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

**Andrew Huberman** (0:00)
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 MOLLE.
MDMA stands for methylene-dioxy-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, methylene-dioxy methamphetamine, 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. And I want to be very clear that at this point in time, June, 2023, MDMA is still a schedule one drug. That is, it is highly illegal to possess or sell in the United States. And today we are going to talk about some of the path to legality that's underway. We are also going to talk about the history of MDMA and why it became illegal. And we are going to talk about the key difference between recreational use and therapeutic use and the important components of the studies exploring MDMA in the clinical setting for the treatment of PTSD. So during today's discussion, we will talk about what MDMA really is, how it works at the level of neurons, which brain circuits it activates and deactivates. And in doing so, you will come to understand why it is so exciting as a treatment for PTSD. We will also of course talk about the results of these clinical trials using MDMA for the treatment of PTSD. They are incredibly exciting. In fact, the field of psychiatry has never before seen the kind of success in treatment of PTSD with any other compound that they are seeing and achieving with the appropriate safe use of MDMA. And when I say appropriate, that means in conjunction with nine therapy sessions. So this is an area that really deserves some time for us to discuss because again, there is a distinct difference between the recreational and the therapeutic use of MDMA. We will also talk about the toxicity of MDMA. This is a very important issue because many of you have perhaps heard that MDMA quote unquote puts holes in your brain or kills serotonin neurons or kills dopamine neurons. And indeed MDMA because of its similarity to methamphetamine, which is highly neurotoxic, MDMA can be neurotoxic. However, there are ways to use MDMA therapeutically that avoid its toxicity. And yet there are still questions about its toxicity and its long-term effects, both after acute use, meaning just one to three times, as well as chronic use, meaning people who have taken it many, many times. We'll talk about the spacing between sessions of MDMA. We will talk about dosages. We will also talk about things that people do and that can be done to offset some of the potential toxicity of MDMA. So by the end of today's discussion, you will have a thorough understanding of what MDMA is, what it isn't, what is known about what it does, what is known about what it doesn't do, as well as some of the still outstanding questions about MDMA that remain to be resolved. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is however, part of my desire and effort to bring zero cost to consumer information about science and science related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is Helix Sleep. Helix Sleep makes mattresses and pillows that are of the absolute highest quality. I started sleeping on a Helix mattress over two years ago. And since starting to sleep on a Helix mattress, I've had the best sleep of my life. And that's because the mattress is tailored to my unique sleep needs. Everybody has unique sleep needs. 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Again, if you're interested, you can go to helixsleep.com/huberman, for up to $350 off and two free pillows. Today's episode is also brought to us by Roca. Roca makes eyeglasses and sunglasses that are the absolute highest quality. The company was founded by two all-American swimmers from Stanford and everything about Roca eyeglasses and sunglasses were designed with performance in mind. I've spent a lifetime working on the biology, the visual system, and I can tell you that your visual system has to contend with an enormous number of different challenges in order for you to be able to see clearly. Roca understands those challenges and has designed their eyeglasses and sunglasses accordingly so that you always see with perfect clarity. Their eyeglasses and sunglasses were initially designed for sports performance and as a consequence, they are very lightweight, which is great. They also won't slip off your face if you get sweaty. 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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.com/huberman to save 20% off. Again, that's hvmn.com/huberman to save 20%. Let's talk about MDMA. MDMA or ecstasy is a fascinating compound. And I say fascinating from the perspective of its chemical structure, which is highly unusual. I say fascinating because it has an incredible set of subjective effects in terms of how it makes people feel. And it has a fascinating history. So let's just briefly start with the history of MDMA. MDMA was synthesized by the drug company Merck in the early 1900s, but it actually was never applied to any particular clinical use. And it wasn't really explored much in any laboratories at all. And then it was later rediscovered by a guy named Alexander Schulgen, who was a bit of a renegade drug chemist who was designing different drugs for the purpose of understanding their subjective effects on humans. So there's a long history of Schulgen designing drugs. He was after all a chemist. And then taking those drugs himself. And then if he liked the effects of a particular drug or rather if he thought that it had potential clinical utility, he would give it to his wife. Then she would give him her notes about those drugs. And then they