The Science of MDMA & Its Therapeutic Uses: Benefits & Risks | Huberman Lab Podcast
Date: 2023-06-12 | Duration: 02:17:34
Transcript
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 Mali MDMA stands for methylene dioxy methamphetamine that’s right you heard the word methamphetamine in there and MDMA has properties similar to
0:30 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
1:00 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
1:30 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 a achieving incredible early results in clinical trials for its
2:00 use as an empathogen for the treatment of PTSD in clinical therapeutic settings I want to be very clear that at this point in time June 2023 MDMA is still a schedule one drug that is it is highly illegal to possess or sell in the United States and today we are going to talk about some of the path to legality that’s underway we are also going to talk about the history of MDMA and why it became illegal and we are going to talk about the key difference between
2:30 recreational use and therapeutic use and the important components of the studies exploring MDMA in the clinical setting for the treatment of PTSD so during today’s discussion we will talk about what MDMA really is how it works at the level of neurons which brain circuits it activates and deactivates and in doing so you will come to understand why it is so exciting as a treatment for PTSD will you will also of course talk about the results of of these clinical trials using MDMA for the treatment of PTSD
3:00 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
3:30 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 avoid its toxicity and yet there are still questions about its toxicity and its
4:00 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
4:30 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 the absolute highest quality I
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7:00 and enter the code huberman to save 20 off your order again that’s Roca roka.com and enter the code huberman at checkout 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
7:30 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 which gives me a lot of energy during workouts or during bouts of cognitive
8:00 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
8:30 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 shulgin who was a bit of a renegade drug chemist who was designing different drugs for
9:00 the purpose of understanding their subjective effects on humans so there’s a long history of Shogun 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
9:30 consisted of therapists and Physicians so this was a really underground kind of operation it was technically not illegal when it started because MDMA wasn’t illegal when it started but over the several decades that Shogun and his wife and this group were doing this kind of exploration MDMA did become illegal and he fell under 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
10:00 MDMA is a synthetic compound as far as we know it does not exist anywhere in nature so unlike similar compounds such as mescaline because MDMA and masculine are very similar in their chemical properties and to some extent their subjective properties unlike mescaline which can be found in the plant kingdom or LSD which comes from 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
10:30 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
11:00 interested in the story of Alexander Shogun and the drugs he synthesized and the group that he built up to take these drugs and try them and actually had several members of this group using these drugs in therapy with their patients for a long period of time both before and after MDMA became illegal there’s a wonderful book called pikal that stands for p-i-k-h-a-l p call is the title of the book which Shogun wrote which describes
11:30 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 pcall 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
12:00 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
12:30 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
13:00 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
13:30 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
14:00 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
14:30 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 dioxy 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
15:00 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
15:30 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
16:00 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 can modulate the activity of other neurons it can either increase or decrease the activity of other neurons now at the end of the neuron that what we call the axonal Bouton okay axon is the wire component of the neuron that can reach to another side in the brain and then release the neurotransmitter or neuromodulator there
16:30 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
17:00 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
17:30 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
18:00 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 end of MDMA which is that it leads to enormous increases in
18:30 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 dioxide methamphetamine and it has another incredible property which is that it doesn’t just lead to
19:00 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’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
19:30 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
20:00 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
20:30 than the amount of dopamine released 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
21:00 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 and so that’s the dopamine effect the dopaminergic tone goes way up
21:30 so it’s a stimulant people feel really alert they feel like talking a lot they feel very excited they feel a lot of positive motivation these are classic effects of drugs that promote the release of dopamine including amphetamine cocaine Etc but ordinarily that’s not such a good thing because what happens is there’s then a crash in the dopamine levels and then people feel depressed they feel lethargic they they don’t feel good at all MDMA seems to cause these increases in dopamine and
22:00 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
22:30 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
23:00 experiences from the past which so 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 serotonin then you have more in your knowledge base now about MDMA than you need in order to understand the rest of our discussion
23:30 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 it’s chemical basis Etc you can find that like all episodes at hubermanlab.com I also did an episode with expert guest Dr Robin Carhart Harris who’s at University of California San Francisco who’s pioneering a lot of the studies on the clinical application of psilocybin
24:00 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 5hd just stands for serotonin the 5ht 2A receptor to create very mystical type experiences they are considered classic psychedelics and are very introspective
24:30 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 methodaspartate 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
25:00 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
25:30 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 enactogen it’s creating more affiliation it’s affiliative okay so it’s a very distinct compound and I think this is important to understand because when we hear the word psychedelic a lot of people tend to lump together LSD psilocybin and MDMA if
26:00 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 actogen 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
26:30 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
27:00 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
27:30 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 you will also learn later when
28:00 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
28:30 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 then the big increases in serotonin the 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
29:00 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
29:30 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
30:00 just the willingness to engage socially and to confide in a therapist or another person but the intense desire to do so and when I say intense desire that takes us back to the dopamine system remember dopamine even though when increased in the brain can increase our mood it is largely responsible for increasing our sense of motivation and desire for something and to do something so the increase in dopamine that’s created by MDMA seems to make people
30:30 what I call forward Center of mass you know they want to do something they’re very motivated to do something and the increases in serotonin acting on the serotonin 1B receptor seems to be what creates this desire to bond or create trust or to have a discussion of real things both things that are positive but also to explore things that are difficult and this I realize is going to be a little bit of a mind Bend for people to to understand but one of the key things that
31:00 quality MDMA therapy consists of is not just having a very good rapport and communication with a therapist that’s guiding the PTSD treatment but also Rapport and a willingness to engage in conversations with oneself yeah 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
31:30 who’s a world expert in trauma Paul Conte explained as trauma is an event that fundamentally changes the way that our brain works for the worse okay so not every bad event of our past is trauma but events that change the way that we think our emotional tone or our behavior in ways going forward that are not adaptive for us They don’t serve us well either because they are highly distracting or because um they create anxiety or because they
32:00 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
32:30 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 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
33:00 then we will explore the toxicity issue and then we will explore the clinical studies of which I can promise you are extremely exciting but until we understand the neural circuit phenomena and of course until we consider the neurotoxicity issues I don’t think those clinical findings can be appreciated in their full value but now I’d like to talk about what MDMA really does in the brain both in the short term while someone is under the influence of the drug and in the long term what sorts of neuroplastic or rewiring changes does
33:30 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 ag-1 is a vitamin mineral probiotic drink that covers all of your foundational nutritional needs I’ve been taking athletic green 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 are usually twice a day is that it gets to be in the
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34:30 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 Etc 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 supply of vitamin D3 K2 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
35:00 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 arresting 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
35:30 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
36:00 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
36:30 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
37:00 the general population hey who out there is taking MDMA how many times have you taken it and come on into the laboratory and we will image your brain and compare people who have for instance taken MDMA zero times to people who have taken MDMA one time or five times or believe it or not there’s some studies sitting right here in front of me on my desk of people who have taken MDMA more than 200 times and ask the same sorts of questions
37:30 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
38:00 of Studies have been done in humans and there are also a large number of studies in animal models exploring how the social activity of laboratory mice changes when they are under the effects of MDMA or even studies believe it or not on the effects of MDMA encephalopods cephalopods include octopuses as well as cuttlefish and other Aquatic animals that are known for having complex Behavior some people believe that the cephalopods are extremely intelligent
