This episode was recorded live, via Zoom, in collaboration with The Greene Space at WNYC, our hometown radio partner. We gathered three medical researchers to talk about how a variety of drugs often used for recreational purposes are increasingly being used in medical settings. It is a topic of great interest these days — one example being Michael Pollan’s best-selling book How to Change Your Mind: What the New Science of Psychedelics Teaches Us About Consciousness, Dying, Addiction, Depression, and Transcendence. The substances we’ll be discussing today are ketamine, MDMA and CBD. The entire Zoom conversation lasted 90 minutes; and you can watch it above. This episode was edited down to podcast length.
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Stephen DUBNER: Good evening and thanks for tuning in. As you likely know, there are many natural and synthetic psychedelic substances. They have 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 Hofmann 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 as 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 unalleviated, in the form of scientific knowledge unattained. 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. They are James Murrough, Rachel Yehuda and Yasmin Hurd. James, Rachel and Yasmin, good evening and thank you so much for being here.
MULTIPLE: Good evening.
DUBNER: So, here’s the plan: I would like to ask each of you to introduce yourselves briefly, and then we’ll open up the conversation more broadly. So, let’s start with James Murrough. Would you tell us quickly about your research specialty and how that feeds into your clinical practice?
James MURROUGH: Sure, Stephen. I’m a psychiatrist at Mount Sinai and I did my residency there — started in 2005 — went on to do a research fellowship, and currently I direct a clinical research program focused on finding causes and treatments for depression and related conditions, such as anxiety. When I was just a trainee, Dennis Charney had started what was a very 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, I got involved in that.
DUBNER: Dennis Charney, we should say, is now dean of the Mount Sinai medical school; and before that, he did ketamine research at both Yale and the National Institute of Mental Health. So, James, you came to Sinai as a resident — and now fast forward for us.
MURROUGH: And fast forward 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.
DUBNER: And ketamine, it is, as I understand, a very popular surgical anesthetic, correct?
MURROUGH: Yeah, ketamine is a medicine that was synthesized and approved as an anesthetic.
DUBNER: But also a big party drug in some points in its history, yes? In the ’80s and ’90s? Maybe now?
MURROUGH: It’s still used recreationally. It’s actually classified as what’s called a “dissociative anesthetic.” And apparently that’s the only drug sort of approved by the F.D.A. that’s a “dissociative anesthetic.” It causes a unique, altered state of mind when taken at certain doses, and sort of a hallucinogenic state almost, and it got famous for folks taking it at raves and things like that.
DUBNER: Okay. So, for those of you keeping score at home, that was James and he’s your ketamine guy. Now, let’s move on to Rachel Yehuda. Rachel, would you tell us quickly about your research specialty and, again, how it feeds into the treatment?
Rachel YEHUDA: Well, I’ve been studying post-traumatic stress disorder since the late 1980s, and I’ve been at Mount Sinai since 1991. I think we were among the very first medical schools to establish a 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 epigenetics, looking at resilience. And in the course of that work, we’ve tried a lot of treatments and done a lot of treatment trials on PTSD. And those studies haven’t really provided great outcomes. And I heard about MDMA a few years ago—
DUBNER: You have to tell us how you heard about it. Because, like a lot of people, you first discovered MDMA at the Burning Man festival, I understand, yes?
YEHUDA: That is true. But my mentor in all things MDMA was Rick Doblin, who really encouraged me to go to the MAPS training.
DUBNER: MAPS stands for what, please?
YEHUDA: The Multidisciplinary Association for Psychedelic Studies.
YEHUDA: And they’re largely responsible for sponsoring all of the work that’s been done on MDMA in the last 30 years or so.
DUBNER: And just to clarify, MDMA is also known as ecstasy and molly and has been widely used recreationally. And Rachel, as I understand, MAPS offers a training program for medical practitioners who may want to use MDMA to facilitate therapy.
YEHUDA: Yes. And after I did the training and had some other experiences talking to people, I was very eager to bring it to Mount Sinai. There are so many questions about how it works, why it works, for whom it works. And it’s a whole frontier out there.
DUBNER: Okay. Let’s keep circling on and cover the basics. Yasmin Hurd, 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 how it’s used and in what kind of treatment?
