. But ordinarily, that's not such a good thing, because what happens is there's then a crash in the dopamine levels, and then people feel depressed, they feel lethargic, they don't feel Good at all. MDMA seems to cause these increases in dopamine and all the accompanying effects I just described. But by also causing big increases in serotonin, it activates neural networks that are associated with feeling more socially connected. In fact, we'll talk about data in a little bit where people have had their brains imaged while under the influence of mdma. And it's very clear that people who have taken MDMA look at faces that ordinarily they would rate as fearful and rate them as less fearful. They see faces that are smiling, and they rate those smiling, happy faces as more positive than they would off the drug. The big increases in serotonin create what we call a pro social effect. And that combined with the dopaminergic increase in mood and the stimulation effect creates this thing that we call an empathogen, where, and this is very important, the empathy isn't just for other people, it's also for oneself and one's own experiences happening in the moment, as well as empathy for experiences from the past which, as you can imagine, could be very beneficial for the treatment of ptsd. Okay, so hopefully the way I describe the biology of MDMA makes some sense. If you didn't get anything out of the description I provided except the understanding that MDMA is unusual in that it causes big increases in dopamine and even bigger increases in serotonin, then you have more in your knowledge base now about MDMA than you need in order to understand the rest of our discussion. Before we go any further, I do want to separate MDMA out from some other compounds which are referred to as psychedelics. And I recently did a podcast episode all about psilocybin and its therapeutic exploration and its chemical basis, et cetera. You can find that like all episodes@hubermanlab.com I also did an episode with expert guest Dr. Robin Carthart Harris, who's at University of California, San Francisco, who's pioneering a lot of the studies on the clinical application of psilocybin. Psilocybin and LSD are mainly going to increase serotonin activation in the brain. In fact, they very closely resemble serotonin itself and they activate what's called the 5ht2a or serotonin. 5ht just stands for serotonin, the 5ht2a receptor to create very mystical type experiences. They are considered classic psychedelics and are very introspective. And as I described in, those episodes are being explored extensively now for the treatment of major depression. A different compound that's being used for the Treatment of depression is ketamine. I will do an entire episode all about ketamine. Ketamine is actually a N methyl D aspartate receptor blocker, NMDA receptor blocker. That shouldn't mean anything to most of you, but it is a dissociative anesthetic, not unlike pcp, what used to be called angel dust on the street. Ketamine is being used as a treatment for depression. It is currently legal. So unlike psilocybin and lsd, which are granted breakthrough status for the study of depression, but are not yet legal, they are still illegal. And of course, as I mentioned earlier, MDMA has breakthrough status but is still illegal. Ketamine is being used for the treatment of depression and it does so, as its name suggests, a dissociative anesthetic by creating a sense of dissociation from emotions. Okay, now I raise this distinction between psilocybin and lsd, which are mystical in their effects. Ketamine, which is dissociative in its effects with mdma, which is an empathogen or sometimes called an anactogen. But as an empathogen or an anactogen, it's creating more affiliation, it's affiliative. Okay, so it's a very distinct compound. And I think this is important to understand because when we hear the word psychedelic, a lot of people tend to lump together lsd, psilocybin and mdma. If you talk to researchers in these areas, they will tell you that MDMA really isn't that much of a psychedelic. It's an empathogen with stimulant properties, and it also has the serotonergic component that makes it an empathogen or an anactogenic. So MDMA is very different than the other psychedelics. And my hunch is that over the next few years we will stop talking about MDMA as a psychedelic because it does not tend to produce visual hallucinations or auditory hallucinations of the sort that classic psychedelics do. And in general, it is more of a mood impacting drug than it is mystical. Okay, so we'll get into some of the brain networks and which ones are activated while under the influence of mdma. But I do think it's very important to segment out MDMA from the other so called classic psychedelics and also segment it out from ketamine. Thanks to some really terrific studies, both in animal models and in humans, we now understand a lot of what makes MDMA produce these incredibly unique effects. And when I say unique, I mean unique from drugs like psilocybin. And LSD and ketamine and from methamphetamine for that matter. And it's really the combination of big increases in dopamine and even bigger increases in serotonin that create a situation where people have more energy. And yet despite having more energy, they don't feel irritated, they feel a lot of pleasure. They seem to want to be in the state of having a lot of energy. This will become important as we talk about anxiety and the anxiety symptoms of ptsd. It also, because of the big increases in serotonin, produces a sense of emotional warmth towards others and towards oneself. That's the empathogen component. And for reasons that