38:30 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 Google Dolan’s laboratory at Johns Hopkins school of medicine showing that if you give octopuses MDMA they like to spend more time with other octopuses than they do if they are not on MDMA and that might sound like kind of a um kind of a
39:00 playful experiment just done uh in order to entertain oneself and the octopuses perhaps but actually in that study they identified the serotonin transporter in octopuses and show that it has a lot of homology similarity to human serotonin transporter receptors and so what that really speaks to is the fact that the pro-social effects of MDMA that are observed in mice and in humans and in octopuses all have a common basis which is the activation of more serotonin release in particular brain networks
39:30 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 lab in the
40:00 department of Psychiatry and behavioral neuroscience at the University of Chicago in 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
40:30 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
41:00 particular subjective experience to any one particular brain area the amygdala is actually a complex it’s actually called the amygdaloid complex and has a lot of different sub areas and it’s involved in a lot of things besides fear and threat detection nonetheless when people are under the influence of MDMA and you show them a face that is grimacing or would otherwise be rated as quite threatening they tend to rate it as less threatening in addition they tend to respond to happy faces or even slightly happy faces as more
41:30 kind or more generous or happier than they would when they are not on MDMA again the faces that are being shown are not of people on MDMA that would be an interesting experiment but that’s not what they did here what’s Happening Here is people are being given MDMA and then they are raiding in a subjective way the 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
42:00 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 a you know somebody looking a little bit of scans at somebody to really you know wide-eyed and looking angry like they’re you know gonna 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
42:30 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 Etc there’s been fairly tight
43:00 dosage control of MDMA in these studies it’s not perfectly matched from study to study but it’s pretty darn close which makes interpreting results across studies a lot easier for me and therefore for you the typical dosages of MDMA used in these neuroimaging studies and in the clinical studies of PTSD that we’re going to talk about later range anywhere from 0.75 milligrams per kilogram of body weight to 1.5
43:30 milligrams per kilogram of body weight so for somebody like me I weigh 220 pounds that’s 100 milligrams 1.5 milligrams per kilogram of body weight would therefore be 150 milligrams in a single dose okay a dosage of one milligram per kilogram of body weight would mean 100 milligrams for my 100 kilograms okay somebody lighter than 100 kilograms would obviously take less MDMA in one of these
44:00 studies but in general the range of MDMA that’s been explored is 0.75 to 1.5 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 hundred 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
44:30 into the session so another 75 milligrams later and I should point out that there is not always the inclusion of the so-called booster and in some cases lower doses of MDMA such as the 0.75 milligrams per kilogram dosages are used why am I getting so into the details of dosages well if we are going to talk about toxicity of MDMA we absolutely have to talk about dosages because like any drug the toxicity of MDMA does
45:00 scale with the dosage that’s applied not just the frequency of MDMA use we hear a lot about that you know someone has taken MDMA one time or four times or 200 times we hear about frequency of use but rarely do we hear about the specific dosages that are taken in any one particular session so when we talk about the subjective effects or the brain networks that are activated when people take MDMA in general we’re talking about dosages somewhere between 0.75
45:30 and 1.5 milligrams per kilogram of body weight although typically you’re going to see studies both clinical and more research explorative using anywhere from 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
46:00 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
46:30 intercept now even though you’re always intercepting a little bit you can intercept now to a great degree if you were to for instance close your eyes or simply focus on the contact points between your body and any surface that you happen to be contacting so maybe the backs of your legs against a chair or your feet against the floor or the bottoms of your shoes or sandals your nervous system is constantly sensing those contact points but normally they’re not under your conscious awareness unless you direct Your
47:00 interceptive 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 interception it can be about the fullness of your gut it can be about how happy or sad you are it can be about how tired or alert you happen to feel but that’s interception and it is distinctly different from exteriorception which is your ability and tendency to focus on things beyond the confines of your skin so this could
47:30 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 extra reception the insula is a brain area that is absolutely critical for interception so much so that it has a map of the complete body surface including our internal organs in other words if you put somebody into an fmri machine or you were to record
48:00 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 I feel something going on in my gut and on my left side and then as you were to March that stimulation across the insula you would find that they would now be paying attention to their legs or just to one leg or to their whole body or to the sensations in their face or their head so there’s a systematic map of interoception in the
48:30 insula and there are direct connections between the amygdala and the insula and the amygdala despite getting this reputation as just being a fear Center or a threat detection Center is actually part of a much larger set of networks that include inputs from the hippocampus an area of the brain that’s involved in memory formation and Storage and what is observed is that people who have PTSD tend to have greater or rather stronger connections between the
49:00 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 interception 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
49:30 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
50:00 getting them to recall a traumatic event or even looking at the resting state of connectivity between the amygdala and the insula so those experiments have been done and what’s also been done is to give people 1.5 milligrams per kilogram of MDMA and to look at the 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
50:30 before during and after the drug there’s a weakening of connections between the amygdala and the insula and that scales very directly with the relief of symptoms from PTSD so this is really exciting because it’s one thing to see a brain Network get activated or inactivated or you say okay in one person a certain connection between threat centers and the interceptive centers of the brain was let’s say arbitrary units let’s say it was level eight out of ten for that
51:00 person right these things are normalized for a particular person and then after taking MDMA and doing PTSD therapy it was five out of ten or four out of ten that’s a good experiment but what’s far more powerful is to observe that in that patient or that person and then to see a change that’s perhaps less dramatic so a shift from 8 out of 10 to 7 out of ten in another person and to see less shift
51:30 in brain connectivity in the same network and then perhaps in the person that went from full-blown PT PSD to full remission of PTSD something that believe it or not has been observed in single sessions with MDMA if that person demonstrates an even greater reduction in the connections between the amygdala and the incilla well then that gives even more confidence that this connection between the amygdala and the insula is actually perhaps causally related to the reduction in symptoms of PTSD or even if
52:00 it’s just correlated with reduction in symptoms of PTSD the fact that the degree of reduction of connection of this circuit scales with the reduction in clinically relevant symptoms that’s a very powerful finding because it moves things away from Pure correlation although this brain area is active or less active over time and you know this person has more or fewer symptoms of PTSD to something that starts to look like a mechanistic and logical framework for understanding PTSD as well as the effects of MDMA and
52:30 for understanding how changes in the brain underlie relief from PTSD okay so again even if you just could grasp the idea that you have a brain area the amygdala that’s involved in threat detection and it provides inputs to another brain area called the insula which is involved in this thing called interoception and that reductions in those connections between the amygdala and the insula scale with or correlate with reductions in PTSD symptoms as a consequence of people taking MDMA so if
53:00 you have that under your mental belt I promise you you understand far more about how MDMA impacts the brain in the short and long term the 99.9 percent of people out there however it’s also important you understand a few other things that MDMA does to the brain as well as what it doesn’t do to the brain first of all classic psychedelics like psilocybin and LSD as I mentioned earlier are known to create more lateral connectivity between different areas of the so-called neocortex and these are long-lasting changes that are thought to underlie
53:30 both some of the relief from major depression but also some of the enhanced creativity and some of the other things that have been observed with psilocybin treatment and again if you’re interested in psilocybin treatments and psilocybin itself please check out the episode that I did on psilocybin and the guest episode with Dr Robin Carhartt Harris those episodes like all other episodes of The huberman Lab podcast can be found at hubermanlab.com it’s a fully searchable site so you can put keywords into the search function it will take you to specific time stamps every episode is time stamps you can navigate
54:00 to topics of particular interest to you feel free to go there and listen to those episodes about psilocybin MDMA by contrast does not seem to produce long lasting increases in lateral connectivity between those same brain networks probably because it impacts a different serotonin receptors it does however seem to change resting state functional connectivity Within These limbic structures like the amygdala and related structures that are associated with threat detection now this is interesting and it actually was
54:30 highlighted very nicely in a study I’ll provide a link to in our show note caption which actually has Dr Robin Carter Harris as the first author so not only has he done incredible work on psilocybin and LSD and DMT in Ayahuasca in his laboratory but also on MDMA and the particular study I have in mind here showed that people who take MDMA at more or less the dosage that we talked about earlier report Mark increases in positive mood as well as decreased blood flow to the
55:00 amygdala and hippocampus so again these threat detection centers of the brain and brain areas associated with memory and those changes are seen both while under the influence of MDMA and afterwards when the brain is simply at rest so it really does appear that MDMA creates neuroplasticity that changes the overall level of activation of these threat detection networks and their connections to memory systems in a way that’s pervasive over time and that doesn’t require any particular probe
55:30 with a negative stimulus I’ll translate to English what that means is that during the MDMA session people report feeling less threatened more pro-social towards others more empathic towards others and themselves 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