Yasmin HURD: I am the director of the Addiction Institute at Mount Sinai and my drug of choice — actually, there are multiple. We actually have one of the largest clinical-addiction services in the country, treating over 6,000 people with opiate-use disorder. And I look at addiction from the perspective of what increases risk. And also I’m a neurobiologist, looking at what happens in the brains of people who have a substance-use disorder, and can we start thinking about novel treatments? And when we looked at risk factors — you know, early cannabis use — we see strongly increased risk for substance-use disorders later in life, as well as certain psychiatric disorders. And our animal models confirm that.
DUBNER: When you say your animal models confirm that, that suggests that the correlation between early use and later problems is not behavioral. It’s chemical, yes?
HURD: Correct. So these rats, for example, their mothers tell them to stay away from certain other kids. But they still develop certain sensitivities to opioids, for example, later in life. But in our animal models, we study THC, which is 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 an opposite effect. We saw that it actually reduced heroin-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. That was actually over 10 years ago, before CBD became so popular.
DUBNER: Okay, very good. So, I’d love to go around one more time. And I’d like to get from you a little bit of the background or history on the drug or drugs that you study. Because the story of how these drugs are invented or discovered, and then what they’re used for initially, and how they get repurposed a hundred 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 James, we’ll start with you again and ketamine, please?
MURROUGH: Absolutely. So ketamine has been known to the medical community for decades. It was actually initially synthesized to be an anesthetic and is used for that reason today widely. In terms of what this molecule is, it’s unique in terms of anesthetics and certainly it’s very unique in terms of antidepressants. There’s no antidepressant drug which acts like it does in the brain. This interferes with signaling in a specific type of receptor in the brain called the N.M.D.A. receptor that’s very important for learning and memory and what’s called neuroplasticity.
It seems to help brain circuits adapt to the environment. It’s part of the glutamate system, and glutamate is the primary transmitter in the brain, which excites neurons and makes them fire more, and that’s basically how information is transmitted in the brain. It looks like — jumping ahead a little bit, from brain-imaging studies and things like that — that if you give ketamine, it 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 in people, you can operate on them. And they 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 of consciousness at high doses. And initially a very small study, with, I think, eight people at Yale that was published in 2000, show that if you give an intravenous infusion of this powerful anesthetic drug, but at a low dose — 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.
DUBNER: And how long does that last typically?
MURROUGH: It only lasted a few days. And since then, it looks like it’s variable. For some people, it could last more than a week. But it’s certainly temporary.
DUBNER: Now we should say, there is one ketamine — or ketamine-derived drug — on the market now, a prescription nasal spray, correct?
MURROUGH: That’s right. A form of ketamine, if you will, a so-called enantiomer called esketamine, was approved last year as an antidepressant. And it was the first antidepressant approved which, from a chemical perspective, was not like the rest. The only drug that worked on this system of glutamate — rather than something like, for example, Prozac affects things like serotonin as does all the other dozens of antidepressants on the market. But this one is different.
DUBNER: As I understand it — correct me if I’m wrong, please — this is called Spravato?
DUBNER: Distributed or sold by Janssen. 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 there, correct?
MURROUGH: Yeah, that’s exactly right.
DUBNER: Okay. I understand you treat what’s called “treatment-resistant depression.” 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 twice a week and it is a medicinal treatment of depression. There is no psychotherapy attached to the administration of that drug, correct?
MURROUGH: That’s exactly right. So, “treatment-resistant depression” — and sometimes my patients remind me that that might not be the best term — because as psychiatrists, or so-called psychopharmacologists — which is basically just a fancy word for a psychiatrist that focuses on using medicine instead of psychotherapy, I fall into that camp — we do a lot of cheerleading with our patients, right? So, depression for many people, they respond beautifully to psychotherapy or an antidepressant, a standard what we call 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 their doctor and it eventually resolves.
But unfortunately for some patients, there’s a more severe course 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. They tell you, “I went to my doctor and they said, ‘Okay, Prozac didn’t work.’ And then I tried another drug and then another,” and this is 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, what are you going to get? So that’s why this was sort of a big deal.
