An array of drugs often used for recreation are now being studied and used in psychiatry. Stephen Dubner of Freakonomics Radio and three Mount Sinai neuroscientists discuss how ketamine, cannabis, and ecstasy are showing promise as potential treatments for treatment-resistant depression, opioid addiction, and post-traumatic stress disorder. They discuss the science and public policy regarding these substances, as well as the potential benfits and possible downsides. This episode was recorded live, via Zoom, in collaboration with The Greene Space at WNYC. good evening and thanks for tuning in. I'm Stephen Dubner, and this is a special live presentation of Freakonomics radio in collaboration with W. N. Y. C s Green Space and the Mount Sinai Health System. As you likely know, there are many natural and synthetic psychedelic substances. They've been used by countless cultures for centuries, perhaps millennia, for many purposes. Medicinal, religious, social, recreational and so on. The first synthetic hallucinogenic molecule, LSD, was discovered by the Swiss chemist Albert Hoffmann in 1938 and it came to be considered a wonder drug helpful not only in expanding consciousness but potentially treating mental illness. Before long, there were thousands of medical studies underway on LSD and other psychedelic drugs. But of course, drugs are susceptible to abuse, and the U. S government, as part of its wider war on drugs, effectively killed off that research and those drugs and many others were made illegal. For the most part, European and other governments followed. Economists think of the war on drugs as a failure. For the most part, much of the law enforcement community does is well for the medical community in particular. The war on drugs produced widespread collateral damage in the form of treatments undiscovered in the form of human suffering, UN. Alleviated in the form of scientific knowledge, UN attained today that is changing. Cultural attitudes have shifted. Public policy has started to move as well, albeit haltingly and inconsistently. And scientists around the world are once again looking at these and a variety of unorthodox drugs in the hopes of finding new treatments for mental illness, addiction, PTSD and other maladies. Tonight we have gathered a trio of medical researchers at the forefront of this work, all three from the Mount Sinai health System right here in New York City. And our mission is to learn as much as we can from them in our roughly 90 minutes together. They are James Murrow, Rachel Yehuda and Yasmin Heard James, Rachel. And he has been good evening. And thank you so much for being here. Good evening. We will get to some real introductions in a minute, But first I have to ask before we begin in regards to your research and the place where you do it. Is there something in the water at Mount Sinai, or would we find the same concentration of research into nontraditional drugs at other big teaching hospitals. I'm curious. I think it's starting to happen. I think that a lot of academic medical centers air starting to understand that it is very important to study psychedelics for the therapeutic potential. And it represents really the most promising new development in psychiatric medicine. Is there anything in particular at Mount Sinai, though, having to do with whether it's fundraising, administration, research, history, etcetera? That leads to this concentration? Or is it not really a notable concentration? E do think that it's a notable, uh, concentration and even the dean of Mount Sinai and James Skin test. You know, when he was at Yale, started looking at ketamine before then his journey? Yes, before it was, you know, even popular. Similarly, some of the work that we were doing with cannabis before people thought that, um, there may be any medicinal component of cannabis for treating addictions are the mental disorders. We were doing it before everyone else. So I think the pack the other institutions are now following us. Great. So here's the plan. I would like to ask each of you to introduce yourselves briefly, after which we'll circle through the three of you. One more time to get a bit of information on your drug of choice, and then we'll open up the conversation more broadly. So let's start with James Murrow. Would you tell us quickly about James, your research specialty and how that feeds into your clinical practice? Sure, Stephen. Great to be with you s. Oh, I'm a psychiatrist at Mount Sinai and I've been there. I did. My residency there started in 2005 went on to do a research fellowship, and currently I direct a research clinical research program focused on finding causes and treatments for depression and related conditions such as, um, anxiety. And I know we're gonna be talking about ketamine, among other things tonight. And when I was a just a trainee, a resident Yasmin mentioned Dennis Charney. He had started what was a very nascent early research program in looking at whether ketamine could have rapid antidepressant effects and as a resident hanging around, looking to get involved in something, and I got involved in that and fast forward, you know, more than 10 years, we and others are still doing research to understand how ketamine works. Who it works for and what it can tell us about depression and point the way towards even other treatments. Maybe we haven't even thought of yet, right and ketamine again, just very briefly, because we'll get into more of this later. It is, as I understand it, very pop popular surgical anesthetic. Correct? Yes, yeah, ketamine is, ah, medicine that was synthesized and approved as an anesthetic in, I believe, the 19 fifties, but also a big party drug in some points in its history. Yes, in the nineties. Maybe now I don't know. You know, I think it's still particularly in certain cultures. It's still used recreationally. Um, it's actually classified as what's called a dissociative anesthetic, and apparently that's the only drug sort of approved by the FDA. That's a quote disassociative anesthetic. It causes a unique, altered state of mind when taking in certain doses. And, um, sort of a hallucinogenic state almost. And it got famous for sort of folks taking it at raves and and things like that. Okay, so for those of you keeping score at home, that was James And he is your ketamine guy. Now let's move on to Rachel Yehuda. Rachel with you. Would you tell us quickly about your research specialty and again how it feeds into the treatment? Oh, yeah, sure. Well, I've been studying post traumatic stress disorder since the late 19 eighties, and I've been at Mount Sinai since 1991. And to Yasmin's point, I mean, Mount Sinai does do a lot of things first. And I think we were among the very first medical schools to establish the Center for the Study of Traumatic Stress and PTSD. And for the last 30 years, we've been investigating the biology of post traumatic stress disorder, the epi genetics, looking at resilience. And in the course of that work, we've tried a lot of treatments. I've done a lot of treatment trials and PTSD, and, um, those studies haven't really provided great outcomes. And I heard about M d m a a few years ago. You have to tell us how you heard about it. We're because, like a lot of people, you first discovered M. D m a at the Burning Man festival, and that is true. But my meant for in all things, MGM awas Rick Doblin, who really encouraged me to go to the maps, training and map stands for what? Please, the multidisciplinary association for psychedelic studies. Okay. And they're largely responsible for sponsoring all of the work that's been done in M D M a, um, in the last gets 30 years or so and so, Yeah, so I just heard about I m d m a. And after I did the training and had some other experiences talking to people, um, I was very eager to bring it to Mount Sinai. There's so many questions about how it works, why it works for whom it works and the whole frontier out there. What we've what the field now knows is that there's a signal from phase two and now phase three studies enough to probably make MGM assisted psychotherapy legal. But there's so much work to dio, you just mentioned a very important distinction that again we'll get into later. But your your treatment with M. D. M. A. Is in order to facilitate psychotherapy. Correct. Which stands against how ketamine is used. Correct. Okay, Okay. So again, we have so much of such great interest to talk about that hopefully will cover it all. But let's keep circling on and cover the basics. Yasmin heard. Would you tell us a little bit about your research specialty and especially in your case, the somewhat circuitous route of your drug of choice and and how it's used in in what kind of treatment? Yes, So I am the director of the Addiction Institute at Sinai and my drug of choice. Actually, there multiple. We We actually have one of the largest clinical addiction, um, services in the country with over treating over 6000 people with opioid use disorder. And I look at addiction from the perspective of what increases risk and also, um, a neurobiologist looking at what happens in the brains of people who have a substance use disorder like opioids and can what we know about how the brain works. Can we start thinking about novel treatments? And when we looked at risk factors, you know, early cannabis use? Absolutely. We see strongly increased risk for, um, substance use disorders later in life, and as well of certain psychiatric disorders. And our animal models, you know, confirmed that. And so I'm sorry to interrupt when you say your animal models confirmed that. That suggests that the correlation between early use and later problems is not behavioral Its chemical Yes, correct. So these rats, for example, their mothers, you know, tell them to stay away from certain other other kids. But you know, they still develop certain sensitivities toe opioids, for example, later in life. And but we in our animal models, we study THC, which is the psychoactive the part of the cannabis plant that creates the high. And one day I said, let's at least look at another cannabinoid in the cannabis plant and we started looking at cannabidiol CBD, and there we actually saw on opposite