would share them with their friends. And it was a small group of friends who consisted of therapists and physicians. So this was a really underground kind of operation. It was technically not illegal when it started because MDMA wasn't illegal when it started. But over the several decades that Shulkin 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 PICAL that stands for P-I-K-H-A-L. PICAL 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. PICAL stands for phenolethylamines I have known and loved. Phenolethylamines is the category of drug for which MDMA belongs to. And it's a long book, but a very interesting one, both from the perspective of understanding the history of MDMA and what MDMA is and the effects that it produces. But it's also an interesting book because it will teach you a lot about the history of the pharmaceutical industry, the war on drugs in the United States, and the interaction between illegal drug exploration and drugs for clinical treatment of psychiatric challenges. So right now this is a very important issue because MDMA is currently granted breakthrough status, which means it's now something that scientists and clinicians can study if they have authorization to do that. It is, as I mentioned earlier, still a schedule on drugs, so it's illegal to possess unless you are one of these scientists who has been granted permission to study it in the clinical setting or the laboratory setting. And right now we are on the cusp of MDMA becoming legal, but again, it is not yet legal. And this is something I'm going to touch back on a few times during today's episode. Later, for instance, when we talk about the potential toxicity of MDMA, its ability potentially to kill neurons and the neurons, it has been hypothesized to kill are neurons of the serotonin and dopamine type. So this is something you would not want. Let's just recall that killing off of or death of dopamine neurons is the underlying basis for Parkinson's disease, which is a movement disorder where people have difficulty generating smooth movements and in very severe form, they can't move at all and they sort of become locked in to some extent. And it also has cognitive effects. So you don't want to lose dopamine neurons and loss of serotonergic neurons is known to impact mood negatively, mood regulation negatively, et cetera. The story of MDMA and its potential neurotoxicity comes slam right up against this issue of legality. And what we'll get into a little bit later is that there has been a sort of race in the scientific community consisting of two groups. One set of groups trying to establish the toxicity of MDMA so that it does not become legal again. And another group trying to establish the utility and the lack of toxicity in MDMA so that it does become legal again for the treatment of PTSD. So even though the story PECAL relates to events that took place largely in the 1970s, 80s and 90s, right now MDMA and its toxicity or lack of toxicity, its legality or lack of legality are really key issues. So as you're listening to this, I'm giving you a real time blow by blow of what led up to where we are now, but we will also want to think about how what's happening right now, including the description of these data on MDMA may or may not impact the potential legal status of MDMA. Okay, so what is MDMA? MDMA is 3,4-methylene-dioxymethamphetamine, 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 Vivants, which basically are either combinations of amphetamines or single types of amphetamines that have either a quick release or a long release. Now, MDMA, because it has this methamphetamine component, prevents the reuptake of dopamine, and in doing so creates net increases in dopamine. So for those of you that don't have a background in neurobiology, let me just briefly explain. I'll make this very simple. Neurons or nerve cells release chemicals at their sites of communication, which are called synapses. Synapses are little gaps between neurons. And what happens is the neurons spit out these little spherical balls, which we call vesicles or vesicles, depending on where in the world you live, they'll either be called vesicles or vesicles. And those little vesicles contain neurotransmitter or what's technically referred to as a neuromodulator. Dopamine is a neuromodulator. It can modulate the activity of other neurons. It can either increase or decrease the activity of other neurons. Now, at the end of the neuron, what we call the axonal bouton, okay, the axon is the wire component of the neuron that can reach to another site in the brain and then release the neurotransmitter or neuromodulator there. At those axonal 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 and neurotransmitter someplace else. So sort of a chain reaction, or else it will suppress its activity and the flow of communication from one neuron to the next will be stopped. Okay, so MDMA doesn't prevent the release of dopamine at the synapse. It does quite the opposite. It actually prevents the sucking up of the dopamine that's been released and that does not bind to the receptors. So basically what it does is it blocks these things called dopamine transporters. And the transporters are the things that suck back up the dopamine that's been released that has not bound to receptors. So because it blocks that sucking up process, there's more dopamine around in the synapse to hang out and then bind to receptors once some become available. Okay, the other thing that the methamphetamine component of MDMA does just like methamphetamine is that it actually gets into what we call the