DUBNER: Now, Rachel, MDMA. I’d like you to describe again a little bit of the back story of the drug. But then I’m really curious to know not just how chemically MDMA or the MDMA derivation differs from the ketamine derivation, but also how the application differs, including psychotherapy.
YEHUDA: Yeah, MDMA was first synthesized by Merck in 1912, and it was originally supposed to be an intermediary compound towards making a drug that stops bleeding. The drug basically stayed dormant for a while. The patent ran out. And in the ’50s and ’60s, of course, the C.I.A. and the Department of Defense were very, very interested in all psychedelics — LSD, all of them — because they wanted to better understand their mind-altering properties or whether they could be used to kind of get secrets from people. We don’t know anything about what the outcome of that research was. But what we do know is that in the ’60s and ’70s, MDMA surfaced as a drug that was used clinically by therapists. It wasn’t illegal to use MDMA then, and—
DUBNER: Was there F.D.A. approval or was that not necessary?
YEHUDA: No, there wasn’t F.D.A. approval, but it wasn’t—
DUBNER: Meaning it was just used off-label?
YEHUDA: It was used. And no randomized clinical trials like we’re used to, but kind of word-of-mouth on it spread. And actually, it was called “Adam” because people felt it restored patients to their innocence state. It was actually called “Empathy.” It’s a drug that increases empathy and connectedness and prosocial behavior, for yourself and others.
DUBNER: As James said, the treatment with ketamine is medicinal. The treatment with MDMA is, as I understand it, to open the doors of perception slightly to allow psychotherapy to get at the depression. Is that about right?
YEHUDA: Yes. If you’re put in the exact right state where you’re not afraid of your emotional reactions or your memories, you have maximum interpersonal trust, a minimum self-blame or guilt or any of those things. This is the state that is a perfect place to be to start processing very difficult, traumatic memories and really catalyzing a therapeutic process. So unlike ketamine — and James told you how it works in the brain — I could tell you similarly about the molecule of MDMA 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 a therapeutic process?” And the metaphor that’s often used 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 real. You’re actually allowing yourself to have a tool so that you can really see things that actually are there, things that are really important that aren’t that obvious or cannot be looked at in any other way. And so once they started to understand that that was the purpose of MDMA, it really clicked into place as something that is very necessary.
Because trauma survivors with PTSD, they don’t want to look at their traumatic experiences. They don’t want to look at the reasons that they’re kind of stuck where they are. Because it’s very, very painful. Trauma 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. But with MDMA, you have an eight-hour session where you’ve got a lot of time to process the events.
DUBNER: Wait. And if you’re the therapist, you’re the therapist for the entire eight hours?
YEHUDA: You have a co-therapist. So there are two therapists, usually a male and a female. And they’re with the patient through the three sessions of preparation, the eight-hour MDMA session, the three sessions of integration, and then you do it again a few times.
YEHUDA: So it’s not a quick fix at all. 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 in labor, right—
DUBNER: Again, just as “treatment-resistant depression” is not the greatest sell, I don’t know if labor is also—
YEHUDA:Well, but hear me out. Hear me out. Because if you are in labor to have a baby, the last thing that anyone is going to do is tell you after the first or second contraction, “Well, our time is up for today.” They’re going to be sitting by your side until you keep going with the process and the contractions get closer and closer together.
DUBNER: All right, Rachel.
YEHUDA: And finally, at the end of the day—
DUBNER: You saved it.
YEHUDA: You got something.
DUBNER: All right, you saved that one.
YEHUDA: You’ve really got something important.
DUBNER: I do have one more quick question for Rachel before we move on from MDMA. You, Rachel, are a scholar of and have researched, for years, PTSD. You are using MDMA to treat PTSD, first medicinally as a means to get there therapeutically. Is the MDMA treatment that you propose particularly useful for PTSD? Or is that the avenue you’ve pursued because PTSD is a particular specialty? Do you have any ideas about how useful MDMA would be for other maladies?
YEHUDA: We have just gotten our F.D.A. approval so that we can begin a study. So we haven’t actually treated anybody yet. But we’re very close now. That was a very big hurdle. The F.D.A. has designated MDMA-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 powerful way to foster psychotherapy for almost any condition in which life experience contributes to the symptoms. And I don’t know of any in which it doesn’t.