effect. We saw it on that actually reduced, harrowing seeking behavior in the rat model. And then we started thinking, Wow, could this potentially work for our human subjects and started doing clinical trials? How long ago was that that you had the idea to use CBD in that way? That was actually over 10 years ago before I became eso popular in in our water. Now even right. Okay, very good. Eso I'd love to go around one more time. The three of you will just do the same order if you don't mind and very like to get from you very briefly if you haven't covered it yet. But in each case, a little bit of the background or history on the drug or drugs that you study because you know, the story of how these drugs are invented or discovered than what they're used for initially and how they get repurposed 100 times is fascinating. But I'm also curious to know how each of your drugs is unique. And by that I mean not just in terms of chemical composition, but how they help a clinician achieve your goal. Okay, so let's James will start with you again. And ketamine, please. Sure. Absolutely. So as I mentioned eso, ketamine is has been known to the medical community for decades. I believe it was actually synthesized. I think a PCP actually was synthesized first and was found to cause some behavioral problems hallucinations, and but it was actually initially synthesized to be an anesthetic. And then ketamine was sort of a derivative or synthesized based on that to be better tolerated as an anesthetic and actually was marketed and is used, uh, for that reason, uh, today, widely and just briefly in terms of what this molecule is um, it's unique, as I mentioned before, in terms of anesthetics. And certainly, as you'll hear, it's very unique in terms of anti depressants. There's no antidepressant drug which acts like it does in the brain. Uh, this interferes with signaling in a specific type of receptor in the brain called the NMDA receptor. That's very important for learning and memory and what's called neural plasticity, it seems to help brain circuits adapt to the environment. Um, it's part of the glutamate system, and glutamate is the primary transmitter in the brain, which excites neurons and makes them fire mawr. And that's basically how information is transmitted in the brain. Um, it looks like jumping ahead a little bit from brain imaging studies and things like that that if you give ketamine, it's sort of somehow disrupts or scrambles temporarily the function of circuits in the brain, which ultimately give rise to consciousness. That's actually why at high enough doses you block consciousness and people, uh, you can operate on them on day don't actually have a memory, even though they don't go to sleep in a standard sense. Like if you were to receive something else, like propofol, so people don't go to sleep. They enter some kind of what's called disconnection State, and they have a profound alteration consciousness at high doses. And, as was mentioned earlier, um, initially a very small study with I think eight people at Yale that was published in 2000 showed that if you give an intravenous infusion of this and a powerful anesthetic drug, but at a low dose a dose of quarter, you know a quarter of the dose, you would need to actually have an anesthetic state. They got altered temporarily, and then the next day they reported a lifting of their depression. And how long and how long does that last? Typically, it only lasted a few days on DSO. Since then, it looks like it's variable, for some people could last more than a week, but it's certainly temporary, but we should say there is one ketamine or ketamine derived drug on the market now. Correct? That's right, a form of ketamine, if you will. A so called an anthem er called S Ketamine, was approved last year as an antidepressant, and it was the first antidepressant improved, which, from a chemical perspective, was not like the rest three only drug that worked on this system of glutamate rather than something like, for example, Prozac affect things like serotonin, as does all the other dozens of antidepressants on the market. But this one is different as I understand it. Correct me if I'm wrong. Please. This is called Spray Votto, Exactly. Distributed or sold by Jansen. And I also understand that just for the record, Mount Sinai, with whom you're all affiliated, does have a financial interest in that drug. Some of the research is licensed from their correct or part. Yeah, that's exactly right. And in fact, uh, he has been mentioned. Dennis Charney. He was part of the team, along with John Crystalline others at Yale that did the very first study. He then moved to the N i. H. A few years later, they replicated it. And by the time I was a resident Mount Sinai, he had come to Mount Sinai on sort of. We started kind of the third study. So, um and obviously was successful. Went through phase three FDA approval, and here we are pretty remarkable. Well, let me ask you a question that I want you to answer quickly and it's going to segue into what I want to get to with Rachel. Next. Um Okay, um, I understand you treat what's called treatment resistant depression. So 1st, 1st of all, I want to know a little bit about the population for whom this ketamine derived drug is most successful. But then I also want to know. It sounds like it's a medicine I take. Understand. It's a nasal spray. Correct? That's right. Medicine. I take twice a week, and it is a medicinal treatment of depression. There is no psychotherapy attached to the administration of that drug. Correct? That's exactly right. Yeah. So treatment resistant depression. And sometimes, you know, my my patients remind me that that might not be the best term because part of s psychiatrists or so called psychopharmacologist, which is basically just a fancy word for a psychiatrist that focuses on using medicine instead of psychotherapy. I fall into that camp. Um, we do a lot of cheerleading with our patients, right? So depression. You know, for many people, they respond beautifully to ah, psychotherapy or an antidepressant. A standard what we called conventional antidepressant. And that's great. And we never see those patients right because they're treated in primary care. Or maybe they don't even go to the doctor and eventually resolves. But unfortunately for some patients, there's a more severe course, and and they just don't respond whether it's their brain. Chemistry is different. Giving more serotonin in the brain is not doing the trick for them. Um, and in terms of how to define it. So we see this pattern where we think about one third of patients will do up to a half will do well with a a medicine and they do well, but But after a while. But we see this group, uh, that actually does not do well. Many people will respond to changing from one antidepressant to another. Patients that have gone through this No, they tell you I go into my doctor and that's okay. President didn't work, and then I tried another drug and then another in this sort of trial and error. The problem was, if you have a trial and error approach, but every medicine works the same in the brain. Look, where you going to get eso. That's why this was sort of ah, big deal, right? So it's so interesting now, Rachel M D M A. I'd like you to describe again a little bit of the back story of the drug. Mhm what? It was originally intended for what the compound was intended for. But then I'm really curious to know how not just how chemically your approach differ. How the how m d mayor the m d a m d m a derivation differs from the ketamine derivation, but also how the application differs, including psychotherapy. Well, yeah, I'm 19. Um, M d M A. Was first synthesized by Merck in 1912. And it was originally supposed to be an intermediary compound towards making a drug that stops bleeding, and it was actually patented two years later because it was found to have psychoactive properties. So there's probably a story. They're not unlike the one he told with Albert Hoffman, but I don't know what it is. Um, the drug basically stayed dormant for a while. Patton ran out, and in the fifties and sixties off course, the CIA and the Department of Defense were very, very interested in all psychedelics, LSD, all of them because they wanted to better understand the the their mind altering properties or whether they could be used to kind of get secrets from people. Um, we don't know anything about what the outcome of that research was. But what we do know is that in the sixties and seventies, M. D. M. A. Surfaced as a drug that was used clinically my therapists on. But it was absolutely It wasn't illegal to use m d m a. Then was there FDA approval or was that not necessary? No, There was an FDA approval, but it wasn't meaning. It was just used off label. It was used. And it was It wasn't anything in the literature that wasn't that much in the literature. No randomized clinical trials like we're used thio but kind of word of mouth on its spread. And actually, it was called Adam because it was people felt it restored patients to their innocents state. It was actually called empathy because M. D. M. A. Is actually an intact region. It's a drug that increases empathy and connectiveness and pro social behavior for yourself and others. Just I want you to continue. But for people who are listening, some people will recognize the drug names. Some will not m d M. A. Though many people associate with Ecstasy, the party drug or the recreational drug, Is it the same thing? If not, how is it different? Well, yes, when the drug started to be used recreationally, which wasn't until really the early 19 eighties. The manufacturers of MGM A didn't think empathy was a very good party drug name. So they actually changed it. And so that's how ecstasy M d m a got its name. I live on the Upper West Side. I think empathy would have gone over really well. Yeah. So anyway, that is what happened there. Um, So, um, it was used clinically quite a lot. And the the story is that a chemist by the name of Sasha Sheldon, who's known as the godfather of psychedelics, was introduced to M d. M a. And he synthesized it. And 1976 and he tried it himself. And he, um, thought it was amazing