56:00 MDMA all of which point in the direction of lowered levels of threat detection heightened levels of positivity pro-social components of the brain more active threat detection centers of the brain less active now earlier we talked about MDMA as a drug that potently increases dopamine and even more potently increases serotonin largely acting through this serotonin 1B receptor now without getting into too many more details before moving on to
56:30 issues of toxicity around MDMA I do want to touch on what I think is perhaps the finest of the animal model studies of MDMA that explored which brain networks and which chemical that is serotonin or dopamine is responsible for say the motivational components of MDMA versus the pro-social effects of MDMA and then it also raises a really important point which I haven’t mentioned yet in this episode which is the role of oxytocin
57:00 something that many of you have perhaps heard of the paper that I’m going to describe is from the laboratory of Dr Robert malenka he’s a colleague of mine at Stanford University School of Medicine Psychiatry and Behavioral Sciences he is both a Pioneer and luminary in the field of neuroplasticity of how the brain wires and forms memories and can change itself over time in response to experience as well as the study of drugs of abuse as well as the study of drugs like MDMA and now additional compounds
57:30 that can provide therapeutic support in certain conditions the study which I will provide a link to in the show note caption is entitled distinct neural mechanisms for the pro-social and rewarding properties of MDMA and I’m just going to summarize the major results of this study it’s a study that was done on mice and I realized that a lot of people will hear that and think ah what relevance does that have to humans but when thinking about the effects of dopamine and serotonin in the types of circuits that we’ve been talking about thus far these circuits that are subcortical as
58:00 we refer to them so these are limbic circuits these are hypothalamic circuits these are what are called mesolymbic circuits these are all names for circuits that are highly conserved between mice and humans and so results in mice really do translate quite well to results in humans at least insofar as the effects of MDMA and which neurochemicals are involved is concerned so what they found in the study using a huge array of beautiful techniques such as inactivation of specific brain areas activation of specific brain areas drug
58:30 antagonists to prevent oxytocin function or drug antagonist to prevent specific receptors involved in the serotonin pathway lots and lots of tools in their toolkit what they found is that MDMA causing the release of dopamine is what really establishes the rewarding effects of an experience this isn’t really a surprise we’ve known that MDMA just like cocaine or Methamphetamine or Adderall for that matter or Vyvanse for that matter
59:00 creates big increases in dopamine that tend to couple an experience with a sense of reward and lead to changes in the neural circuitry that make the animal or human more likely to seek out that same experience again okay these are the rewarding or sometimes called reinforcing properties of dopamine that take place in the so-called mesolimbic reward pathway if you want to learn about mesolimic reward Pathways and dopamine and how they control everything from your level of motivation to your tendency to procrastinate or overcome
59:30 procrastination I’ve done two episodes about dopamine you can simply go to hubermanlab.com put dopamine into the search function and you’ll find at least two episodes on that topic and you’ll also find a number of different tools related to how one can better regulate their own patterns of dopamine release for sake of motivation Etc so MDMA is increasing dopamine to increase reward to a particular experience what’s the experience well this paper beautifully parses the fact that it is serotonin release
60:00 within a structure called the nucleus accumbens which is part of the reward pathway which is rewarding the experience of social interaction now they do this by putting mice in arenas where they have the option of either spending time with other mice or not spending time with other mice and blocking the activation of certain brain areas and again using drug antagonists Etc and what they find is that it really is the activation of the serotonin 1B receptor in the nucleus of Commons by MDMA that leads to this pro-social effect of MDMA
60:30 so that’s really nice to know because there’s always been this conundrum of okay psilocybin and LSD are basically like serotonin they activate the serotonin 2A receptor MDMA has this huge serotonergic component tons of Serotonin released when one takes MDMA but very different effects in the short and long term very different subjective effects very different patterns of change activity in the brain in the short and long term well that’s because MDMA is activating
61:00 the serotonin-1b receptor not the serotonin 2A receptor and it’s doing so in a completely different set of brain networks as is LSD and psilocybin so what happens when an animal or a person takes MDMA is that social connection is strongly rewarded and reinforced making social connection more likely after the drug wears off now that’s one component of social connection but in addition people who take MDMA in the clinical therapeutic setting for the treatment of PTSD often report feeling more empathy
61:30 and compassion for themselves during the session but also for long periods of time maybe even indefinitely after the so it really seems that the addition of this huge release of Serotonin by MDMA on top of the release of dopamine sets in motion two parallel circuits one for rewarding something anything that’s the dopamine component and then fortunately because the increase in serotonin caused by MDMA
62:00 increases empathy and sociability for and with others but also for oneself the motivation that’s reinforced that’s wired into the brain seems to be a motivation to perceive others as more kind but also to be kinder to oneself now I realize that for some of you who are listening to this you’re probably saying well of course right you know serotonin is pro-social and dopamine is motivation so you put the two together and people become more motivated to be
62:30 social and kinder to themselves ah but it didn’t necessarily have to be that way right it is very hard to go from a statement like drug a produces effects b c and d to neurochemicals b c and d cause motivation and sociability and therefore when you take that drug you’re going to get all of that stuff in fact we have to go back to our understanding the MDMA despite causing a big increase in serotonin also causes huge increases
63:00 in dopamine and it does so with this molecule that is methamphetamine now methamphetamine is not known to be a pro-social drug in fact a study I just referred to as well as some human Studies have explored how the application of methamphetamine so not MDMA but pure methamphetamine impacts social interactions and what it does to social interactions it’s very profound it dramatically reduces one’s tendency to engage in social interaction so this
63:30 really speaks to the poly pharmacology as it’s called of MDMA the fact that serotonin and dopamine are released together has distinctly different effects than if just dopamine or just serotonin is increased so much so that it’s worth taking a step back and talking about another class of drugs which dramatically increases serotonin which are the ssris The Selective serotonin reuptake Inhibitors ssris such as fluoxetine Prozac as well as Zoloft
64:00 and of course there are many other accessories out there citalopram Etc they block the reuptake of Serotonin and thereby lead to net increases in the amount of Serotonin and yet those drugs are not known to create even close to the same sorts of effects as MDMA in fact there have been human and animal studies showing that if you give somebody an SSRI prior to them taking MDMA you actually block the pro-social
64:30 and empathogenic effects of MDMA now you might say why in the world would that be aren’t these drugs just increasing serotonin and the increase in serotonin is pro-social ETC ah well that speaks to the complexity of all this poly pharmacology and the fact that it’s really the activation of Serotonin at particular receptors in this case the serotonin 1B receptor in particular brain areas in this case the nucleus accumbens a brain area associated with
65:00 motivation and reward that largely explains the effects of MDMA in making people and animals and octopuses included for that matter more pro-social and more empathic towards themselves it’s not just an issue of raising the levels of one neurochemical it’s really about raising levels of a particular neurochemical acting in particular receptors in particular brain areas and in the case of MDMA the fact that
65:30 there’s also dopamine increased in those very same brain areas right I don’t think I mentioned this before but the nucleus accumbens is part of that mesolimbic reward pathway that is essentially establishing a reward for whatever is happening at the moment so the way to conceptualize MDMA and its effects on the brain both subjectively and mechanistically is that it’s an empathogen for which empathy and social connection is very strongly reinforced while under the influence of the drug and in a way so intense and Powerful
66:00 that those neural networks get stronger and persist in being more active for long periods of time after the drug has worn off I’d like to just take a brief break and thank one of our sponsors which is element element is an electrolyte drink that has everything you need and nothing you don’t that means plenty of salt sodium magnesium and potassium the so-called electrolytes and no sugar now salt magnesium and potassium are critical to the function of all the cells in your body in particular to the function of your nerve
66:30 cells also called neurons and we now know that even slight reductions in electrolyte concentrations or dehydration of the body can lead to deficits and cognitive and physical performance element contains a science-backed electrolyte ratio of 1000 milligrams that’s one gram of sodium 200 milligrams of potassium and 60 milligrams of magnesium I typically drink element first thing in the morning when I wake up in order to hydrate my body and make sure I have enough electrolytes and while I do any kind of physical training and after physical
67:00 training as well especially if I’ve been sweating a lot and certainly I drink element in my water when I’m in the sauna and after going in the sauna because that causes quite a lot of sweat setting if you’d like to try element you can go to drink element that’s lmnt.com huberman to claim a free element sample pack with your purchase again that’s drink element lmnt.com huberman now one of the things that’s been explored in both the animal literature and the human literature is that MDMA doesn’t just increase dopamine and doesn’t just
67:30 increase serotonin but it also profoundly increases levels of oxytocin release in the brain now oxytocin is considered what’s called a neuro hormone because it acts as both a neurotransmitter or I guess if we were going to be really specific we’d say a neuromodulator because it tends to modulate the activity of a bunch of other circuits and a hormone how can we say it’s a hormone or a modulator or transmitter well hormonal effects tend to be effects that act not just locally but on many sites within the brain and
68:00 body as well and oxytocin is known to do that as well as to work locally so that’s why we call a neuro hormone it activates neurons and is associated with neural networks related to pair bonding both between parent and child both mother and child and father and child or caretaker and child not just biological parent as well as bonding between friends bonding between lovers and it’s thought to actually be involved in the process that is the painful process of breaking
68:30 of bonds when people are no longer available to us as caretakers or as partners either by way of breakup death departure Etc in fact there are even data suggesting that humans can have strong oxytocin responses to their pets in particular dogs and their dogs can have strong oxytocin patterns of release in response to their owners I think for any dog lovers or dog owners certainly includes me I’m raising my hand that comes as no surprise anyone that’s