we still don't understand, it seems to increase trust. And the increases in trust turn out to be vital because as you will also learn later when we look at the clinical trials exploring MDMA for the treatment of ptsd, the major effect of MDMA for the treatment of PTSD is not to cure ptsd, but rather to make the therapy, the talk therapy for PTSD, much more effective. This is a very important point. In fact, so important I'm going to repeat it at least three times during today's episode. Mdma, taken on its own, does not cure ptsd. MDMA can augment or boost the effects of talk therapy for ptsd, and it does that through the engagement of specific neural circuits. But before we talk about what those neural circuits are, I want to emphasize that the increases in serotonin that MDMA produces seem to act on different receptors than the big increases in serotonin that LSD and psilocybin produce. So if you listen to the episode that I did on psilocybin, we haven't done yet one on lsd, but the mechanisms are very similar for psilocybin and lsd, whereby psilocybin and LSD very closely mimic the molecule serotonin itself, but seem to have a more selective activation of just the so called serotonin 2A receptor, abbreviated 5HT2A. And that leads to more interconnectedness between different brain areas, more consideration of new possibilities about events from the past, present and future, and also the opening of so called neuroplasticity of rewiring of neural connections that persist long after the psilocybin or LSD effects have worn off. Now, MDMA can activate the serotonin 2A receptor, but it seems that it largely activates the serotonin 1B receptor. Now what does that mean? Activation of the serotonin 1B receptor seems to be what gives MDMA its Very strong impact on the neural circuits of the brain that relate to trust and to social engagement. Not just the willingness to engage socially and to confide in a therapist or another person, but the intense desire to do so. And when I say intense desire, that takes us back to the dopamine system. Remember, dopamine, even though when increased in the brain can increase our mood, it is largely responsible for increasing our sense of motivation and desire for. For something and to do something. So the increase in dopamine that's created by MDMA seems to make people what I call forward center of mass. You know, they want to do something, they're very motivated to do something. And the increases in serotonin acting on the serotonin 1B receptor seems to be what creates this desire to bond or create trust or to have a discussion of real things. Both things that are positive, but also to explore things through that are difficult. And this, I realize, is going to be a little bit of a mind bend for people to understand. But one of the key things that quality MDMA therapy consists of is not just having a very good rapport and communication with the therapist that's guiding the PTSD treatment, but also rapport and a willingness to engage in conversations with oneself. I think that most of us can relate to the fact that we have experiences, some of which are hard, some of which are great, and everything in between. Trauma is, I believe, best defined by the words that a former guest on this podcast who's a world expert in trauma, Paul Conti, explained as, trauma is an event that fundamentally changes the way that our brain works for the worse. Okay, so not every bad event of our past is trauma, but events that change the way that we think, our emotional tone, or our behavior in ways going forward that are not adaptive for us. They don't serve us well, either because they are highly distracting or because they create anxiety or because they disrupt sleep or any number of different things that are maladaptive consequences. That's what really defines trauma. And when under the influence of MDMA, because of those parallel increases in dopamine and serotonin, people seem far more willing to both trust the therapists that they're talking about that trauma with, but also to trust their own ability to, quote, unquote, go internal and think about the challenging thing or things. Because oftentimes trauma can consist of many events, not just one event, and the thought patterns around that and the context around that, and therein to be able to explore new possibilities, to essentially rewire their relationship to that trauma. So I promise that a little bit later we'll talk about the direct application of MDMA for the treatment of ptsd. But now I'd like to shift off of the chemical changes that MDMA produces and some of the subjective changes. These increases in trust and pleasure and energy and emotional warmth to some of the brain circuits that are activated and modified by MDMA use. And then we will explore the toxicity issue and then we will explore the clinical studies of which I can promise you are extremely exciting. But until we understand the neural circuit phenomena, and of course, until we consider the neurotoxicity issues, I don't think those clinical findings can be appreciated in their full value. But now I'd like to talk about what MDMA really does in the brain, both in the short term while someone is under the influence of the drug and in the long term. What sorts of neuroplastic or rewiring changes do does MDMA produce and how can those be beneficial or perhaps not beneficial? I'd like to take a quick break and acknowledge one of our sponsors, Athletic Greens. Athletic greens, now called AG1, is a vitamin, mineral probiotic drink that covers all of your foundational nutritional needs. I've been taking athletic greens since 2012, so I'm delighted that they're sponsoring