DUBNER: Right. Other conditions may not require eight-hour sessions necessarily?
YEHUDA: Well, no. That’s how long the journey lasts. So it’s the kind of thing where once you take off, you can’t get off until the plane lands, you know?
DUBNER: So bring a book. Yasmin, most people listening — I would say everybody listening — is familiar to some degree with marijuana and its history and uses. 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 CBD?
HURD: So, the cannabis plant has over 500 chemicals. Over about 140 of them are cannabinoids. As I said before, THC, that’s the cannabinoid that induces the high, the rewarding effects. And THC is known to also induce psychosis. And depending on the dose of THC, people say can reduce their anxiety, but it often exacerbates their—
DUBNER: There’s a lot of variance in the population, correct?
HURD: Absolutely. But it’s often dose-dependent. And THC is the most concentrated cannabinoid in the cannabis plant. Unfortunately, over the decades, the cannabis on the street, the THC concentrations have increased tremendously. At the same time, CBD, cannabidiol, was the second-most concentrated in the normal cannabis plant. And the concentration of cannabidiol on the regular cannabis that’s smoked recreationally has gone down over the years. So you have a much stronger THC-to-CBD ratio.
DUBNER: I assume the THC was increased by selective breeding for the purpose of making people — right? Making it more concentrated.
HURD: Exactly. Improving the high.
DUBNER: What about the CBD decrease, though? Is that just a side effect of increasing the THC?
HURD: That was an initial side effect. However, as people started to become more interested in CBD — so CBD does not induce the high. Sometimes people say, “Oh, we’ve been, you know, taking this really great CBD that makes us high.” You know, you’re not. Because CBD doesn’t make you high. One of the things that initial studies showed is that it’s even had this anti-anxiety effect. And then they started to even look at it for psychosis, so they could see that it seemed to have antipsychotic properties.
For our studies, it was a bit serendipitous because we just wanted to study another cannabinoid, when we were making all these conclusions about, “cannabis.” But we were really studying THC. And so when we saw this, you could say the yin to yang of how THC and CBD tended to do not opposite things, but for the rewarding effects, they had opposite things — for the anxiety, for the psychosis effects. So we wondered about, in regard to addiction, when looking at opioids, and there CBD tended to reduce craving, reduce anxiety, in our first clinical studies.
DUBNER: When were your first clinical studies of using CBD to treat opioid addiction?
HURD: So, we first did safety studies. So, cannabis, as everybody knows, we’ve gone in this country from prohibition to now, many states legalizing the use of cannabis. So, when we first started to look at cannabidiol it was still considered under the cannabis and was a Schedule I drug, meaning there are a lot of hoops that you have to jump through as a researcher to work with a Schedule I drug, even if everybody on the street has access to it.
DUBNER: And supply, I understand, is limited, right? Isn’t there one farm in Mississippi that grows all the research-grade marijuana? I may be wrong on that.
HURD: Right, for the cannabis. And that’s changing a little bit — but yes, for cannabis. But for cannabidiol, there were also very few companies back then making cannabidiol. Last year, we finished a little larger study — and still not large, but we replicated the results where we showed that CBD reduced cue-induced craving and cue-induced anxiety in people who have a heroin-use disorder. And we focus on cues because, people don’t realize, in addiction, it’s not the reward that drives addiction. It’s a lot of the negative states and the craving and anxiety. And the cues in your environment trigger a 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 try for substitution therapies.
DUBNER: Buprenorphine, for instance?
HURD: 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 have addictive properties. And they have to be monitored clinically, very carefully. So we’re looking at trying to find non-addictive new therapies for addiction, and CBD fell within that.
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We’ve been discussing the clinical uses of drugs better associated with their recreational use. Our guests are three researchers at the Mount Sinai Health System in New York: James Murrough, a ketamine researcher; Rachel Yehuda, who works with MDMA, better known as ecstasy; and Yasmin Hurd, an addiction researcher who’s been studying CBD.