69:00 ever had to put down a dog or has lost a dog and hear no disrespect to the cat owners but I’m just referring to the studies that have been done on humans and dogs you can certainly relate to the incredible pain of that loss oxytocin is thought to be involved in bonding between people and other creatures as well as the breaking of those bonds MDMA is known to powerfully increase oxytocin release in fact there’s a really nice study on this done in humans
69:30 this is a study I’ll provide a link to in the show note captions entitled plasma oxytocin concentrations following MDMA or intranasal oxytocin in humans nowadays oxytocin is available by nasal inhaler to be honest I don’t know the legality around it I don’t know if it’s a gray Market or but what I’m about to tell you will basically discourage you from wanting to take it because what they found in the study was people given either 0.75 or 1.5
70:00 of MDMA experienced increases in oxytocin however it was only the group that took 1.5 milligrams per kilogram of body weight of MDMA that experienced the really big significant changes in oxytocin and when I say really big really highly statistically significant what they observed is that in the placebo group because of course they include a placebo group the amount of circulating oxytocin was 18.6 picograms per milliliter which
70:30 to you probably means nothing and to me also sort of means nothing because those units of oxytocin can’t be directly related to any kind of direct experience of feeling bonded or not bonded that’s just a number but nonetheless it provides a baseline to compare to the average levels of oxytocin in the bloodstream of people that were given 1.5 milligrams per kilogram of MDMA which is 83.7 picograms per milliliter that equates to nearly a five-fold increase in the amount of circulating
71:00 oxytocin when people are under the influence of MDMA now this study had a bunch of different conditions not just MDMA of different doses not just placebo they also had people take oxytocin by nasal spray which we know can change levels of circulating oxytocin and indeed when measured in the study it did change levels of circulating oxytocin and the end point in the study was to have people give subjective ratings of their feelings of
71:30 connectedness to one another as well as rate and here I’m just drawing directly from the paper of how much they like the feeling how much they felt high they measure their heart rate their systolic pressure their diastolic blood pressure Etc and they looked at how social people felt they looked at how insightful people felt and the key takeaway 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 produced by taking
72:00 MDMA are the source of the pro-social effects of MDMA and that’s also what was found in the animal studies of MDMA where in those studies mice were given MDMA at comparable doses the doses were a little bit higher than used in the human studies but at comparable doses big increases in oxytocin were observed increases in sociability of those mice were observed just as they
72:30 are in humans that take MDMA but in those mice they were also given a drug to block the oxytocin receptor and lo and behold no changes in sociability were observed in humans that take oxytocin by nasal spray you can see big increases in oxytocin that’s not surprising gets across the blood-brain barrier oxytocin goes up and levels of sociability do not increase so what this points to is a situation where MDMA is increasing dopamine to
73:00 increase motivation and to reward something what gets rewarded well what gets rewarded is the serotonin activation of particular brain networks associated with sociability and the dramatic increases in oxytocin that are very very real when people take MDMA do not appear to underlie any of the known short or long-term subjective effects of MDMA now a conclusion like that needs to have a caveat and the caveat is that as
73:30 far as we know the big increases in oxytocin that are produced by MDMA aren’t doing anything for the sorts of effects that we’ve been talking about here sociability empathy Etc but there could be other effects of oxytocin that we’re just not aware of that said the data from both animal models and in humans really point to the fact that the increases in oxytocin that are produced by MDMA are not directly related to any of the short and long-term effects of MDMA that we are most familiar with namely motivation sociability increase
74:00 empathy or the long-standing changes in neural circuitry that underlie for instance reduce threat detection or reduce connectivity between threats detection centers of the brain and in terreception so is the big increase in oxytocin produced by MDMA completely irrelevant in the context of this discussion we don’t know it appears that it’s not very relevant is oxytocin a meaningless molecule right after all they gave these people nasal infusions
74:30 of oxytocin oxytocin and went way up they didn’t observe anything very interesting or significant in the context of sociability but we do know that oxytocin can play a powerful role in pair bonding and in human human animal bonding of various kinds from other experiments that have been done so I don’t want to diminish the incredible power that oxytocin has in our brains and bodies but it doesn’t appear that the MDMA induced increases in oxytocin which are enormous have much to do with
75:00 anything related to the value of MDMA as a treatment for PTSD or for its subjective effects on empathy sociability or any of those other factors either now perhaps the one caveat to that is that hair Harriet Dewitt’s laboratory which I referred to earlier has looked at how variations in oxytocin receptor genes vary between people so it turns out that some people have an allele a basically a version of the oxytocin receptor that is different from other people that makes oxytocin
75:30 work differently and actually less effectively in activating certain brain networks and it does appear that when those people take MDMA they actually it experience less of a pro-social effect of the drug now that spits in the face of everything I just said about oxytocin not being involved in the effects of MDMA on pro-sociability and empathy I think the bulk of the data really points to the fact that it’s the serotonin increases combined with the dopamine increases caused by MDMA that
76:00 lead to most of the understood effects and that oxytocin if it’s playing a role is going to play a more minor role let’s talk about the safety and potential neurotoxicity of MDMA and here I really want to highlight that our discussion today is couched in a discussion about the application of pure MDMA to animals or humans in the context of laboratory or clinical studies this is really important to point out because I would
76:30 be remiss if I didn’t note that there is a lot of recreational use of MDMA in fact it was the recreational use of MDMA in the 1980s but really that took off even exploded in the 1990s with so-called Rave culture that created the massive attention on illegality of MDMA and put the drug enforcement agencies onto MDMA as a drug that they wanted to and indeed do restrict in fact just
77:00 today in anticipation of this episode I put MDMA into the search function on Google and clicked news and there were at least two reports of major MDMA seizures and bus so again I want to highlight the fact that MDMA is still illegal to possess or sell and certainly to traffic I also want to highlight the fact that nowadays all recreational drugs but certainly MDMA included are often in fact very often contaminated with fentanyl and while
77:30 fentanyl has certain clinical uses fentanyl is highly deadly the current estimates are as much as 60 percent maybe even 80 percent of drugs that are sold on the gray Market are being repackaged or reformulated with fentanyl and there have been a lot of fentanyl related deaths both in kids and adults so the sourcing of MDMA is extremely important and the safety issues simply cannot be overlooked and I say that not to protect me I say that to protect you right the last thing
78:00 any of us want is for someone to take a compound thinking it’s one compound and it contains another compound and I’m getting hurt or even dying and that is happening a lot a lot and it is certainly happening a lot for people that think that they’re buying MDMA the use of MDMA in the laboratory or in the clinical setting with pure MDMA has also been explored for the potential neurotoxicity of MDMA so how would methamphetamine and MDMA be neurotoxic well that’s because they
78:30 increase dopamine in the case of methamphetamine and dopamine and serotonin in the case of MDMA and they do so to a very high degree the big increases in dopamine and serotonin but in particular the big increases in dopamine tend to promote electrical activity of other neurons remember these are after all neuromodulators they modulate up or down the activity of other neurons and dopamine tends to modulate the activity of other neurons up so dopamine itself is not neurotoxic but when a lot of dopamine is released it is
79:00 neurotoxic and it’s well known that even a single dose of methamphetamine can be neurotoxic not just for dopamine neurons but for other types of neurons as well including serotonergic neurons put differently we know that the brains of people that take methamphetamine degenerate to a smaller or to a large degree depending on how often they take the drug how potent the drug is and whether or not they combine it with other drugs and yes if you heard that combining caffeine with amphetamines can increase the
79:30 neurotoxicity of amphetamines such as methamphetamine that is true if you’ve heard that taking caffeine within the hours or same day as MDMA can increase the toxicity of MDMA that does appear to be true based on animal studies now there are not a lot of studies looking at the toxicity of MDMA in humans but there are a few there are also studies looking at the toxicity of MDMA in animal models including non-human primate models now this is a very complex literature a lot of results not all over the place but
80:00 they’re scattered in a number of ways first of all some of the animal Studies have used dosages of MDMA as high as two as high as three milligrams per kilogram of body weight and even in upwards of that but even for the animal studies that used a range of dosages from 0.75 to 1.5 there is some evidence that in laboratory Miser rats there can be some loss of serotonergic tone in the brains
80:30 of animals that have been administered MDMA now notice I said serotonergic tone I didn’t say serotonin neurons because of the way that MDMA Works in encouraging or promoting big releases in dopamine big releases in serotonin it’s not surprising that if the animals that were given MDMA are subsequently sacrificed say later that day or the next day or maybe even a week or two weeks later and those brains are stained for proteins that are related to the synthesis or release of Serotonin it’s
81:00 not surprising that there would be reductions in those sorts of proteins right after all a lot of dopamine and serotonin is released and it can be depleted but I should point out depletion of a neuromodulator in the short term is not the same thing as depletion of that neuromodulator in the long term nor is it the same as loss of the neurons that release dopamine and serotonin itself so there are data pointing to the fact that repeated administration of MDMA
81:30 at dosages that are very much within lines with what we’re talking about today 1.5 milligrams per kilogram of body weight can lower total amounts of Serotonin or other proteins in the serotonin synthesis pathway or dopamine or proteins that are in the dopamine synthesis pathway in specific areas of the brain related to reinforcement related to mood related to motivation Etc however the primate studies or I should say the non-human primate studies which are the sorts of animal studies that most closely mimic what one expects to see in
82:00 the human brain because after all mice and the effects of these drugs and mice do translate to humans but it’s thought that non-human primates provide a model that’s far more similar to humans there the data start to get kind of complicated in a way that suggests that MDMA might not be as neurotoxic as is thought based on the rodent studies and this gets into a whole history of back and forth between different Laboratories and governing bodies who are trying to