that it put him in a state of tremendous self reflection and self honesty. And I actually nicknamed M d. M a. His low calorie martini. But he was very taken with the amount of self compassion. Onda how unpleasant memories were less disturbing, and he really couldn't wait to tell his, um, psychiatrist, his psychologist friend about it. Um, and he asked his friend to try this drug, and, um, he did, and he was about to retire. But he basically said, this is amazing. And he personally distributed to something like 4000 different. Um, therapist. So this was definitely being used a some point because, um, Sheldon published the synthesis directions. This became available for people to use and then actually, um, misuse and abuse. And that's when in the eighties, the DEA and the FDA decided that they would have to make this drug illegal. You know, it's a tangential question, but I'd like to ask you or any of the others could answer. But when that happens, when a drug begins to be used recreationally or when a drug begins to be abused generally, is there any kind of cost benefit analysis done at any of the institutions that regulate? To say, you know what, it's true this is the cost of having access to this drug. But let's wait against the benefits and all the different channels of those benefits. Does that happen? That did not happen with MGM A. Um, Actually, when the d a. Of declared its intention to make m d m a illegal, many clinicians tried to petition them to make it a Schedule three drug if they were worried about abuse. Because a schedule one drug means that you don't think that the drug has any therapeutic benefit schedule Three drugs means you're concerned you don't want anyone toe be able to use it, but that there is therapeutic potential there. And what happened was there weren't a lot of data. If you go on to Google Scholar or Pub Med, you will not see a lot of data before 1985 that supported a decision scientifically to make this drug illegal. It was just a concern that people were liking it too much and potentially misusing it, and potentially could leave toe other behaviors. Those so they those same people have never looked at alcohol consumption. Apparently, however, well, you know, I mean, what's really interesting here is that the clinicians actually petitioned the d A to change its mind. Rick Doblin, who I mentioned before tried to sue the D A and the judge that was hearing the case actually sided with the petitioner's to try to make it a Schedule three. But it was overruled. Why? Because there weren't any clinical data, the word demise, clinical trials. And that's why setting up a center, a Mount Sinai and being able to do the research. It's so critical because in the absence of scientific data, then things happen for political reasons or social reasons. But they're not evidence based. They're not based on the science that needs to guide these kinds of decision makings were talking a lot these days about following the science. And what's really good now is that there seems to be data now emerging from Phase two and Phase three trials that are going to be what's necessary to make the FDA hopefully be able to approve M. D. A. On the basis of its therapeutic, uh, potential, and tell us just very quickly again, we've We've glanced at it a couple times. As James said, the treatment with ketamine is medicinal. The treatment with M. D. M. A. Is, as I understand it, it's to open the doors of perception slightly to allow psychotherapy to get at the Depression. Is that about right? Yes. If if you put in the exact right state where you know you're not afraid of your emotional reactions or your memories, what you have maximum interpersonal trust and minimum self blame or guilt or any of those things. This is the state that is a perfect place to be in order to start processing very difficult traumatic memories and really catalyzing a therapeutic process. So, unlike ketamine, and James told you about how it works in the brain, I could tell you similarly about the molecule of MGM, and I could tell you about how it works in the brain. But I'm not sure that those short term pharmacologic effects really explain what happens. And you might ask, Why do you need a drug to catalyze the therapeutic process? And the metaphor that's often used for that is that psychedelics to the mind are what the telescope is to astronomy and what the microscope is to biology. It's not that all of a sudden you see things you're hallucinating, things that didn't exist or that aren't riel. You're actually allowing yourself to have a tool so that you could really see things that actually are there things that are really important that really aren't that obvious or cannot be looked at in any other way. And so once I started to understand that, that was the purpose of of M. D. M. A. It really clicked into place as something that is very necessary because trauma survivors with PTSD they don't wanna look at their traumatic experiences. They don't wanna look at the reasons that they're kind of stuck where they are, because it's very, very painful. Trump survivors also have a lot of shame and guilt and self blame, and it's just very, very hard, almost brutal, to try to think about doing that kind of honest reflection and in usually a short period of time. Most sessions in psychotherapy are about an hour or an hour and a half. Oh, them D. M. A. You have an eight hour session where you got a lot of time to kind of process it. And if you're the therapist, it's you. You're the therapist for the entire eight hours you have a co therapists. So the model that was developed by maps is that there is. There are two therapists, usually male and female, and there with the patient through the three sessions of preparation. Theeighties our M d m. A session, the three sessions of integration and then you do it again a few times s. Oh, it's not a quick fix at all, but but there's something about being able to do this in an eight hour period that's not interrupted and a session where you don't say Okay, our time is up just when you're getting to the good stuff. And the metaphor that I like to use for this is like pregnancy. It's like labor. So when you're trying, when you're in labor right again, just this treatment resistance, depression is not the greatest sell. I don't know. It s also hear me out here me out. Because if you're if you are in labor to have a baby, the last thing that anyone's going to do is tell you after the first or second contraction, while our time is up for today, they're gonna be sitting by your side until you keep going with the process and the contractions get closer and closer together on Finally, at the end of the day, you've got something. You've really got something important I do wanna Yasmine, I'm I'm dying to talk about cannabis with you, CBD and THC and so on. But I do have one more quick question for Rachel before we move on from M d. M. A. You Rachel are a scholar of and of research for years, PTSD. You are using M d m a to treat PTSD first medicinal e as a means to get their therapeutically. Just if you could answer very briefly. Is the M. D. M a treatment that you propose particularly useful for ptsd? Or is that the avenue you've pursued? Because PTSD is ah, particular specialty. Do you have any ideas about how useful MGM A would be for other Valenti's? Yeah, Thank you for asking. So we have just gotten our FDA approval so that we could begin a study, so we haven't actually treated anybody yet. Um, but we're very close now. That was a very big hurdle. And it is. The FDA has designated MGM assisted psychotherapy breakthrough treatment for PTSD, but I don't think that this is going to be restricted to PTSD. I think that this is a very, um, powerful way to foster psychotherapy for almost any condition in which life experience contributes to this to the symptoms and then I don't know of any. We just doesn't write other conditions may not require eight hours sessions necessarily. Well, no, that's how long the that's how long the journey last. So it's the kind of thing where once you take off, you can't get it off until the plane lands, you know, bring a book. Okay. All right. Yeah. I mean, so yeah. Most people listening, I would say everybody listening is familiar to some degree with marijuana and its history and uses. Um, many people are familiar with THC. Probably more people now are familiar with CBD, so just give us a quick, taxonomic lesson. What's what? What does what and why are you working with with CBD? How is how is that different? So the cannabis plant has over 500 chemicals over about 140 of them are cannabinoids a Z. I said before THC which many people on the street note that's the cannabinoid that, um is associative That induces the high, the rewarding effects, other cannabinoids and and THC is the most concentrated cannabinoid in the cannabis plan. Unfortunately, over the decades the cannabis on the street, the THC concentrations have increased tremendously. So you know, even compared to a few decades ago, it's nearly 2000% increase in in the THC concentration a same time. CBD cannabidiol is the second most concentrated in was the second most concentrated in the normal cannabis cannabis plan and the concentration of cannabidiol on the regular candidates. That's, you know, smoke recreationally has gone down over the years, So that ratio So you have a much stronger THC to CBD ratio. So unlike pardon the interruption, but was I assume the THC was increased by selective breeding for the purpose of making people right, making it more concentrated Exactly. What about moving the high? What about the CBD decrease? That was that just a side effect of increasing the THC. That was an initial side effect, however, as people started to become more interested in in CBD. So CBD does not induce the high. So sometimes people say, Oh, we've been, you know, taking this really great CBD that makes us high. You know, you're not, uh, you somebody has not given you, um CBD cause CBD doesn't make you high mhm in fact, you know from the early studies that people started looking at other cannabinoids, then THC, one of the things that initial studies show that it's even have this anti anxiety effect. So