Ketamine, as we’ve heard, is already being used to treat severe depression. The F.D.A. recently approved Stage III clinical trials to treat PTSD patients with MDMA-assisted psychotherapy after an earlier round of MDMA studies showed promising results. So there is much room for optimism in this area. But what I wanted to learn next from our guests was the most legitimate criticism they’ve heard about their respective areas of focus. Murrough, a psychiatrist who treats severe depression, recalled how skeptical his fellow researchers were about administering ketamine, a highly addictive drug which, in higher doses, is used as a surgical anesthetic.
MURROUGH: You know, antidepressants take weeks or months to work. That’s the mantra. But no drug company, no one had ever identified a medicine that was outside that mold. So 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 said, “All right, we’re gonna give it not once, but we’re gonna give it on a Monday, Wednesday, Friday schedule, just like we’d give electroconvulsive 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 psychiatry conferences. This would have been 2007. And people would come up to me, particularly addiction researchers—
MURROUGH: And I was a research fellow at the time, at Mount Sinai. People would basically say, “You’re crazy. They have depression. Now you’re giving them another problem.”
HURD: I was one of them.
DUBNER: Why was that, Yasmin?
HURD: Because I am an addiction researcher. I direct the Addiction Institute.
MURROUGH: I didn’t want to say it, but, yes, please.
HURD: So everything comes back to — this is what’s important — dose matters. And many people now think that all of these psychedelic drugs, 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 recreationally use these at high doses and have significant problems. So I was very skeptical. So I was the one with my hand up.
MURROUGH: Yes. And Yasmin was very gentle and, you know, really a mentor to me at those days, and pulled me aside and said, “You know, just make sure, you know, everything — you’re going slow.” Because here was a drug that was being put up under consideration for approval as an antidepressant with a known history and documented abuse potential. There was no debate about that. The F.D.A. knew this. The F.D.A. worked with industry to design all the studies that they thought would sort of satisfy their risk.
DUBNER: James, I have to say, you’re a very clever fellow because I invited you all to each offer the most legitimate critique of your drug.
MURROUGH: What did I do?
DUBNER: And somehow you ended up still having ketamine be the hero of the story. No, I respect that. I guess one way to think about this, Rachel, with MDMA — let’s just look down the road a little bit. Let’s say there is approval, there’s treatment, there’s widespread treatment. 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. Opioids were not only allowed through medical channels, but were promised to be non-addictive — 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 legal drugs which are already being abused often. I’ve got one that we maybe wisely made illegal back in the 1980s. And now you, Dr. Yehuda, would like 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 the possibility of a party drug becoming so widely available. To that, you say what?
YEHUDA: 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 the gains may not last forever. You may find yourself needing to come back into therapy because you haven’t gone through the process of being able to look through that microscope at what you need to see and be able to 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 II and phase III trials, the side effects that have been noted were very, very benign. The kind of things that have been noted in party use of MDMA 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 MDMA.
So from a chemical perspective, there’s nothing in the molecule that we haven’t seen before and that we already are using in our current treatments for people. So all drugs can be abused. Even a drug like aspirin can be used for purposes of suicide. The reason that we study what we study, the reason we are here, what psychiatry research is about, is to help people understand how to use medications properly and when not to use them. The idea is to be careful and thoughtful and scientific, and get the information that is needed in order to give people proper information.
Certainly psychedelics should not be in the same category as cocaine or opiates or heroin or crystal meth. I mean, those are compounds that you’ve got to really worry about. But MDMA and psychedelics are generally not like that. And you know what? It’s hard to abuse psychedelics. It’s hard to take them every day. It’s really — doesn’t work that way. And people that might take something recreationally, we don’t know if that is pure MDMA. 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 provide science and information, then you’re giving people tools.
DUBNER: 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 Covid since — but 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 devices that were hurting and killing people were, as I understand, black market THC pods and not e-cigarettes. I’m curious how each of you may look at regulation in that regard to see where you invite the right kind of regulation, because the absence of regulation can lead to really terrible outcomes.