82:30 keep MDMA legal as well as people such as the Sasha Shoguns of the world and people in the therapy community that are excited about the potential for MDMA becoming legal for the treatment of PTSD and it really centers around one or two both of which were published in very high profile journals and the one that I’ll highlight because the results are now very clear and conclusive is a study that was published back in 2002 which was entitled severe dopaminergic
83:00 neurotoxicity in primates after a common recreational dose regimen of MDMA or ecstasy this paper was published in the journal science which is one of the three Apex journals for publishing scientific research so there’s science nature and cell those are the top top journals most stringent journals to get scientific manuscripts into the paper received a lot of attention because as you can imagine based on the title it suggested that even recreational doses of ecstasy even if it’s pure ecstasy and it doesn’t have
83:30 contamination from additional methamphetamine or other things in it is neurotoxic to serotonergic and or dopaminergic neurons this is largely where MDMA got the reputation for quote unquote putting holes in your brain however this study came under a lot of scrutiny for a couple of reasons first of all and I’m certainly not saying this but it was argued that the authors of the study were perhaps trying to prevent the legalization of MDMA for the treatment
84:00 of PTSD as far as I know there’s no direct evidence that that statement is true but you will actually find that in some of the scientific journals in fact I was able to find a an editorial that was published in the biomedical journal in 2003 which argued somehow that Dr riccarte was accused of quote rushing his results into print because of legislation designed to curb ecstasy use before U.S Congress so you know there were some uh connotations or I’d rather there were some strong
84:30 suggestions that there was a political backing to trying to get this study done quickly and into print and so forth I don’t think that ever really got resolved what did get resolved however is that the very study in question was retracted okay so the authors themselves published a letter of retraction that unfortunately is not as well recognized as the paper that stimulated this idea that MDMA is neurotoxic in primates and keep in mind that we are human primates non-human primates being
85:00 the closest model to human primates that we are aware of but to make a long story short there were some issues of labeling of MDMA versus other drugs in the laboratory there were some issues of mislabeling all of which were eventually acknowledged by the authors of the study and they concluded in fact they verified based on some very detailed analysis that what these monkeys were injected with was not actually MDMA but rather was methamphetamine itself
85:30 so what’s not often acknowledged is the retraction of the paper on neurotoxicity and unfortunately the neurotoxicity issue is often what’s mentioned now keep in mind there are studies in rodents showing neurotoxicity of MDMA perhaps even at recreational doses but to date at least to my knowledge there don’t seem to be any data in either non-human primates or in humans showing toxicity of MDMA at clinically relevant doses provided it is pure MDMA
86:00 I want to be very clear I’m not saying that if you can get pure MDMA that you should take it or that it won’t be neurotoxic certainly we can expect that because of the huge known variation in dopamine receptors in serotonin receptors and of course because of the known interactions between MDMA and other compounds in particular caffeine but also drugs such as cocaine or other stimulants that some people might experience more toxicity to a given dose of MDMA
86:30 compared to somebody else and there’s really no way to detect that susceptibility to neurotoxicity now what we do know is that there are people in the general population that have taken a lot of MDMA anywhere from 1 to 200 or sometimes even in excess of 400 doses of MDMA and they’re now our studies that have explored the neurotoxicity and perhaps even more importantly the neurocognitive and behavioral effects of taking MDMA either zero times one time
87:00 five times forty times 200 times etc etc and one of the what I would consider Landmark studies in this area is a study entitled residual neurocognitive features of long-term ecstasy users with minimal exposure to other drugs and those words with minimal exposure to other drugs is really key in the context of this conversation because as I mentioned before interactions between drugs what’s called polypharmacology can create neurotoxicity it’s unclear if MDMA is
87:30 neurotoxic but we know methamphetamine on its own is neurotoxic we also know that people often will combine MDMA and methamphetamine we also know that a lot of so-called MDMA out there is mostly methamphetamine with only a little bit of MDMA so a study of the sort that I’m about to describe where it is essentially confirmed that people were taking pure MDMA and not taking any other drugs is of immense value this
88:00 study has been a little bit controversial in fact I’ve talked about it before I talked about the Joe Rogan podcast I’ve talked about it briefly with a guest on this podcast Dr Nolan Williams who’s a triple board certified physician psychiatrist and neurologist at Stanford School of Medicine and it’s an interesting study and a little bit controversial because it relied on a population of people who have taken MDMA anywhere from one to two hundred times and who’ve not taken any other drugs including caffeine and the
88:30 population in mind here is a population of people living in Utah who self-identify as members of the Church of Latter-day Saints sometimes referred to as Mormons sometimes referred to as LDS or of the Church of Latter-day Saints the Church of Latter-day Saints as I understand does not allow for taking of certain compound certain drugs certain certainly most recreational drugs alcohol even caffeine and I’m sure
89:00 there’s some variation on some of those themes depending on where people live and the certain communities that they happen to be in I am in no way shape or form um declaring that I’m an expert on Latter-Day Saints I have a couple of friends who are LDS happen to be very nice people as far as I know they were not the people in this study but this study really emphasized ecstasy users they’re called who have not taken other drugs who self-identify as LDS and the major takeaway of this study was
89:30 that for moderate meaning people who have taken ecstasy anywhere from 22 to 50 times in their lifetime as well as heavy users of MDMA so these are people who have taken MDMA anywhere from 660 to 450 times in their lifetime there was little evidence of decreased cognitive performance in standard assays for cognitive performance now there were some effects showing poorer here I’m
90:00 quoting from the findings poor strategic self-regulation quote possibly reflecting increased impulsivity however when you see a conclusion like that you should immediately be thinking chicken versus egg right it could be that people that are more impulsive and that have less strategic self-regulation are more likely to take ecstasy 450 times you could conclude that or you could conclude that people who have taken ecstasy 75 times or 25 times Etc
90:30 are degrading their levels of self-control and thereby increasing impulsivity the direction of the effect is not known these are purely correlations nonetheless this study and a few others like it really stand as our best evidence believe it or not as to how ecstasy taken many times because after all these people are taken anywhere from 22 to 450 doses of ecstasy in their lifetime is producing severe detriments in
91:00 cognitive performance and that simply does not appear to be the case now unfortunately there are no data looking at the brains of these individuals looking at for instance which brain structures are active or less active or perhaps even looking at levels of Serotonin or dopamine all things that can be done with positron emission tomography Imaging functional MRI Etc hopefully those studies will be done in the not too distant future but if we were to just take a step back from all the data the data in mice in rats and non-human primates the retraction of the study in non-human primates which showed
91:30 the primates that showed neurodegeneration were not given MDMA as it was thought by the researchers but rather as later was acknowledged we’re actually given methamphetamine and we take into account these moderate and heavy users of MDMA who as far as we know are being honest and haven’t taken any other drugs and we look at the clinical studies where people who have never taken MDMA are given one or two or three defined doses of pure MDMA we’ll talk about those studies in a moment I think the
92:00 Gestalt the top Contour the overall view of those studies is that provided it as pure MDMA and provided the individual is not consuming other drugs which have the potential to be neurotoxic and provided that it’s being done in a controlled clinical setting the risk for toxicity seems quite a bit lower than the popular press has promoted and yet there is still the risk of neurotoxicity
92:30 if people are taking high doses of MDMA or taking it very frequently or certainly if they are taking it in conjunction with other drugs or or I should say and or taking MDMA in settings that can promote neurotoxicity and the settings I’m referring to are any settings in which blood pressure or body temperature have the propensity to be greatly increased every study in mice in non-human primates and in humans in which MDMA is administered has observed
93:00 significant increases in blood pressure and heart rate MDMA is after all a psychostimulant it’s a sympathomimetic talked about sympathomimetics and what that means in the episode on Adderall and Vyvanse and ADHD but basically it’s ramping up the activity of the sympathetic nervous system which is your fight or flight system okay this is why people who take these drugs get big pupils you know big pupils of the eyes that’s why they feel agitated they want to talk a lot they feel like they want to move a lot that’s why people take it to dance at Raves Etc but when people
93:30 take sympathomimetics whether or not it’s MDMA or amphetamine or cocaine or even caffeine there’s an increase in blood pressure and heart rate but also body temperature and if that’s done in an environment in which there’s very little temperature regulation so people aren’t for instance drinking enough fluids and electrolytes it’s very hot in the room you can get neurotoxicity based on temperature effects and that’s because serotonin and dopamine also act on the so-called medial pre-optic area of the hypothalamus which is involved in temperature regulation if you’re curious
94:00 about temperature regulation I covered a lot of that in the episodes of the Hebrew and Lab podcast on deliberate coal exposure and deliberate heat exposure this is an area I used to work on many years ago as a research scientist before moving on to other topics to research in my laboratory big increases in body temperature are not good the body and in particular your brain can tolerate decreases in body temperature that are pretty robust and you can still stay safe you’re not going to kill neurons but
94:30 even an increase of three or four degrees in body temperature can start to kill off neurons so when thinking about the potential neurotoxicity of MDMA the conditions that is the environmental conditions the behavioral conditions under which somebody takes MDMA are vitally important at least important I would argue as any other compounds they might be ingesting with MDMA so that’s something really serious to consider so if somebody says MDMA puts holes in your brain you would be correct in being
95:00 skeptical or at least giving them some counter Arguments for that statement but if somebody says MDMA is not toxic well then you would be equally valid in saying ah wait but we need to think about the conditions under which MDMA is being taken is it pure MDMA or is it mostly methamphetamine in which case it would be very toxic is it MDMA alone or in conjunction with caffeine within that same 24-hour period is it MDMA while moving around a lot or being outdoors or being in an environment perhaps a rave or dance type environment where