that was one of the first things that people started to see. And then they started to even look at it for psychosis so that they could see that it seemed to have anti psychotic properties. So those were the initial things that people saw. Um, and like I said, for our studies, it was in a in a bit serendipitous because we just wanted to study another cannabinoid when we were making all these conclusions about quote unquote cannabis. But we were really studying THC and THC is known to also induced psychosis. And depending on the dose of THC, you people say, can reduce their anxiety. But it often exacerbates there. There's a lot of variants in the population. Correct? Absolutely. But it's often dose dependent. And so when we saw this in a way, you could say the yin to yang off how THC and CBD tended to do not opposite things, but in because you know, for the rewarding effects they had opposite things for even the anxiety for the psychosis effects. So we wondered about in regard to addiction and looking at opioids And there, um, CBD tended to do reduce craving reduced anxiety that in our first clinical studies, when was your first clinical studies of using CBD to treat opioid addiction? Eso We first did a safety studies. So unfortunately, cannabis azi Everybody knows until recently we have gone, you know, in this country we have gone from prohibition off, um of cannabis used to. Now you know, many states legalizing the use of cannabis on those have been more recent years. So when we first started to look at cannabis or cannabidiol, I should say, um, it was still considered onto the cannabis and was a schedule one drug meaning, you know, it was very difficult. Thio there a lot of hoops that you have to drum through as a as a researcher toe work with a schedule one drug. Even if everybody on the street has access to it, it's tougher for us to. And supply, I understand, is limited, right? Isn't there one farm in Mississippi that grows all the research grade marijuana? I may be right for candidates, and that's changing a little bit. But yes, for cannabis. But for Cannabidiol, there were very also very few companies back then, making cannabidiol at that time. G W Pharmaceuticals, um, was one of the first companies really looking at the medicinal aspects of cannabis, not for recreational use. And so we were able to work with their product to start and the F d. Um, we first had to do a safety study so that if someone had cannabis and they also had taken an opioid, could there be a negative interaction? So we first did a safety study in about 25th 2015. It finished, and then we finished our on. Then we did a pilot study around. That's about five years ago. And then, um, two years ago, we published it. Last year. We finished a little larger studying, still not large, but we replicated the results where we showed that CBD reduced um, que induced craving and cue induced anxiety. And people who have a heroin use disorder on DWI focus on cues because people don't realize in addiction, it's not necessarily that people are. It's not the reward that drives addiction. It's a lot of the negative states and the craving and anxiety and accusing your environment trigger. Ah, lot of the craving. And this is one of the things where often for treatments of addiction, we either go for harm reduction. Where we we try for substitution therapies, which have exactly methadone, and they've saved millions of lives. But they come with their own problems because they themselves are a scheduled drug. They themselves can, you know, um, have addictive properties, and they should be. They have to be monitored clinically very carefully. Eso we're looking trying to find nonaddictive new therapies for addiction and CBD fell within with okay. And are there other addictions besides opioids that you're considering CBD to treat alcohol, Cocaine, etcetera? Yes. So other groups have started to look at. For example. Um not surprisingly, cannabis use disorder. People are surprised to know that cannabis use disorder about it's actually pretty high in this country. About 30% of the people who use cannabis develop a cannabis use disorder, so it's similar to other drugs like heroin or cocaine that you can get addicted to it. Many people think you can't get addicted to cannabis and studies air showing now that CBD a recent study came out showing that CBD did decrease, um, cannabis use and increase the abstinence period with cannabis. There also studies with, um cigarettes for nicotine use and also for alcohol. They're not that many studies. Unfortunately, this is the thing Ah, lot of these air done. For example, a lot of the alcohol studies have been done in animal models s. So far we haven't seen there. There are a number of clinical studies about to start so and those animal models also showed potential benefit of of CBD, so we'll see whether or not the clinical studies replicate. So let me let me now pull back, and I'll invite anyone to answer any question. Um, But for the three of you, um, I guess I guess what I really wanna ask is for you to hoist yourself on your own petard is by by which I mean in each of your cases. And I realized the three are very different from each other as best as I understand it. And and I appreciate that there are different drugs. Obviously, they're different mechanisms. It seems like you all have slightly different mindsets, your philosophies of thinking about how toe how to use these. Um, can I ask you whoever is willing to tell me what's the most legitimate criticism You've heard of your own research, indoor treatment, whether it has to do with efficacy or potential for abuse or whatnot? I mean, Stephen, I can jump in on that one. I know we were chatting a couple of days ago, so I was sharing that when you know, when we were when I was first. Get involved in the studies that, you know, you mentioned bravado in the approved treatment, but, you know, years before that at Mount Sinai and a few other places, we were studying intravenous ketamine, which was seen as it's a drug of addiction. It's a potent anesthetic, Um, and the people in the elevator, what you were working on or did you keep quiet? Well, in those days, we kept it a little bit quiet because, you know, there was a lot of there's a lot of skepticism in the field. I mean, you have to remember three idea of taking someone with a treatment resistant chronic depression, right? That hasn't responded to many drugs, maybe hasn't even responded to electro convulsive therapy. You give them an injection of an anesthetic and their depression scores, you know they have scales To measure these things is, you know, they basically look like they're going to what's called remission, where they don't have depression. And, ah, lot of treatments and medicine over the years sort of have this dramatic history, whether these sort of awakening effects. And, you know, in the early days we saw this in the early trials and and the studies were focused on give one dose. The next day you see them and sometimes it, you know, it wasn't always the case, but sometimes, I mean, they would walk in the clinic and they looked like a different person. Their face looked brighter. Um, no one had seen anything like this before. Probably rightly so. The scientific community didn't believe it because it didn't fit with the paradigm. Right? Uh, antidepressants take, and you don't think they were just doing ecstasy at night when they went home? Maybe that explains it because, you know, antidepressants take weeks or months toe work. That's the mantra. That's you know, since the early days of antidepressants, Since the discovery of SS arise serotonin reuptake inhibitors in the eighties. Um, we started patient of medicine. We say hang in there for a couple of weeks. You might feel a little worse. It first. Um, but hang in there, You're gonna feel better in a couple of weeks or a month or two. That was not satisfying, but no drug company know no one had ever identified a medicine that really changed. That was outside that mold. So here here was this ketamine finding. People didn't believe it, and we were the first group to say Okay. So for years, people have been studying one dose. Well, what happens if you keep giving it? So we sort of took the the model of E C. T. And said, All right, we're going to give it not once, but we're gonna give it on a Monday Wednesday, Friday schedule, just like you'd give electro convulsive therapy for severe depression for a couple of weeks and see how they do. And I remember. And Yasmin probably remembers this. I remember presenting this data at, you know, psychiatry conferences. This would have been 2007 and people come up to me predict particularly addiction. Researchers basically say right and say And I was a research fellow at the time. And Mount Sinai People basically say You're crazy, they have depression now. Now you're giving them another problem. So when I look at where we are now with a drug is a ketamine drug. I mean it is. Ketamine is approved by the FDA for the treatment of depression. When I think about just a few years ago when people were saying This is not a good idea and and there are still people that are saying they're still watching E I was one of e. Why was that? Because I am an addiction researcher. E didn't want to say, but yes, please eso you know because and everything comes back to this is what's important dose matters. And many people now think that all of these psychedelic drugs that they can now they hear these miracle stories and that they can now just do this at home or these drive by clinics. And it's not so. I was worried because we see the opposite side. We see when people recreational use these at higher doses at high doses, and you know have significant problems. So I was very skeptical. So I was the one with my hand up. Yes, and Yasmin was very gentle And, you know, really a mentor to me in those days when pulled me aside and said, You know, just make sure you know everything. You're going slow your so, um and and and Steven just I want to circle back to, ah, question you had earlier about does the FDA way the risk because here was a drug that was being put up under consideration for approval is an antidepressant