the podcast. The reason I started taking athletic greens and the reason I still take athletic greens once or usually twice a day, is that it gets me the probiotics that I need for gut health. Our gut is very important. It's populated by gut microbiota that communicate with the brain, the immune system, and basically all the biological systems of our body to strongly impact our immediate and long term health. And those probiotics and athletic greens are optimal and vital for microbiotic health. In addition, Athletic Greens contains a number of adaptogens, vitamins and minerals that make sure that all of my foundational nutritional needs are met. And it tastes great. If you'd like to try Athletic greens, you can go to athleticgreens.com huberman and they'll give you five free travel packs that make it really easy to mix up athletic greens while you're on the road, in the car, on the plane, et cetera, and they'll give you a year's supply of vitamin D3K2. Again, that's athleticgreens.com Huberman to get the five free travel packs and the year's supply of vitamin D3. So in order to understand what MDMA does to the human brain, we need to take a step back and really define the sorts of experiments that One could do so, for instance, you could take a person who's never ingested MDMA and put them into an FMRI machine, which is functional magnetic resonance imaging. Put them into the FMRI machine and just have them sit there with their eyes closed, what we would call resting functional connectivity or resting state functional connectivity, and simply look at how interconnected certain brain areas are, which brain areas are active, which brain areas are less active at rest. This is an important thing to do, not just to provide a baseline for understanding what the drug MDMA will subsequently do, but also because it addresses what's called the default mode network. The default mode network, or dmn, is the network that is active in our brains when we aren't really attending to anything specific outside us, and we're not trying to think about anything specific or accomplish anything specific. It actually relates to our sense of imagination and daydreaming. It has a lot to do with our self referencing, you know, what we're thinking about ourselves. This may come as no surprise, but if you're just sitting there on the bus or, you know, around the dinner table and you're not paying attention to what's going on, in large part, your brain is in this default mode network and you're thinking about yourself. Okay, so we can get a sense of what the default mode network activation is. We can get a sense of which brain areas are more or less active simply by putting somebody into an FMRI machine. Then of course, you could give somebody MDMA while they are in the FMRI machine and see how the activation of different brain networks changes. And then of course, you could analyze how the default mode networks and other brain networks change in the days and weeks and even years after the drug has worn off. So called neuroplasticity effects. What changed in a permanent or pervasive way. Okay, so that's sort of one basic paradigm for exploring the effects of drugs like MDMA on the brain. The other way that you can explore the effects of MDMA on the brain is to ask people in the general population, hey, who out there has taken mdma? How many times have you taken it? And come on into the laboratory and we will image your brain and compare people who have, for instance, taken MDMA 0 times to people who have taken MDMA 1 time or 5 times? Or believe it or not, there's some studies sitting right here in front of me on my desk of people who have taken MDMA more than 200 times and ask the same sorts of questions. Which brain areas are more or less active Those studies have been done as well. And of course, one can do studies where you give people different dosages of MDMA as well as giving people MDMA and then giving them specific stimuli, meaning not just asking them to sit there in the FMRI scanner with eyes closed, looking at the resting state, functional connectivity, but also how the brain responds to the presentation of happy faces or sad faces or images of oneself, or even images that recall memories of traumatic events and so on. So fortunately, all of those sorts of studies have been done in humans. And there are also a large number of studies in animal models exploring how the social activity of laboratory mice changes when they are under the effects of mdma. There are even studies, believe it or not, on the effects of MDMA in cephalopods. Cephalopods include include octopuses as well as cuttlefish and other aquatic animals that are known for having complex behavior. Some people believe that the cephalopods are extremely intelligent. You know, the obsession with cephalopods is something that really intrigues me. I actually used to have cuttlefish in my laboratory. We did not put them on mdma. But there is a study that's been published in the journal Current Biology. It's a cell press journal, excellent journal. This is from Gouldolin's laboratory at Johns Hopkins School of Medicine, showing that if you give octopuses mdma, they like to spend more time with other octopuses than they do if they are not on mdma. And that might sound like kind of a, kind of a playful experiment just done in order to entertain oneself and the octopuses perhaps. But actually in that study they identified the serotonin transporter in octopuses and, and show that it has a lot of homology similarity to human serotonin transporter receptors. And so what that really speaks to is the fact that the pro social effects of MDMA that are observed in mice and in