95:30 temperature is going up well in that case it could be very neurotoxic so pharmacology of MDMA counts but so does poly pharmacology the ingestion of other compounds not just during the MDMA session but also in the 24 hours before and after that MDMA session and behaviors will certainly impact temperature which will impact whether or not MDMA is neurotoxic or not and despite my efforts I couldn’t find out whether or not the LDS Community has officially sanctioned the
96:00 use of MDMA certainly that’s one possibility but I have no evidence for that or rather whether or not certain people within the LDS Community have allowed themselves given themselves permission to use MDMA and they are not using other drugs what I do understand to be the case is that people within the LDS Community are discouraged from using drugs like caffeine or cocaine or alcohol and this particular population of people that was explored in this
96:30 self-identify as LDS and self-identify as having taken MDMA anywhere from 22 to 450 times but where they got permission for that whether or not it was from someone else or from themselves I do not know what I do know is that within the acknowledgments of the paper there’s actually a thank you to the person that identified this quote unique population for our study so I welcome you to take a look at the paper and if any of you know more about if and how a particular subgroup within
97:00 the LDS Community is allowed to take MDMA perhaps you want to put those in the comment section on YouTube before moving to our discussion about what MDMA is doing and the effects that people are seeing in the clinical studies for the treatment of PTSD which by the way are extremely exciting I can’t wait to share these data with you I do want to touch on something that anyone who’s heard about MDMA or perhaps used MDMA is familiar with and that’s the so-called crash that people experience
97:30 after MDMA there are a lot of myths about the post-mdma crash and there’s a lot of lore out there on the internet about how to offset the crash and a lot of lore about how to prevent the potential neurotoxicity of MDMA earlier we talked about some of the major points around offsetting neurotoxicity so certainly making sure that any MDMA that one takes is in the legal clinical setting that it’s therefore pure MDMA right that it’s not cut with other things which certainly can increase
98:00 toxicity controlling the temperature of one’s environment restricting caffeine intake at least on the day of MDMA ingestion but certainly the day before and the day after would be advantageous well simply because of the way that caffeine and activation of the adenosine receptor as well as caffeine’s effects on dopamine receptors can interact with the potential again potential neurotoxicity of MDMA but the crash that one experiences after MDMA is actually a
98:30 phenomenon very common to the crash that one experiences after ingestion of any type of stimulant cocaine amphetamine Etc and the crash that we’re referring to is a drop in mood increase in lethargy feelings of lack of motivation many people have wrongly assumed that the crash was due to quote unquote depletion of Serotonin or depletion of dopamine or maybe even death of serotonergic and dopaminergic neurons and while certainly that could be the case it’s very unlikely that that would be the case in
99:00 the immediate 24 or 48 hours after MDMA ingestion that said you will see protocols that people put out on the internet such as oh you know after taking MDMA you should take a bunch of you know 5-HTP or other precursors to serotonin or dopamine which come in amino acid forms so L-tryptophan for instance is the amino acid precursor to serotonin it’s in the serotonin synthesis pathway you’ll hear that people will take
99:30 l-tyrosine which is the amino acid precursor to dopamine as a way to try and buffer or increase dopamine during the so-called period of the crash there’s really no evidence that any of those things can be beneficial and there is actually some reason to believe that it might be detrimental because if anything taking L-tryptophan and taking l-tyrosine would actually further deplete serotonin and dopamine so the logic there is simply not very good what
100:00 is clear however is that MDMA can cause not just profound increases in dopamine serotonin and oxytocin but that anytime there’s a big increase in dopamine there is going to be a post-dopominergic increase in prolactin release and prolactin is a hormone sometimes considered a neural hormone but it’s really a hormone that’s involved in a lot of things milk let down in lactating women it’s involved in setting the refractory period to sexual arousal and erection and ejaculation in males
100:30 after ejaculation it’s involved in lots of different functions in the brain and body including the laying down of body fat stores and it’s also associated with increases in lethargy decreases in dopamine this is why drugs that increase dopamine are known to decrease prolactin at least in the short term this is wise drugs like cabergoline for instance that increase dopamine are used as ways to suppress prolactin now MDMA ingestion is
101:00 known to dramatically increase prolactin and people are starting to realize that it perhaps is the increase in prolactin that occurs both during and for some period of time probably hours or days after ingestion of MDMA that leads to at least some components of the so-called crash that feeling of lethargy and lack of motivation maybe diminished mood Etc and for that reason some people have started to explore the use of things like p5p which is essentially a
101:30 metabolite of vitamin B6 which is known to suppress prolactin as a way to try and buffer some of that crash to my knowledge there are no human data yet exploring the use of p5p or other vitamin B6 derivatives or capergoline or things of that sort to reduce prolactin in a controlled standardized clinical trial kind of manner but I’ve spoken to some of the clinicians that are using MDMA legally
102:00 within the context of the treatment of PTSD and this is an area that’s starting to receive some additional attention so I just mentioned it briefly here because for instance there’s a lot of ideas out there that people should be taking L-tryptophan they should be taking l-tyrosine they should be taking magnesium other things Etc after taking MDMA in order to recover from the post-mdma crash more quickly but it’s really the increase in prolactin which speaks most directly to the subjective effects of the so-called
102:30 crash so by my read of the mechanisms of MDMA the neurochemicals it releases the neural hormones that it promotes the release of prolactin in particular this p5p suppression of prolactin is perhaps the one that’s most intriguing and that really has any kind of mechanistic basis so I promise that going forward as the scientists and clinicians that are using MDMA for the treatment of PTSD and other conditions such as alcohol use disorder start to explore the use of post-mdma session p5p and other modes of
103:00 suppressing prolactin for the hours and days after MDMA promise to update you on those findings throughout today’s episode I’ve been referring to clinical studies that is clinical trials exploring the use of MDMA in order to augment treatment for PTSD so let’s just take a moment and talk about what PTSD is PTSD is post-traumatic stress disorder trauma is anything that modifies the brain to function less well going
103:30 forward you know physical trauma you can have emotional trauma typically PTSD is used to refer to emotional trauma caused by either single events so you can imagine you know car accident sexual assault these could be first person experiences so things that happen to somebody that leads to trauma and then PTSD these can also be third person events where someone observes something that is traumatic to them
104:00 maybe somebody being killed dismembered any number of different things that could be very traumatic in the immediate and long term and of course PTSD need not be caused only by single event traumas but by multiple event traumas entire relationships entire childhoods wartime experiences combinations of different traumas and on and on there are so many different forms of trauma if any of you are interested in trauma and its treatment I highly recommend the book trauma by Dr Paul
104:30 Conte he’s an MD medical doctor psychiatrist he was featured as a guest on this podcast he’s been on a number of other prominent podcasts we will provide a link in our show note captions to the book trauma I consider that book to be the best book in terms of describing what trauma is and isn’t and how it leads to PTSD it also describes some of Dr Paul Conti’s own experiences with trauma and his own treatment of trauma in his patient population which is quite wide-ranging men women young people older people and a variety of traumatic
105:00 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 Conti did on this episode that’s talk therapy for which the patient sometimes referred to as the client but more traditionally referred to as the patient and the therapist so a psychologist or psychiatrist has Good Rapport and as a consequence of that
105:30 Rapport there is the feeling of support that there is a safe place in which to explore the trauma and what’s happening in one’s current life in order to understand how that trauma is fitting into adaptive and maladaptive behaviors and emotional states now in addition to Rapport and support being critical there’s a third component of effective talk therapy for trauma which is Insight or one’s ability to come to an understanding of why one feels the way they do
106:00 and to link that to some larger context that brings about some degree of relief and that’s where things start to get a little bit abstract and that’s also where we start to see that while trauma therapy in the form of talk therapy can be very effective about half of people that undergo talk therapy and talk therapy alone for the treatment of PTSD achieve no long-lasting relief of symptoms and an even smaller number of
106:30 them undergo complete remittance of their PTSD okay so their symptoms can lessen they can get some improvement but that Improvement is often slight or is transient and for those that do achieve relief it’s often not complete remission of the PTSD itself now in addition to talk therapy for PTSD there is of course prescription drug therapies and most often these fall under the category of ssris selective
107:00 serotonin reuptake Inhibitors and it’s well known that ssris can be in limited circumstances effective for the treatment of PTSD it has been shown for instance that as many as 40 maybe as many as 60 of people that take ssris for the treatment of PTSD get some symptom relief now that is not to say that ssris don’t have side effects they can have side effects some of you are probably familiar with these side effects things like blunting of libido blunting of
107:30 appetite or increases in appetite in some cases disruption of sleep wake rhythms motivation Etc so there’s often an exploration for the so-called minimal effective dose that provides some symptom relief to PTSD but that doesn’t introduce unwanted side effects and of course there’s a third situation where people are taking ssris and doing talk therapy for PTSD and what’s very clear is that anytime you add quality talk therapy to a drug treatment you’re going to improve the outcomes for that drug treatment the reverse is not always true it’s not
108:00 always the case that adding prescription drug treatment to talk therapy improves outcomes for talk therapy although that has been observed in a number of studies now the whole idea of exploring the use of MDMA for the treatment of PTSD stem from the fact that even in people who are getting quality talk therapy and again we can Define quality talk therapy as Good Rapport between patient and clinician as well as feelings of support as well as potential insight
108:30 and even when ssris are combined with that quality talk therapy there’s still a large number of people who simply do not achieve significant or long-lasting relief from their PTSD and an even fewer number who go into full remittance of their PTSD that is despite being diligent and hardworking in their talk therapy despite the therapist being very committed despite the use of ssris in conjunction with a talk therapy those people often still qualify as having PTSD and the goal of course is for