with a known history and documented abuse potential that there's no there was no debate about that. The FDA knew this theory. FDA worked with industry to design all the studies that they thought would, you know, sort of satisfy their risk. Um, there was an interesting article in the New England Journal of Medicine actually written by some of the regulators at the FDA to explain their decision. There's been a fair amount of controversy around it. Um, and they basically said, Look, way know that their risks. James, I have to say, you are a very clever fellow because I invited you all to each offer the most legitimate critique of your drug and what I do. And somehow you ended up still having ketamine be the hero of the story. But no, I respect that. I'm totally okay with that. Let me let me ask. Similarly of Yasmin and or Rachel, Um, you know, I guess One way toe. One way to think about this. Rachel with M. D. M A. Let's just look down the road a little bit. I have no idea how this would actually work, but let's say there's approval. There's treatment, there's widespread treatment. It gets back to the way it was in the eighties. Or maybe even much, much more. And then, of course, we see that things are, you know, there's always the possibility of overuse and abuse. And you know this country, the world really has such a complicated history. When it comes to drugs that are allowed or disallowed, alcohol is now allowed, and it has demonstrably done much, much, much physical and mental damage to billions of people. Uh, opioids were not only allowed through medical channels but were promised to be nonaddictive. Many, some of them at least and turned out to not be. And we're seeing the collateral damage from that now. So let's pretend that that's my position, that there are drugs. There are legal drugs which are already being abused. Often, I've got one that we may be wisely made illegal back in the 19 eighties. And now you, doctor, you who would like toe to bring this back. I understand in a controlled therapeutic setting and so on. But I'm concerned about the welfare of our population, and I don't really want a possibility of a party drug becoming so widely available to that. You say what? Yes, Well, to that I say that if there were other treatments that really worked for PTSD, this wouldn't be such an emergency. But it is an emergency and part of the reason that current treatments just don't work as well. You get a little bit of a symptom reduction, but that the gains may not last forever. You may find yourself needing to come back into therapy, um, because you haven't gone through the process of being able to look through that microscope, but what you need to see and be ableto kind of accommodate and make space for it in the psychedelic field. We talk a lot about something called Set and Setting, and this is a very important part of the conversation. Set refers to the intention that you have when you take a psychedelic and setting refers to where you are when you take that psychedelic. If your purpose of taking a psychedelic is for healing, then the psychedelic will be healing for you. And if you take this psychedelic in a setting that is conducive to that healing with the proper trained persons that can help guide you through it, this is safe. In fact, in the Phase two and Phase three trials, uh, the first, the side effects that have been noted very, very benign, the kind of things that have been noted in party. You sew them D m a. Have to do with dehydration or hypothermia. I mean, they have to do with a lot of other behaviors that when you're partying, might be bad for you, and not simply the fact that you're taking the M. D. M. A. So from accountable perspective, there's nothing in the molecule that we haven't seen before and that we are We already are used are using, um, in our current treatments for people so all drugs could be abused. Even a drug like aspirin could be used for purposes of suicide. Um, the reason that we study what we study, the reason we're here. What psychiatry research is about is to help people understand how to use medications properly and when not to use them. Eso The idea isn't just completely hear no evil, See no evil. Don't don't get better, you know, because there might be some risk that somebody else might misuse. A substance theory idea is to be careful and thoughtful and scientific and get the information that is needed in order to be able to give people proper information. When you just say we're when you have a paternalistic, we're worried you might abuse it. I mean, what is that saying? Really, that's not such great messaging, but certainly psychedelics should not be in the same category as cocaine or opiates, heroin or the crystal meth. I mean, those are our compounds that you've got to really worry about. But I'm getting may Psychedelics are generally not like that, and you know what? It's hard to abuse psychedelics. It's hard to take them every day. I mean, if you know it's really doesn't work that way and people that might take something recreational Lee, we don't know if that is pure M. D. M. A. We don't know what that's cut with. We don't know if the ecstasy that you buy in an unregulated way doesn't have methamphetamine in it, or caffeine or cocaine or anything like that. When you regulate and make things available through a legal channel and provides science and information, then you're giving people tools. I'm curious. I'm curious. This is a question for Rachel or any of you. When you talk about how regulation works or sometimes fails, I'm reminded of it seems a long time ago now because we've had co vid since. But, you know, the E cigarette crisis from just last year was really interesting because, to my mind it was an argument for good regulation. And there's been kind of no regulation because, as it turns out, most of the most of the devices that were hurting and killing people were, as I understand it, black market THC pods and not e cigarettes. I'm curious weather. First of all, if if that's not an accurate summation. Someone please correct me. But I'm also curious how each of you may look at your regulation in that regard to see where you know where you invite the right kind of regulation. Because because the absence of regulation could lead to really terrible outcomes. E I just want to finish the thought on the M d m a in reference to that question, because the way that they're proposing to legalize M d m A, there's an enormous amount of risk mitigation strategies that are in place once theme FDA approves it, it's gonna be almost impossible to get unless you've gone through the training to become an M d. M. A assistant psychotherapist. Um, and you're gonna be able to get the M d m A for the first five years from only one place in one source. S o. I think that, you know, in some cases, regulation is good in other cases, you know? Maybe not. But I just wanted a really say that when the FDA takes on something like this, they're really thinking about how to do this safely and properly. And, um, to minimize, um, adverse events. Yasmin, it sounded like you had. Excuse me. Something to say about regulation in that regard? No. Absolutely. And I do think at the end of the day, the role of government is to protect its citizens. So I completely understand the FDA and you know, all of the government regulations or when they think about the regulations that are needed. And we don't wanna be naive, it doesn't matter. Even if the FDA approves or not, There are people who will absolutely abused their companies already who are, you know, thes terrible companies making products and making people think that those their products are going to be, You know, the scientists approved medications. There's so many things being sold on the Internet. So there is a market for people to get bad products that will not be from the sole source that the FDA will improve. So we we know that people are gonna abuse or misuse no matter what the FDA says. And even if, for example, for Cannabidiol, like I said now it's everywhere. You know, When I started, no one knew what CBD waas. Now everybody does, including the grandmothers, you know, and but we also have a lot off companies making CBD, Andi their CBD, the things that are in CBD or not even CBD. There's even synthetic cannabis that's put into it. There's lead, there's mold. So you do need the government to make sure that the products that air being used that are available to the citizens are are products that are safe. And that is that circumstance that you're describing with with CBD is that a product of the lack of federal federal legalization? So this is states legalized. But then there's essentially very little regulation. Yes, Is that the way we're? What about what about state health departments? Your state health boards, though, don't they write regulation? They do. But I mean again, you know. So, for example, in New York, New York State, New York City, that people were putting CBD into food and they were able to go in and stop some of these restaurants and someone that we're doing it because that is illegal. It's eso you. Safety is a key thing for both from the state and federal. But from the cannabis side, there are the policies. The state policies don't necessarily match with the federal policies, and that's a huge problem, Um, in in the field and for me. I think that you know the question you asked in terms of the risk benefits, Do they calculate that they don't really, because of the first thing that the stuff, it's about protecting its citizens and they look at anything being. If a few people die, that's enough. So let's, you know, let's make sure way block this. However, they should work with scientists because information is critical because it was really sad. People are going to go out as soon as they hear, but Rachel just said, Oh, this can. They can now deal with their their long pain and they're going to start going and say, OK, let me go find this. If it's not in my Rachel's lives far away, I can get to Rachel So you know we'll find somebody. Yes. So if they were, if the FDA work with scientists to have more fast track research done on these products, we could have have the answers to