YEHUDA: The way that they’re proposing to legalize MDMA, there’s an enormous amount of risk-mitigation strategies that are in place. Once the F.D.A. approves it, it’s going to be almost impossible to get unless you’ve gone through the training to become an MDMA-assisted psychotherapist, and you’re going to be able to get the MDMA for the first five years from only one place and one source. So I think that in some cases, regulation is good. In other cases, maybe not. But I just wanted to really say that when the F.D.A. takes on something like this, they’re really thinking about how to do this safely and properly and to minimize adverse events.
DUBNER: Yasmin, it sounded like you had something to say about regulation in that regard?
HURD: 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 F.D.A. and all of the government regulations, or when they think about the regulations that are needed. And we don’t want to be naive. It doesn’t matter even if the F.D.A. approves or not. There are people who will absolutely abuse. For example, for cannabidiol, now it’s everywhere. When I started, no one knew what CBD was. Now everybody does, including the grandmothers.
But we also have a lot of companies making CBD and the things that are in CBD are not even CBD. There is even synthetic cannabis that’s put into it. There is lead. There’s mold. So you do need the government to make sure that the products that are being used, that are available to its citizens, are safe. However, they should work with scientists. If the F.D.A. worked with scientists to have more fast-tracked research done on these products, we could have the answers to provide the clinicians with the answers, to provide the general public with the answers. I think it’s the slow movement that sometimes makes it worse.
DUBNER: Do any of you have faith that the very rapid acceleration that’s involved in the search for a Covid vaccine, which will obviously go through the F.D.A., that that may change the kind of mindset of speed of approval, generally? No. That’s a no from you, Yasmin?
YEHUDA: I think it might.
DUBNER: Rachel, yes. And James, yours is already approved, so you don’t care, right?
MURROUGH: And actually, it was pretty fast that.
HURD: Yeah, yours was.
MURROUGH: Ketamine was approved. And I’ll just make a point about, just picking up what from what Yasmin said — again, in the early days before there was F.D.A.-regulated products related to ketamine and people were trying to find an alternative antidepressant, they heard about some of the early research. And these so-called ketamine clinics started springing up. Sometimes they were anesthesiologists, sometimes there were psychiatrists. You come in the office, you hook up an I.V., you get ketamine.
People such as Yasmin and many others, and even us — made us quite uncomfortable. And we got the question all the time. Here was the big question that we struggled with and to some degree we have a little bit of information, but still struggle with this. Let’s say I get this injection of ketamine and I’m — my depression is gone. Maybe it just improved, but it’s — I’m better. But then you probably have to keep taking it. So how long can you take ketamine before you’ve got problems?
DUBNER: And what turned out to be the answer that satisfied people in that?
DUBNER: I mean, it’s — it is addictive, yes?
MURROUGH: It’s addictive.
DUBNER: But in the dose that’s medicinal, I assume it’s not. Is that the idea?
MURROUGH: I’m not sure we completely know. Many of us were surprised how quickly it got to market. The F.D.A. will grant approval to market a drug with strings attached. It says, “You’ve got to keep following these people.”
DUBNER: So, is ketamine a forever drug? If I start to use it, I’ll probably use it for the rest of my life?
MURROUGH: You know, Stephen, often patients will ask us, if we say we recommend a certain treatment, they say, “Well, how long do I have to take my antidepressant?” And the answer is, the data suggests that if you respond to your antidepressant and then you stop it, your chance of having a relapse or a recurrence is substantially higher than if you stayed on it. And those studies usually often look out a few years, and ketamine looks to be the same.
DUBNER: Rachel, this strikes me as one of the many differences between not just ketamine and MDMA per se, but the treatment model.
DUBNER: One is a medicinal and the other is a medically-aided therapeutic.
DUBNER: I have two questions, actually. I want to know how the drug would be administered, how the psychotherapy would be conducted, and then what happens next? Is it one or two eight-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 MDMA is so necessary is because the plight of the people suffering PTSD is so grave, and that there are no other options.
YEHUDA: There are no good options.
DUBNER: So, 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.
YEHUDA: Yeah, I mean, to jump off of what James said, the difference in the model is that we’re not proposing that the MDMA, or the psychedelic, whatever it may be, is something that continuously has to be taken. What the idea here is, is that there is a blockage and that you keep redundantly going over and over and over, kind of like a hamster’s running wheel, 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 breakthrough is up to you.