109:00 somebody to receive treatment that allows them to no longer meet the criteria for having PTSD not just in terms of a clinical evaluation but that they themselves report feeling much better not feeling overwhelmed with the symptomology of PTSD now the symptomology for PTSD is vast and it’s far too vast to go into into a lot of detail right now I think most people are familiar with a stereotyped example of PTSD this is the soldier that comes back from overseas
109:30 that has been in gun fights or in battles of different kinds has likely seen casualties and severe injuries and that upon return to a safe environment is still experiencing a lot of anxiety and sometimes panic attacks that occur seemingly at random or they can be sparked by you know the classic stereotyped example is you know a car backfires and then the person suddenly feels as if they’re back in battle that sort of thing does happen certainly but there are a whole other category of symptoms of PTSD which include
110:00 dissociative symptoms of PTSD people who have PTSD 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 PTSD of either the dissociative type or other symptomology of PTSD and keep in mind that one can have both dissociative and non-dissociative symptoms of PTSD such
110:30 as anxiety and panic are at a far greater risk of substance abuse so the current estimates are that people with PTSD no matter what type of PTSD dissociative symptoms or or otherwise you know panic attacks or both are at a much greater risk of having addictions to either illicit drugs or prescription drugs or both so things like alcohol use disorder is very common in people with PTSD opioid use disorder
111:00 is very common stimulant use disorder and on and on so people with PTSD suffer at a number of different levels and there are all these what are called comorbidities with PTSD including addiction but also depression anxiety and so you can start to see how ptst sets up a whole Cascade of things that make living life extremely problematic at the level of basic relationships functioning in the workplace and even when mental health appears to be in check oftentimes people are
111:30 holding a lot in so they have cardiovascular and cerebral vascular deficits that cause a lot of problems in their immediate and long-term physical health so PTSD is a very serious issue the current estimates are that as many as eight percent of people in the United States have PTSD and again the estimates around comorbidities range anywhere from you know 17 to 46 or as high as 65 percent of people with PTSD having comorbidities for other mental health issues and addiction in particular so finding lasting relief to PTSD is
112:00 extremely important and made even more important by the fact that many people with PTSD sadly end up committing suicide so suicide rates are far greater in people with PTSD the exact rates of increase and suicidality in people with PTSD are a little bit hard to arrive at in the statistics because of all the comorbidities but suffice to say that suicide is far more likely in people with PTSD along with all the other issues that PTSD brings about now PTSD creates all the problems that it does
112:30 largely through changes in brain circuitry as well as neural communication between the brain and body many people have perhaps heard of the book the body keeps the score which is a very successful and popular book about the idea that trauma can be quote unquote stored in the body to be clear traumas can’t actually be stored in the body you don’t actually store memories in the body what you store are activation of neural circuits that include brain and body and
113:00 they all seem to Center back into the insula that structure that we talked about earlier this structure in our brain that has a map of our body’s surface so contrary to popular belief we don’t store memories in the body or trauma in the body in a way that for instance working out a knot or a pain in one’s lower back will relieve the trauma it sometimes can activate a memory of the trauma but when one is doing that what you’re really doing is activating neural circuits that reside within the brain within the insula that correspond
113:30 to Sensations within the body now I don’t want to diminish the role of the body and the formation and the Persistence of PTSD and I certainly think the book the body keeps the score is a pioneering book it’s in fact an important book uh but I want to emphasize that the modern Neuroscience really points to the fact that PTSD is caused by the exact sorts of brain Network activations that we were discussing earlier things like heightened levels of activation in the amygdala to insulate pathway which of course would exacerbate bodily
114:00 Sensations related to the trauma or heightened activation of the hippocampus this memory Center in the brain too amygdala to insula circuitry now therefore it should come as no surprise that if MDMA can reduce the levels of activity in the hippocampal to amygdala to insula circuitry and can do so both while someone is under the effects of MDMA but then lead to persistent long-lasting reductions in the activation of those brain networks well then it stands to reason that MDMA could
114:30 be a valid therapeutic for the treatment of PTSD and of course this has been explored and here we can really give a nod and large debt of gratitude to the so-called maps group the maps group is a group that’s operating mainly out of Santa Cruz California but they have a number of different satellite Laboratories and clinical groups both in the US in Canada and abroad where they’ve worked with government organizations to get legal authorization to give MDMA to patients who have PTSD
115:00 to also give them talk therapy and then to compare the effects of talk therapy with MDMA to talk therapy with Placebo alone and there are about three to five studies in this area now that stand as large-scale clinical trials that are showing what can only be described as remarkable results for the treatment of PTSD so rather than going to any one of those studies in immense detail I’m going to summarize across those studies I will provide links to those in the show note captions
115:30 the two that I think are most interesting are the study entitled MDMA assisted therapy for severe PTSD a randomized double-blind placebo-controlled phase three study as well as the study entitled the effects of MDMA assisted therapy on alcohol and substance use in a phase 3 trial for the treatment of severe TSD so as the title suggests both clinical trials involve giving people talk therapy and MDMA or talk therapy and placebo talk about exactly how that was done in a moment and then to look at relief of
116:00 PTSD symptoms but also relief of some of the addictive symptoms that are commonly associated with PTSD so just to give you an overview of what’s happening with these trials and why there’s so much excitement and why we really are on the cusp of legalization of MDMA for the treatment of PTSD in the sorts of clinical context I described when people are given just talk therapy alone or talk therapy with ssris
116:30 they will often as I mentioned earlier experience reductions in their severity of PTSD symptoms and rarely they will experience complete remittance of their PTSD that is they will no longer qualify for PTSD after receiving a number of talk therapy sessions so let’s compare that to what happens when people do talk therapy in conjunction with MDMA and I’ll explain exactly what that means in a moment but it essentially means taking MDMA while doing talk therapy however this is a
117:00 very important however the people who are taking MDMA in these trials have already done talk therapy without MDMA then they’re doing talk therapy under the influence of MDMA and then they are doing sessions of talk therapy not under the influence of MDMA and the entire time they’re doing that with the same two therapists okay in the placebo group people are doing talk therapy with two therapists but they’re not taking MDMA okay so they’re doing the same number of therapy sessions but they’re not taking MDMA so to just get to the key numbers first
117:30 the overall rate for clinically effective response to MDMA assisted therapy is 88 that’s what’s emerging from these trials versus 60 for the placebo and therapy alone so on the face of it you might say okay wow 88 of people who do talk therapy and here I might as well just finally explain how this is done patients are selected because they have PTSD they meet the clinical criteria for they do three 90-minute therapy sessions
118:00 with two therapists talking about their PTSD symptoms talking about to the extent that they can the incident that or incidents the life events that led to that PTSD none of that is done under the influence of any drug okay so everyone in the experiment does that then the group divides into two where half are taking MDMA they take that three times
118:30 during those three times they are also receiving therapy sessions with the same therapists that they were working with before they took MDMA the first session they’re taking 80 milligrams of MDMA and then a 40 milligram booster about an hour and a half to two hours in the second session they are taking a higher dose of MDMA it’s 120 milligrams and then if they elect to they can take a 60 milligram booster about an hour and a half to two hours into the session and then there’s a third session where
119:00 they take again 120 milligrams of MDMA and have the option to take a 60 half to two hours into the session again anytime they’re on MDMA they have therapists there that they’re talking to about their trauma they are either spending time with their eyes closed lying down sometimes in an eye mask and thinking about the trauma thinking about their current state and experience also thinking about what happened before then they’re exiting the eye mask or
119:30 talking to the therapist therapist is taking notes asking questions remember they’ve established a strong Rapport supportive relationship with these therapists prior to taking MDMA in the therapy session and then they also undergo three 90-minute therapy sessions with the two therapists spaced one week apart after the final MDMA session now those that were placed into the placebo condition do everything exactly the same as I just
120:00 described so three 90-minute sessions as prep then three eight hour sessions with those two and then three 90-minute follow-up sessions one week apart but they take a not MDMA so you can see that in these so-called Maps studies these clinical trials for PTSD the conditions are very similar except for the inclusion of the drug MDMA so those rates of success with talk therapy and MDMA again overall rate for
120:30 clinically effective response to MDMA assisted therapy was 88 compared to 60 percent for therapy and placebo what’s even more impressive however is that 67 percent of the people in the MDMA plus therapy treatment group no longer met the criteria for PTSD by the end of the treatment so in other words their PTSD went into remittance now we could say they are quote unquote cured but typically for things like PTSD
121:00 that’s not the language that’s used rather what’s used is statistical evaluation of how the different symptoms like dissociation or anxiety or Sleep Disorders are explored so while to some of you a difference between 60 percent success with talk therapy and Placebo versus 88 success with talk therapy plus MDMA might not seem like that big of a difference it is indeed quite an enormous difference in fact to my knowledge there is no other example of a
121:30 treatment for a psychiatric disorder that is successful to the same magnitude I could be wrong about that I’m sure some psychiatrists out there are going to jump on me about this and please do I would encourage you if you are aware of any therapy plus drug treatment that is effective at rates of greater than 88 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
122:00 a reference to that that would be great for sake of future episodes Etc but nonetheless an 88 percent success rate and here I’m referring to success rate as a significant reduction in clinical symptoms for PTSD and 67 of those people going into full remittance for PTSD by the end of the treatment is pretty spectacular which is why you’re hearing so much these days about the potential transition of MDMA from a schedule one drug for which there are quote unquote No clinical applications to potentially a legal within the