provide the clinicians with the answers to provide the general public with the answers. I think it's a slow movement that sometimes makes it worse. Do any of you have faith that the very rapid acceleration that's, uh, involved in the search for a covert vaccine, which will obviously go through the FDA. That that may change the kind of mindset of speed of approval generally. No, that's a no. From you know, I think it might. Rachel? Rachel? Yes. And James years has already approved, so you don't care, right? Well, I think I actually was pretty fast. I think that was approved. And I'll just make a point about, um, Just picking up what? From what Yasmin said, um, again the early days before there was the nasal spray. Before there was FDA regulated products related to ketamine and people were trying to find an alternative antidepressant. They heard about some of the early research, some of our research and others. And these so called ketamine clinics started springing up. Um, sometimes they were anesthesiologist. Sometimes there were psychiatrists. You come in the office, you hook up on I V. Yet ketamine. The tip people such as Yasmin and many others and and and and even us made us quite uncomfortable. Bond, we got the question all the time being, uh uh, experts in depression and people would refer their treatment refractory cases, people again that have failed not just medicines, but also electro convulsive therapy. Kind of the patients that show up our families saying, Doc, what do I do now? Right? Um, do I go get ketamine? And if I get ketamine, Um, here's a big question that we struggled with and into some degree we have a little bit of information but still struggle with his. Let's say I respond. Let's say I get this injection of ketamine and I'm my Depression is gone often. It's maybe it just improved, but it's I'm better. Um, but then you probably have to keep taking it. So how many? How long can you take ketamine before you've got problems either develop? Yeah. And that That was one of the main problems. And one of the main hurdle turned out what turned out to be the answer that satisfied people on that. I mean, it's it is addictive. Yes, I mean, but in the dose addictive. But in the dose that's medicinal. I assume it's not. Is that the idea? I'm not sure we completely no, I think before the FDA trials, which I think we're set up completed. And Mark, Like I say that I don't know how many years, but it wasn't It was pretty fast. It seemed many of us were surprised in some way how quickly it got to market. Um, but the FDA required the sponsor to do studies that no academic, you know, we study 2050 people, 100 people to hunt people they studied, I assume, north of 1000 people to get treatment weekly or every other week for a year or two and often is the case. Three FDA will grant approval to market a drug with strings attached. That says, you got to keep following these people. You gotta have a registry. You gotta have a whole apparatus in place and the FDA wave these things and they said, um, people are suffering and we're going to give this a try. So is ketamine a forever drug? I If if I start to use it, I'll probably use it for the rest of my life. You know, Stephen, so often patients will ask. We'll ask us if we say we recommend a certain treatment. They say, Well, how long you have to take my antidepressant. And the answer is, the data suggests that if you stop if you were, if you respond to your antidepressant and then you stop it, your chance of having a relapse or recurrence is substantially higher than if you stayed on it. And those those studies usually often look out a few years and ketamine looks to be the same. Rachel, can you talk for a moment about s So this strikes me is one of the one of the many differences between not just ketamine and M d may per se, but the treatment model one is medicinal and the other is a medically aided therapeutic eso Can you just talk? So I have two questions. Actually, I want to know how this works. I want to know how the drug would be administered, how the psychotherapy would be conducted, and then what happens next? Is it 11 or 28 hour sessions and I've solved the problem. I assume it's not that simple. But before you get into that, you mentioned that the reason that M. D. M. A. Is so necessary is because the plate of the people suffering PTSD is so grave and that There are no other options, so you're no good option in answering. Sorry. Thank you. So in answering my first question, my second question would be Could you start by describing who's a median member of the population that you're treating and give us a picture of that patient and what the needs are? Yeah, I mean, so I'll take your first question first that you wanted me to answer second, because it's more natural. You don't want to jump to jump off of what James said. The difference in the model is that we're not proposing that the M. D M A or the psychedelic, whatever it may be, is something that continuously has to be taken just like back to the pregnancy metaphor. You don't have to keep having contractions. Once you have the baby, you might have to raise the child, but that's a different thing altogether. And so what? The idea here is that there's a blockage and that you keep redundantly going over and over and over, kind of like ah, hamsters running wheel or in a treadmill that you just can't make a breakthrough, and somehow the ability to have this kind of a process enables a breakthrough. And then what happens after the break through is up to you, and there's probably more to be done. But it doesn't require the m d. M A assisted psychotherapy any longer, so it allows you to now look at things and approach things a different way. So I think that that's really critical. So for whom? Who? So who should be taking MGM? A. I think that is why we have a center so that we will be able to examine exactly that issue. And in the phase two trials. You know, one of you asked the criticism question before, I mean, one of the one of the things that you could potentially criticize is this idea that the people who would be attracted to these trials might not be the people who are afraid to take psychedelics. Um, and so that's that's a problem. And who might those people be and what kind of education and reassurances might they need? For example, I've noticed that there is a not a large percent of the people enrolled in those trials are people of color. Um, we got to rectify that by doing research that can target and address specific issues that people might have and really understand. What are the barriers? What are the expectations? What are the fears? What are the concerns? Um, but in terms of for whom this is safe, there are some medical contraindications. That's what patients are screened very carefully medically before they enroll in a study. Um, but barring that from a psychological perspective, there don't seem to be too many contra indications. Um, many studies that many drugs that we study, um, exclude patients with co morbid illnesses to the condition we care about or suicidally Ah, whole list of exclusion criteria. Um, that make one wonder for whom is this drug s. So I think that this isn't a drug therapy. This is a drug facilitated process. And it's a paradigm shift. It's a revolution. It's a way to do something different. It's not just saying here's yet the newest version of the same idea, you know, meet the new boss. Same as the old boss. What? You just you want to say it? What you just said about the exclusions suggests that the try alot of phase three trial is very hard to design, though. Yes, for this drug, but the face three tri ALS has a specific goal in mind, and that goal is to get FDA approval. Now. That's the first domino that really should fall here. But once the FDA approves thisted treatment, then we can start to really work with it and ask the hard questions. Um, the therapeutic protocol that maps is designed for Phase three has patients doing three sessions separated by three sessions. A total of 12 psychotherapy, 90 minute sessions. So that's another area of study. I mean, could you get by with less? Do some patients need more? Um, do you need to therapists? I mean, there are a lot of different things that we have to learn, and then we have to learn the mechanisms of action we have. Thio for the phase three trials were involved in doing an epigenetic studies so that patients are collecting Look, uh, the investigators are collecting samples from patients before and after the trial epigenetic study, meaning you want to see how this affects the germline or whatever. It's called the germline so much as the way that gene's function. So, for example, in my lab 15 years before I started being interested in psychedelics. The work that we were doing is studying the neurobiology of psychotherapy. We take Ah lot of blood samples and do brain images and people before they start a course of psychotherapy on Look at them after psychotherapy and then three months later, because we're not interested in how the drug works were interested in what are the biologic changes that consolidate recovery or resilience on DSO? Ah, very important question to ask is whether this process is just accelerated or catalyzed more quickly. But it leads to the same goal in a different and more efficient manner. And the other thing about the M d. M A. Is that when they've done long term studies and they've looked a year and a half later, patients still don't have their PTSD. 75% of the patients that didn't have PTSD at the end point still didn't have it up to 72 months later. And that is not something that you can say for a lot of treatments. That's impressive, because once you've done what you have to do, once you've looked into that microscope and seeing what you have to see, you don't have to keep looking and seeing it. You've got your answer. That's interesting. Yasmin, can I ask you as an addiction specialist, I'm just curious whether, you know, you talked about coming to see BD roughly 10 years ago or thinking of isolating CBD from THC and so on on, I'm just curious. Were you at all philosophically or in any other way opposed or reluctant to use the component of a drug even