humans and in octopuses all have a common basis, which is the activation of more serotonin release in particular brain networks. Okay, so that interesting study on octopuses aside, I think what most of us are interested in is how MDMA impacts the brain. And so I'm going to spell out the three major ways in which MDMA changes the activation of the brain in the short and long term. And here I'm pooling across a number of different studies, but one of the key sets of studies in this area comes from the, what I consider very beautiful work of Harriet DeWitt. Harriet DeWitt runs the Human Behavioral Pharmacology Laboratory in the Department of Psychiatry and behavioral neuroscience at the University of Chicago. And her laboratory has a long history of giving people certain drugs in very specific dosages and then measuring their effects on the brain using different types of imaging, including fmri. And one particular study that I'll highlight is entitled Effects of MDMA on Sociability and Neural Responses to Social Threat and Social Reward. So what the study looked at is how MDMA impacts people's perceptions of others emotional expressions on their face. What they found is that when people are on mdma, their response to threatening faces or other threatening stimuli is reduced. And it's reduced in a very specific way, which is reductions in activity of the amygdala. The amygdala is a structure that some of you may be familiar with. It is known to be involved in the threat detection systems or networks of the brain. It is sometimes called the fear area of the brain. Although I want to caution people against assigning any one particular subjective experience to any one particular brain area. The amygdala is actually a complex, it's actually called the amygdaloid complex and has a lot of different sub areas and it's involved in a lot of things besides fear and threat detection. Nonetheless, when people are under the influence of MDMA and you show them a face that is grimacing or living, would otherwise be rated as quite threatening, they tend to rate it as less threatening. In addition, they tend to respond to happy faces or even slightly happy faces as more kind or more generous or happier than they would when they are not on mdma. Again, the faces that are being shown are not of people on mdma. That would be an interesting experiment, but that's not what they did here. What's happening here is people are being given MDMA and then they are rating in a subjective way the friendliness or the level of threat that they detect in these facial expressions. And of course they have extremes of friendly and threatening. But then they also grade them, right, they titrate them so that they also have mildly threatening and mildly happy faces, etc. So everything from a grin to a smirk to a giant smile, everything from a, from a sort of, you know, somebody looking a little bit askance at somebody to really, you know, wide eyed and looking angry like they're, you know, going to attack you and things of that sort. So what's discovered in the study is that MDMA has a bi directional effect on our perception of others emotions, making people more likely to rate something as positive if it's initially positive or even a little bit positive and less likely to rate a threatening face as more threatening. Now, one thing I have not mentioned thus far are the dosages of MDMA used in this and in other studies. Unfortunately, despite the studies that we're going to talk about, using a lot of different types of people, different ages, different sexes, so male and female located in different parts of the world, even some with ptsd, some not with ptsd, et cetera, there's been fairly tight dosage control of MDMA in these studies. It's not perfectly matched from study to study, but it's pretty darn close, which makes interpreting results across studies a lot easier for me and therefore for you. The typical dosages of MDMA used in these neuroimaging studies and in the clinical studies of PTSD that we're going to talk about later range anywhere from 0.75 mg per kg of body weight to 1.5 mg per kg of body weight. So for somebody like me, I weigh 220 pounds, that's 100 milligrams. 1.5 milligrams per kilogram of body weight would therefore be 150 milligrams in a single dose. Okay. A dosage of 1 milligram per kilogram of body weight would mean 100 milligrams for my 100 kilograms. Okay. Somebody lighter than 100 kilograms would obviously take less MDMA in one of these studies. But in general, the range of MDMA that's been explored is 0.75 to 1.5 milligrams per kilogram of body weight. The exception being in the clinical studies that we'll talk about a little bit later. There's a tendency to explore both an initial dose of 1.5 milligrams per kilogram of body weight. So again, for a 100 kilogram person, that would be 150 milligrams or so, and then a so called booster of half that amount about 90 minutes to two and a half hours into the session. So another 75 milligrams later. And I should point out that there is not always the inclusion of the so called booster and in some cases lower doses of MDMA, such as the 0.75 milligrams per kilogram dosages are used. Why am I getting so into the details? Details of dosages? Well, if we are going to talk about toxicity of mdma, we absolutely have to talk about dosages because like any drug, the toxicity of MDMA does scale with the dosage that's applied, not just the frequency of MDMA use. We hear a lot about that. You know, someone has taken MDMA one time or four times or 200 times. We hear about frequency of use, but but rarely do we hear about the specific dosages that are taken in any one particular