122:30 context of clinical use application of MDMA which it does appear the legislature is at least considering for as early as 2024 maybe even later in 2023 it remains to be seen now a number of other important results have emerged from this and other clinical trials for instance remember earlier I talked about how many people with PTSD also suffer from alcohol use disorder what’s interesting is that for people that were in the MDMA
123:00 plus talk Therapy Group in this and other studies who also had patterns of alcohol use disorder and even some other substance use disorders the MDMA plus talk therapy 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
123:30 other addictive disorders oftentimes will stem from disruptions in neural circuitry that are the same disruptions in neural circuitry that occur in PTSD but often are the consequence of entirely other brain wiring phenomenon what I’m saying here is that just because addiction and PTSD are often co-morbid with one another it was not necessarily the case that treating and resolving PTSD would resolve the alcohol or substance abuse disorder and yet that seems to be the
124:00 case often not always but often in these successful treatments of PTSD so that’s very exciting some of the other particularly exciting results from these clinical trials on MDMA plus talk therapy is that the dissociative form of PTSD has traditionally proved to be especially hard to treat and that’s thought to stem from the fact that successful treatment of PTSD whether or not it’s by talk therapy or talk therapy combined with ssris or talk therapy combined with any drug treatment or behavioral treatment like EMDR eye
124:30 movement desensitization reprogramming or other forms of treatments that are designed to rewire neural circuitry almost always involve the patient getting very close to or at least reporting the traumatic experiences in a lot of detail and you can imagine why for somebody who’s dissociating from that very experience who’s quote unquote checked out and can’t really seem to access the emotional states and the memories because they’re blocked off from them or
125:00 because they’re unwilling to access those memories and really think about the full emotional capacity of those memories that it would be particularly hard to bring them through any kind of treatment for PTSD so it appears that MDMA in providing this pro-social empathic again empathic for others and empathic for self chemical and kind of mental environment as well as the presence of two trusted therapists which one has a really good rapport allows patients with PTSD to really get
125:30 close to those experiences that were traumatic to talk about them and to think about them and in many ways to reframe them in a context that often involves empathy for others and empathy for self now here we’re not necessarily talking about forgiveness of perpetrators although that’s sometimes the case that people will forgive the person that inflicted the trauma on them but more often than not it’s about tying their feelings of trauma and their feelings of depression anxiety dissociation Etc to some sort of larger
126:00 context that allows them to see themselves in the role of agency to be in the role of knowing that yes these things happened and yet by getting close to the emotional load of those things and really being in many ways unafraid to get close to the emotional load of that and having support around that that the emotional load seems diminished and that they experience the emotional load of those experiences as diminished both within the MDMA treatment session and
126:30 afterwards for long periods of time so essentially what happens is these people feel that what once burdened them they can still remember but it no longer burdens them it no longer feels like it’s in their body and in their mind or on Loop or on repeat in a way that’s invasive in a way that interferes with other aspects of normal functioning so when one hears about these kinds of results and when you hear about some of the patient reports and I invite you to do that you can go to the map site which by the way is recruiting subjects for these clinical trials and you’ll also
127:00 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 the combination of MDMA and talk therapy in many ways is not about the drug having a particular effect it’s really about the drug having a particular effect that allows the motivations and the results of talk therapy to really be
127:30 heightened and I think that’s a really key point to make because up until now we’ve really been talking about the neurochemistry of MDMA the potential toxicity or lack thereof of MDMA we’ve been talking about that brain networks Etc but when one thinks about the valid clinical use of MDMA for the treatment of PTSD and I should mention it also had some success in dealing with not only alcohol use disorders and other use disorders associated with PTSD but also relieving the depression associated with PTSD so now MDMA is being explored
128:00 for treatment of not just PTSD but also for depression for alcohol use disorder and for eating disorders as well MDMA seems to be a compound that produces the right kind of subjective and neurochemical milieu in the brain that allows therapy to be that much more potent within a limited number of sessions and when one thinks about the cost of mental health care you know how expensive it is to get therapy over and over and over again which in ideal circumstances people are able to do that either by way of insurance or by their
128:30 own finances or you know I I don’t want to say that the cost of therapy should be reduced because of course therapists have to survive also but the idea here is that people who are suffering would be able to achieve relief from their PTSD their depression their addiction and to be able to do so by hopefully persisting in their therapy over whatever period of time is required but also to assume a circumstance in which somebody only has 10 or 15 or maybe even just three
129:00 opportunities to undergo treatment for PTSD and nonetheless is able to achieve tremendous relief during the session and after the session and it really does seem to be the case that for reasons that you now understand the activation of particular brain networks the suppression of other brain networks in particular this amygdala to insulopathway that when people are under the influence of MDMA in these very safe and therapeutic supportive settings they are able to look at traumatic events and
129:30 the ways that those traumatic events impact them in ways that really allow them to cognitively reframe those events and somatically reframe those events to really change the way that it lives in their body and mind so that it’s no longer invasive and then they can go on and Lead productive adaptive lives and as a final Point related to these clinical studies I of course would be remiss if I didn’t touch on some of the so-called adverse effects because anytime there’s a drug or talk therapy for a mental health issue Adverse Events
130:00 have to be considered and I think it’s quite reassuring that in the case of MDMA therapy there were no increases in the number of suicide attempts or suicidality or obsession with suicide contrast that with the group that received Placebo where there were a certain number of Baseline and predicted obsessions with suicide fortunately at least to my knowledge there was no actual suicide attempt or successful suicide thankfully but the point being
130:30 that the addition of MDMA drug therapy to PTSD talk therapy does not seem to increase the quote-unquote side effects that are sometimes associated with PTSD talk therapy because indeed there can be side effects to exploring PTSD and Trauma as one would expect so overall I would say it’s very exciting times for the exploration of MDMA as an augmented talk therapy for the treatment of PTSD and these other conditions again I think the maps group has done a remarkable job of keeping this within the realm of legal and
131:00 trying to move things forward in terms of legislation to make sure that MDMA isn’t simply made legal and then abused recreationally I know people out there have different views on whether or not drugs like MDMA should be legal or not that’s not what this episode is about what I am very excited about as you can probably tell what I think a lot of people in the psychology and Psychiatry Community are very excited about you say the Mental Health Community at large is that these compounds that for many years we’re only associated with their recreational uses and therefore
131:30 were not well understood because they were often contaminated or taken in combination with other things or by people that never should have been taking them in the first place taken by young kids which is a whole other matter you know a lot of issues and problems associated with these compounds and yet we’re now seeing from these clinical trials when used say properly because really when safety Protocols are obeyed when there’s clinical support it is very clear that
132:00 when MDMA is combined with quality talk therapy that the outcomes are looking tremendously positive it’s by no means a miracle cure it is by no means perfect and time will tell what problems if any arise from the short or long-term use of mdama in this context but I think it’s remarkable that anywhere from two to three sessions with MDMA and talk therapy have been shown to significantly reduce PTSD symptoms and in some cases completely eliminate PTSD symptoms in
132:30 such a wide range of patients and in patients that have experienced both PTSD and these other comorbid disorders I think it’s really remarkable it’s very exciting and I look forward to seeing what the next round of data produce so as is often the case on this podcast today we went into a lot of detail about a subject MDMA is this incredible compound synthesized as far as we know first by humans not by plants not by aliens but by humans and that produces big increases in
133:00 dopamine and serotonin to create these highly motivated pro-social empathic States meaning both empathy for others and for self and that when applied in the context of psychiatric challenges like PTSD and addiction is proving to create a lot of relief for a lot of people where other forms of drug therapy or combination drug and talk therapy had failed before we talked about some of the potential neurotoxicity issues I don’t think that
133:30 is a resolved issue just yet although the bulk of data in humans and non-human primates point to the fact that at reasonable Doses and we talked earlier about what those are at reasonable doses when not combined with other drugs it does not appear that MDMA is exceedingly neurotoxic and it may not be neurotoxic at all of course one needs to be exceedingly cautious when thinking about the use of any sympathomimetic they of course can be neurotoxic anything with methamphetamine in it has
134:00 a potential to be neurotoxic but of course dosage matters context matters we talked about that and of course the purity of drug matters and again I just want to re-emphasize the fentanyl contamination of MDMA that sold on the street and that is being used recreational is of very serious potentially lethal concern I also expect that there will be a lot of interest in these clinical trials that Maps is doing so again you can find links to that in the show note captions and I think in general
134:30 we should acknowledge that we are a very interesting and important time in human history for the treatment of psychiatric disorders and for Neuroscience generally because whether or not we’re talking about psilocybin or LSD or Ayahuasca or ketamine or today’s topic of MDMA regardless of what drug and neurotransmitter neuromodulator systems are involved what we’re really talking about are ways to access neuroplasticity the nervous system’s incredible ability to modify itself in response to
135:00 experience ideally to be modified in adaptive ways that make it function better so that’s really the Crux of what talk therapy and drug therapies are about that’s what the goal of using MDMA as a clinical tool is all about and in that sense I find MDMA to be an incredibly interesting and important topic and I hope you did as well if you’re learning from and or enjoying this podcast please subscribe to our YouTube channel that’s a terrific zero cost way to support us in addition please subscribe to the podcast on both
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