though it's not the component that makes you high, But it's associate with a drug that people used to make you high. Did it feel a little bit like you were, uh, somehow taking a slightly less pure approach to treating addiction? No, I think like, yes, I know I should say a zay said I was studying THC for a very long time. And the pro THC, the pro cannabis people hated me because he saw, like, the developmental effects on then. Now the pro cannabis people love me because I should. C b d S O S o. I think again, in a way, people don't believe this because they think that you as a scientist, because you might get money from the n I h. Or if you just said from different funding sources that you're biased. But you taken agnostic approach. And I think you know both James and Rachel. This is the whole thing. The question is, you have a disorder that there people dying for opiate use disorder. You know, the cove it pandemic has not erase the fact that there is an opioid epidemic with people dying in droves. So do you keep doing the same thing? Or if something shows you that there may be a different option, then something that you had never thought about before And even if it may be another drug that this drug actually is not addictive, So it you know. So I I thought about the fact that it comes from cannabis, But for me, it was I was agnostic by the by the chemistry and what we knew about CBD, or at least what we had started to know about CBD that it had these positive facts. And actually, a number of people are also using CBD for PTSD. There a number of clinical studies going on with now with CBD on different anxiety disorders and ptsd. Rachel, do you have any. Do you have any quick thoughts on CBD and PTSD? Do you know much about that? Well, the word about about cannabis and PTSD I don't know specifically about CBD is that it helps some veterans alleviate their symptoms. They, they that I've heard a lot that it helps them cope with the day to day. Um, but it's not a cure, it's not. It's not a cure. It all. And then the question is, Is it making you feel good so that you're using it as avoidance the material that you need to be doing? And so you know, im tourney? Because on the one hand, somebody suffering you want them to feel good? But on the other hand, it's exactly this kind of approach that we have to reexamine with all of our medications in psychiatry. Is that are we Are we just trying to reduce symptoms and not trying to understand? You know, a lot of people that do the M d m A. Even though it's called Ecstasy, do not experience euphoria. There are moments when you feel very connected and very good, but there are also some very difficult moments, and some people who take psychedelics have very difficult trips, even if afterwards, they say, that was one of the most meaningful things that ever happened to me. So the processing of negative emotion and looking at very difficult events could sometimes be really painful. And, ah, good trauma Focus Therapist helps people through the pain again. Contractions painful, needed necessary. And so we don't wanna numb people out just because the complaining of symptoms we want to get to the root of it and be able to really understand what those symptoms air trying to say, what needs to be worked on, what needs to be done and for certain kinds of psychiatric conditions. Of course, if it's a chemical imbalance, you balance it out. If that's the problem, that's the solution. But when it comes to things that really are about the stuff that happened to you understand, it's different. It's an important point. Yeah, it's been conscious as you quickly we heard a little bit about ketamine, dosage and kind of the cycle of application. The same for M. D. M. A. And therapy, which is obviously very, very different. What do you based on what you know so far, um what uses suspect would be the appropriate dose and frequency for treatment using CBD for, let's say, opioid addiction or other addictions or anything, even anxiety, um, and psychosis. We really don't know. I mean, so the studies that I've done and that we now are carrying out one of the largest were, um, studies. Now face to again on DWI will have hundreds of people. And so we'll see. But everyone is. Um, we still don't know the doses we're looking at, you know, different dose ranges. We're looking at the duration. One thing about CPD that's very interesting from a treatment perspective is that even, um, in our animals that showed us a few weeks after their last injection, we could still see that the effects were still but still, they're the same thing in our human study. A week later, they still show production in their craving and anxiety. So there's something that it doesn't have to be on board daily. So those are things that will be all well, also be testing in terms off looking at, um, you know, people, they do a treatment study, and then that's it. The study study participants go that's it. It ends, but we'll do follow up studies to see how long the CBD effects last. But there's studies going on now all over the world to see the dozing and so on. Um, James, this may be a total misunderstanding or oversight on my part, but the way this conversation has been going, it sort of sounds as though, uh, Yasmin has has has learned a lot, but has a long way to go. Has a lot of work to Dio. Rachel has has learned a lot, but has a long way to go in both cases, including approvals. Whereas you the ketamine guy like you're done like it was approved, I assume that's not actually the case. However, Can you tell us what your mawr or next for ketamine? Well, you know, I do feel a little bit like we used to be, you know, the edgy kids, right? We used to be out there people to come into conference back. I can't believe you're doing this now. It's like the FDA approved drug like man. Or instead, um, you know the idea of the first? I mean, part of what was I think exciting to the scientific community early on with ketamine. Waas. As I mentioned, this was a drug that broke the mold in the sense that it worked on totally different brain system. It worked on totally different timescale, and we still didn't know what caused depression. And so, for me as a researcher, one of the most exciting things was what could this teach us about depression and that And again, I think, if you would take, you know, done polling in 2005 or six or seven and say, What are the chances that in, uh, you know, five or 10 years academy was gonna be on the market? No, we always thought, What could this teach us about depression, and what could we learn about ketamine to spur new treatment discovery for patients? So one of the things that happened early on was that company started to get interesting, interested in trying to develop drugs that affected the glutamate system, the NMD receptor in these different ways, and there's been a whole Siri's off. It's It's interesting that a ketamine again derivative for lack of a better word, is actually the thing on the market in terms of glutamate based treatments for depression. But there have been a whole slew of and will continue to be off medicines understudy that the hope is have potent and rapid therapeutic effects for severe forms of depression for suicide. Ality. We didn't mention that, but that won't have the side effects. They won't have addictive potential. They won't cause this acute, um, confusion for lack of a better term sedation dissociation that ketamine causes. I should just say one thing for the audience to make sure, because one of the strangest things about ketamine is that when you take it, at least in the in the for patients with depression, they when they first received the injection or or the nasal spray. These days, um, it often does not feel good. They feel they feel confused. They feel out of it. They have to sit. They have to be monitored the clinic for a couple hours. Um, the change in the mood state, uh, comes on later a day later, sometimes a few days later. In the early in the early studies, actually, 72 hours after a single dose was the largest effect on depression. That is that side effect every time you take it or is there a habituation? There seems to be a bit of habituation, but it z for most patients, and it remains to some degree. Um, but this disconnection in time with because Rachel mentioned, you know, you don't wanna get numbed out when you take the ketamine and it's in your brain has a very short half life. For 40 minutes or so, you're numbed out, right? You're you've taken a small does of an anesthetic, and early on, people said, Oh, sure, they say they're not depressed anymore. They're just numbed out of their confused. But that what they didn't understand what the drug was doing or what the design of the clinical trials, where which was to measure their mood the next day. Days later, there's no academy in their body, and they say, I don't feel like killing myself anymore. Another, another place to go with this and we've talked about this is that since in some circles, academy really is considered a psychedelic. The idea of academy in assisted psychotherapy is a great idea because it's not so much that people are numbed out, but they're having an out of body experience. And where does your brain go when you're also dissociating? And what are you thinking about? And I know that because we've discussed this, that that that during ketamine, some patients have recovered traumatic memories that have come back and talked about those traumatic memories. So this could be a very powerful tool. And Rachel has that not been tried yet? Not in the way that I mean it hasn't been published. I don't know. I'm sure people are working on this, But you see, if you do it that way, then maybe you could test the hypothesis that you can extend the time between ketamine infusions or ketamine treatment because you can convert it into identifying something that needs to be dealt with and not just simply reducing would. I don't want to say simply because it's a big deal when you have, ah, very seriously depression to be able to reduce your mood. But to be able to use the cattle mean for another purpose also, which is to go underneath and see what what psychological processes, Maybe