So who should be taking MDMA? I think that is why we have a center, so that we will be able to examine exactly that issue. And in the phase II trials, 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. And so that’s a problem. And who might those people be and what kind of education and reassurances might they need?
For example, not a large percent of the people enrolled in those trials are people of color. We got to rectify that and really understand, What are the barriers? What are the expectations? What are the fears? But in terms of for whom this is safe, there are some medical contraindications. That’s why patients are screened very carefully medically before they enroll in a study. But barring that, from a psychological perspective, there don’t seem to be too many contraindications.
DUBNER: Rachel — jumping into Yasmin’s turf for a minute: What can you tell us about PTSD and CBD?
YEHUDA: Well, the word about cannabis and PTSD, I don’t know specifically about CBD, is that it helps some veterans alleviate their symptoms. That I’ve heard a lot, that it helps them cope with the day to day. But it’s not a cure.
YEHUDA: And then the question is, Is it making you feel good so that you’re using it as avoidance?
YEHUDA: And so I’m torn because, on the one hand, somebody’s suffering; you want them to feel good. But on the other hand, it’s exactly this kind of approach that we have to re-examine with all of our medications in psychiatry. Are we just trying to reduce symptoms and not trying to understand? You know, a lot of people that do the MDMA, 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.” And so we don’t want to numb people out just because they’re complaining of symptoms. We want to get to the root of it and be able to really understand what those symptoms are trying to say, what needs to be worked on, what needs to be done.
DUBNER: It’s an important point. Yasmin, can I just ask you quickly, we heard a little bit about ketamine dosage and the cycle of application. The same for MDMA and therapy, which is obviously very, very different. Based on what you know so far, what do you suspect would be the appropriate dose and frequency for treatment using CBD for, let’s say, opioid addiction or other addictions?
HURD: For anything, even anxiety and psychosis. We really don’t know. I mean, we now are carrying out one of the largest studies, now phase II again, and we will have hundreds of people. We are looking at different dose ranges. We’re looking at the duration. One thing about CBD that’s very interesting from a treatment perspective is that even in our animal models, it showed us, a few weeks after their last injection, we could still see that the effects were there. The same thing in our human study. A week later, they still showed reduction in their craving and anxiety. So there’s something that it doesn’t have to be onboard daily. So those are things that we’ll also be testing.
DUBNER: James, this may be a total misunderstanding or oversight on my part, but the way this conversation has been going, it sounds as though Yasmin has learned a lot, but has a long way to go, has a lot of work to do. Rachel 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’s approved.
DUBNER: I assume that’s not actually the case, however. Can you tell us what’s more or next for ketamine?
MURROUGH: Well, I do feel a little bit like we used to be the edgy kids, right? We used to be out there, people coming to conferences are all, “Oh, I can’t believe you’re doing this.” Now it’s like the F.D.A.-approved drug, like, man, boring stuff. For me as a researcher, one of the most exciting things was, 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 companies started to get interested in trying to develop drugs that affected the glutamate system, the N.M.D.A. receptor, in these different ways. And there have been a whole slew of — and will continue to be — medicines under study that the hope is have potent and rapid therapeutic effects for severe forms of depression, for suicidality, but that won’t have the side effects. They won’t have addictive potential. They won’t cause this acute confusion, 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 for patients with depression, when they first receive the injection or the nasal spray these days, it often does not feel good. They feel confused. They feel out of it. They have to sit. They have to be monitored at the clinic for a couple hours. The change in the mood state comes on later, a day later, sometimes a few days later. In the early studies, actually 72 hours after a single dose was the largest effect on depression.
DUBNER: Is that side effect every time you take it or is there habituation?
MURROUGH: There seems to be a bit of habituation, but for most patients it remains to some degree. When you take the ketamine and it’s in your brain, it has a very short half-life. For 40 minutes or so, you’re numbed out, right? You’ve taken a small dose of an anesthetic. And early on, people said, “Oh, sure, they say they’re not depressed anymore. They’re just numbed out or they’re confused.” But they didn’t understand what the drug was doing or what the design of the clinical trials were, which was to measure their mood the next day, days later. There’s no ketamine in their body. And they say, “I don’t feel like killing myself anymore.”