session. So when we talk about the subjective effects or the brain networks that are activated when people take MDMA in general, we're talking about dosages somewhere between 0.75 mg per kg of body weight and 1.5 mg per kg of body weight. Although typically you're going to see studies both clinical and more research explorative, using anywhere from 1 to 1.5 milligrams of MDMA per kilogram of body weight. So that's important to highlight. I told you about the subjective effects of MDMA engaging the responses of people's faces, but I didn't tell you about the brain areas that are responsible, except for the reduction in amygdala activity. Now, one of the key features of PTSD seems to be that there is a heightened connectivity between the amygdala and a brain area called the insula. The insula is a brain area that's very important for something that's called interoception. Interoception is one's perception of our feelings, both pure sensations, but also our emotional states and our feelings of well being or lack of well being for everything from our skin inward. Okay, so that's interoception. You actually can interocept now, even though you're always interocepting a little bit, you can interocept now to a great degree. If you were to, for instance, close your eyes or simply focus on the contact points between your body and any surface that you happen to be contacting. So maybe the backs of your legs against a chair, or your feet against the floor, or the bottoms of your shoes or sandals, Your nervous system is constantly sensing those contact points, but normally they're not under your conscious awareness unless you direct your interoceptive capacity to them. Which is just fancy nerd speak for saying you normally don't notice what's going on from your skin inward unless you focus on it. That focus is interoception. It can be about the fullness of your gut. It can be about how happy or sad you are. It can be about how tired or alert you happen to feel. But that's interoception. And it is distinctly different from exteroception, which is your ability and tendency, tendency to focus on things beyond the Confines of your skin. So this could be visual attention, auditory attention. It could be paying attention to events like birds flying by, whether or not your Uber is showing up, these kinds of things. And we are always in a balance, A push pull of interoception and exteroception. The insula is a brain area that is absolutely critical for interoception, so much so that it has a map of the complete, complete body surface, including our internal organs. In other words, if you put somebody into an FMRI machine or you were to record from the insula with electrodes, as has been done in humans many times now during the course of neurosurgery for other purposes, what you would find is that if you stimulate neurons in one end of the insula, the person will say, oh, you know, I feel something going on in my gut and on my left side. And then as you were to march that stimulation over across the insula, you would find that they would now be paying attention to their legs, or just to one leg or to their whole body, or to the sensations in their face or their head. So there's a systematic map of interoception in the insula, and there are direct connections between the amygdala and the insula. And the amygdala, despite getting this reputation as just being a fear center or threat detection center, is actually part of a much larger set of networks that include inputs from the hippocampus, an area of the brain that's involved in memory formation and storage. And what is observed is that people who have PTSD tend to have greater or rather stronger connections between the amygdala and the insula than is normally observed in people who do not have ptsd. Okay, so there seems to be heightened input from the threat detection centers of the brain to this area of the brain, the insula, that is responsible for our sense of interoception, which provides a logical explanation for why people with PTSD often will feel the memory or sense the discomfort or just feel agitation or even other types of bodily sensations like back pain, or just. Perhaps just a sense within their body that's more generalized. It doesn't even have to be pain, doesn't even have to be negative, but that's associated with the negative memory of some traumatic event or series of events. Okay, so this is a really interesting brain network that I should mention exists in everybody, but that in people with ptsd, seems to have heightened connectivity. And those brain networks can be revealed by putting people with PTSD into functional imaging machines, getting them to recall a traumatic event or even looking at the resting state of color connectivity between the amygdala and the insula. So those experiments have been done and what's also been done is to give people 1.5 milligrams per kilogram of MDMA and to look at the connectivity between the amygdala and the insula and between the hippocampus, the amygdala and the insula. And so what's observed over time in people that have been given mdma, and this is a very important and, and have done therapy for PTSD both before, during and after the drug, there's a weakening of connections between the amygdala and the insula and that scales very directly with the relief of symptoms from ptsd. This is really exciting because it's one thing to see a brain network get activated or inactivated or you say, okay, in one person, a certain connection between threat centers and the intestine interceptive centers of the brain was, let's say, arbitrary units, let's say was level 8 out of 10 for that person. Right. These things are normal.