presynaptic neuron, the neuron that releases the dopamine and it interferes with the repackaging of dopamine into those vesicles. Now you might think, oh, it interferes with the repackaging of dopamine into vesicles and therefore less will be released. But actually what happens is as a consequence of that, a bunch of dopamine builds up in the presynaptic neuron so that when an electrical impulse comes down that neuron and dopamine is released, a huge amount of dopamine is released. And this is one of the characteristic properties of methamphetamine and of MDMA, which is that it leads to enormous increases in the amount of dopamine released and the amount of dopamine that hangs around in the synapse. And therefore it increases what we call dopaminergic tone or dopaminergic drive. That's just a bunch of different ways to describe increases in dopamine. Okay, so that's the main way that MDMA and by extension, methamphetamine increase dopamine. However, MDMA is not just methamphetamine, it's methylene-dioxy methamphetamine, and it has another incredible property, which is that it doesn't just lead to huge increases in dopamine, it also leads to huge increases in serotonin. And that's because there are other neurons that release serotonin and they have serotonin transporters, which are sometimes called CERTs, S-E-R-T-S, serotonin transporters, and they work very much in the same way that dopamine transporters do, right? They basically control the sucking back up of serotonin that's been released into the synapse and that has not bound to serotonin receptors on the other neurons yet. And in doing so, allow more serotonin to hang out and have its effects as those receptors become available for serotonin to bind to them. The other thing MDMA does is it also gets into the presynaptic neuron to impact the packaging of serotonin into something called the vesicle monomine transporter for serotonin. And in doing so, it leads to a big build up 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 adderol, Vyvanse, et cetera, that cause increases in dopamine by blocking reuptake and increasing release of dopamine. MDMA does that, but it also does the same thing for serotonin. And here's a really key point. The increases in serotonin that MDMA creates are at least three times and maybe as much as eight times greater than the amount of dopamine release that MDMA causes. But when you put those two things together, what you basically have is a drug that causes huge increases in dopamine and even bigger increases in serotonin. And remember earlier when I said that MDMA is a purely synthetic compound, as far as we know, it does not exist in any plants or fungus or anything else in nature? Well, this is a very unusual circumstance of having big increases in dopamine and big increases in serotonin caused by the same compound. And that combination of big increases in dopamine and big increases in serotonin are what lead to these highly unusual and yet what seem to be potentially clinically very beneficial effects of having people feel a lot of mood elevation and a lot of stimulation from the stimulant properties of the methamphetamine component. So that's the dopamine effect. The dopaminergic tone goes way up. So it's a stimulant. People feel really alert. They feel like talking a lot. They feel very excited. They feel a lot of positive motivation. These are classic effects of drugs that promote the release of dopamine, including amphetamine, cocaine, et cetera. But ordinarily that's not such a good thing because what happens is there's then a crash in the dopamine levels and then people feel depressed. They feel lethargic. They don't feel good at all. MDMA seems to cause these increases in dopamine and all the accompanying effects I just described. But by also causing big increases in serotonin, it activates neural networks that are associated with feeling more socially connected. In fact, we'll talk about data in a little bit where people have had their brains imaged while under the influence of MDMA. And it's very clear that people who have taken MDMA look at faces that ordinarily they would rate as fearful and rate them as less fearful. They see faces that are smiling and they rate those smiling happy faces as more positive than they would off the drug. The big increases in serotonin create what we call a 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 described the biology of MDMA makes some sense. If you didn't get anything out of the description I provided, except the understanding that MDMA is unusual in that it causes big increases in dopamine and even bigger increases in serotonin, then you have more in your knowledge base now about MDMA than you need in order to understand the rest of our discussion. Before we go any further, I do want to separate MDMA out from some other compounds, which are referred to as psychedelics. And I recently did a podcast episode all about psilocybin and its therapeutic exploration and its chemical basis, et cetera. You can find that like all episodes at hubermanlab.com. I also did an episode with expert guest, Dr. Robin Carthart-Harris, who's at University of California, San Francisco, who's pioneering a lot of the studies on the clinical application of psilocybin. Psilocybin and LSD are mainly going to increase serotonin activation in the brain. In fact, they very closely resemble serotonin itself and they activate what's called the 5-HT2A or serotonin. 5-HT just stands for serotonin. The 5-HT2A receptor to create very mystical type experiences. They are considered classic psychedelics and are very introspective.