driving the Depression in addition to the obvious biological Rachel, can I ask you and James do you think that your populations of patients are pretty similar in terms of receptivity toward psychotherapy. Mhm? I think so. E mean, most patients that we see in the clinic, they just want to get better. And they've often, you know, they've been through the wringer. Yeah. So if we said we have this program where you take this drug and you go through this therapeutic procedure, Yeah, I think that Z on guy will say just on the underscores. Rachel's point, the the way ketamine has been looked at and developed as a treatment for treatment resistant depression has been very straight biomedical model, you know, study the drug. What Rachel suggesting is a whole other way that it could and should be studied. And I agree. Uh, there was There's been a few small studies, actually Yasmin in in substance use disorders. I believe there There's a studying alcohol use disorder where they took, um, you know, good psychotherapeutic base, you know, motivational based treatment for alcohol. And they remember they've done cocaine and they they've given academy injection. When the therapy started. In terms of the now, that's a little bit different. Not that did they have the academy on board during the therapy? Not necessarily. It's like maybe a jump start to get the academy in one day. Then the next day you start your therapy because there's a whole emerging biological understanding of. You could give ketamine or drugs like it, and you allow the brain. Maybe that could last for days to be maybe more plastic. Receptive? Exactly. Yeah, that's one of the things for cocaine. So I mean, we James and I have talked about one of our attending Dr Swift wanted to look at for people cocaine users when they come in, Um, it's a huge. Their depression is severe, and you can't can't approach them. They, you know, whatever you're going to try, it's not gonna work. And there is no treatment for cocaine use disorder. And so, a study from Colombia, they had shown that ketamine an initial study showed promise. So James and I had spoken about Could this be just for that time period that that severe depression during that cocaine withdrawal that you know, you could then use that to at least shorten that that time and be able to them get them more access to treatment straight. It strikes me. You know, we're talking about using all these substances drugs to essentially repair damage or to a pair repair a condition that's, you know, grave serious. Um, are there any thoughts on using these substances or similar substances prophylactically on related conditions or not? I'm just curious. Well, for CBD, yes, it's being now studied for so many disorders. Um, uh, it's that not for schizophrenia, for not addictions, for the anxiety for pain. It's being studied for inflammation. It's being studied for Parkinson's disease is being studied for hunting for everything. That's one of the worries about CBD. I do think that it has medicinal potential, but now you know it's being studied for so many things. Obviously, it's CBD between stated to start, um g W They had carried out a large study for epilepsy for rare childhood disorders, and that's it is FDA approved on Lee for those disorders, and but now it's being studied for everything so or use for everything, even if it's used off label. So that's one of the worries that now it might lose its potential. And that's And as I said, it's now in your coffee and your water that just being in everywhere in society, it minimizes the potential benefit that this could have under you know what, The same straight clinical conditions. Rachel. Any prophylactic thoughts with M. D. M. A. You know, it's interesting because you just gave me an idea because it would be very interesting to go back to all the people that participated in the M. D. M a Phase two and Phase three trials and ask how they're doing with co vid because that would be sort of a naturalistic way to see whether having had this treatment really makes it easier for them to understand and cope with what's going on. So I think that there are naturalistic ways that we can approach that PTSD is hard to deal with. Prophylactically. Do you do it right after the trauma Thio try to do it and people who are at high risk for drama, which is all of us, especially when you say go back to them to see how they're dealing with Kobe. Do you mean on the mental health side? Physiological e would just questionnaire. I would just say I think I think that that's the critical question and that's an important outcome of successful treatment. How do you approach the next thing in your life? Um how do you approach the second arrow, so to speak. I mean, where people that live lives and things are happening to us in a very dynamic and fluid way. And if you're able to kind of take who one kind of process and really learn how to integrate it and really learn to forgive yourself and to have compassion and understanding for yourself and to learn how toe look through that microscope and understand your relationship to the world and everybody else. And oh, and your relationship to your own autobiography is that something that then generalizes to the next time? I would predict that it does. I feel your question. Yeah, I feel like you just composed Yehuda Amichai poem for us out of thin air. So that was Ah, beautiful reflection on on really everything we've been talking about. We've only got a few minutes left. I'd really just like to ask you all simply what did I fail to ask each of you about your particular quest that I should have Or what's one brief thing? Maybe that each of you would like to add before we have to wrap up. Yeah, I would want to just say, because I didn't get a chance to answer that question that you had about the funding, the government and all that. And one of the important things about psychedelics is that there's very little, if any, government funding for this right now because the government doesn't want to fund research and substances that are not legal. And so all the work that's been done has been what done through raised funds. And I think that that the public good of being able to support really important research and not have to worry about whether but funding agency likes it or not has just been a real gift. Thio Humanity. Good point, James or Jasmine. Whoever like to go first. Well, I'll just say briefly, You know one thing. We didn't really talk about suicide tonight, but that's ah ah, huge issue on DSO something in psychiatry. We're very focused on trying to figure out how we can bend the curve on that. Many individuals who died by suicide have depression. Um, certainly, uh, PTSD and and drug addiction. Many other things but on antidepressants traditionally have not been have had some problems. Um, some studies suggest that they could make suicidal thinking a little bit worse than short term. So, um, uh, I just wanted to say that one of the striking things early on with, um the ketamine studies is that if you look at the syndrome of depression, suicidal thinking is one of them. In several studies that was among the largest aspect of the Depression or the most striking thing. Even if patients still didn't feel great, they still had guilt. They still had aspects of their depression. They didn't have suicidal thinking. They didn't have ah feeling or a desire or urge to feel like they didn't want to be alive anymore. That was something that was picked up early by the scientific community. There's now drug development programs to try toe develop medicines for suicide ality, which is actually almost unheard off in psychiatric treatment. Usually, individuals who are suicidal are excluded from trials. You know, back to the comment of who's in these trials s Oh, I think that's just a very exciting area, that there might be something about this mechanism, this brain system that somehow will give us, um, a new anchor to develop anti suicidal medicines. That's really interesting and hopeful. Thank you, Jasmine. Is there 11 last thing from you, you know the time. But for me, I think one of the things that the stigma and you kind of mentioned a little bit. But to me, the stigma off, not a substance use disorders in general, um prevents people from even seeking treatment to start. And that is one thing that we have to deal with. But it's also the stigma off working with these drugs. Now that, you know, people think that Oh, we're just trying to, um, make people high, but we're not. And I just think that they dio dio as I said it, Zad. And so this is a thing. So you're talking about a group that's already stigmatized? They suffer significantly and their families in our society. And the stigma also contributes to lack of funding. Um, even though right now we have a good grand for CBD. But we fight this every day and the staff that takes care of these individuals with substance use disorders, The stigma is one thing in our society we have got to get away from, so that to me, is essential. It's a great point. Well, I'm afraid our 90 minutes are up. I could talk to the three of you for 90 hours. Um, it would be even longer than one of Rachel's, um pregnancy. M D M. A Sessions. Eso I Really I just thank all three of you so much for your time and expertise. It was really I learned a great deal on Thank you very much, Thank you. I'm sure our audience eyes as grateful as I am, I would like to thank the Mount Sinai Health System and especially Alex Collison forgetting this ball rolling. I'd like to thank W N Y C and especially Sochi Gen. David and Ricardo at the Green Space. Thanks also to the Freakonomics radio crew, especially married to Duke, who produced this episode as well as executive producer Alison Craig Low and our technical director Greg Rip in and are very versatile. Intern Emma Terrell Freakonomics radio plays on W. M. I. C. The the FM, 93.9 on Sundays at 8 p.m. And 3 a.m. A. 20 on Saturdays at 2 p.m. And the Freakonomics radio podcast is available. Wherever you get your podcast, we will be back next week with a new one. Until then, take care of yourself. And if you can, someone else to thank you very much. Good night. Thank you. Good night.