YEHUDA: James, another place to go with this, and we’ve talked about this, is that, since in some circles ketamine really is considered a psychedelic, the idea of ketamine-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 during ketamine, some patients have recovered traumatic memories or have come back and talked about those traumatic memories.
MURROUGH: That’s right.
YEHUDA: So this can be a very powerful tool. And—
DUBNER: Rachel, has that not been tried yet?
YEHUDA: 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, not just simply reducing mood. I don’t want to say “simply” because it’s a big deal when you have a very serious depression to be able to reduce your mood. But to be able to use the ketamine for another purpose also, which is to go underneath and see what psychological processes may be driving the depression, in addition to the obvious biologic ones.
MURROUGH: And I will say, just to underscores Rachel’s point, the way ketamine has been looked at and developed as a treatment for “treatment-resistant depression” has been very straight, biomedical model. What Rachel is suggesting is a whole other way that it could and should be studied. And I agree.
DUBNER: So it strikes me, we’re talking about using all these substances, drugs, to essentially repair damage or to repair a condition that’s, you know, grave, serious. Are there any thoughts on using these substances or similar substances prophylactically on related conditions or not?
HURD: Well, for CBD, yes. It’s being now studied for so many disorders. For schizophrenia, for not only the addictions, for the anxiety, for pain. It’s being studied for inflammation. It’s being studied for Parkinson’s disease. That’s one of the worries about CBD. I do think that it has medicinal potential. But now it’s being used for everything, even if it’s used off-label. So that’s one of the worries, that it minimizes the potential benefit that this could have under strict clinical conditions.
DUBNER: Rachel, any prophylactic thoughts with MDMA?
YEHUDA: 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 MDMA phase II and phase III trials and ask how they’re doing with Covid. 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.
DUBNER: Do you mean on the mental-health side? Physiological side? All of the above?
YEHUDA: I would just questionnaire. 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?” I mean, we are people that live lives and things are happening to us in a very dynamic and fluid way. And if you’re able to take one kind of process and learn how to integrate it and really learn to forgive yourself and to have compassion and understanding for yourself and to learn how to look through that microscope and understand your relationship to the world and everybody else and your relationship to your own autobiography, is that something that then generalizes to the next time? I would predict that it does.
DUBNER: Well, I’m afraid our 90 minutes are up. I could talk to the three of you for 90 hours. It would be even longer than one of Rachel’s pregnancy MDMA sessions. I just thank all three of you so much for your time and expertise. I learned a great deal, and thank you very much.
That, again, was Rachel Yehuda, Yasmin Hurd and James Murrough, all from the Mount Sinai Health System, recorded recently in a live Zoom event we held in collaboration with WNYC and their live-event venue The Greene Space.
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Freakonomics Radio is produced by Stitcher and Dubner Productions. This episode was produced by Mary Diduch, and we had lots of help this week from everyone at WNYC’s The Greene Space, especially Jennifer Sendrow, Sachi Ezura, David McLean, Cam Thompson and Ricardo Fernandez. Thanks also to everyone at Mount Sinai — especially our guests and Alex Kolevzon, for planting the seed. Our staff also includes Alison Craiglow, Greg Rippin, Matt Hickey, Corinne Wallace, Daphne Chen and Zack Lapinski. Our intern is Emma Tyrrell. We had help this week from Nellie Osbourne. Our theme song is “Mr. Fortune,” by the Hitchhikers; all the other music was composed by Luis Guerra. You can subscribe to Freakonomics Radio on Apple Podcasts, Stitcher, or wherever you get your podcasts.
- James Murrough, director of the Depression and Anxiety Center for Discovery and Treatment at the Icahn School of Medicine at Mount Sinai.
- Rachel Yehuda, professor of psychiatry and neuroscience, and director of the Traumatic Stress Studies Division at the Mount Sinai School of Medicine.
- Yasmin Hurd, director of the Addiction Institute at Mount Sinai.
- “Ketamine Assisted Psychotherapy (KAP): Patient Demographics, Clinical Data and Outcomes in Three Large Practices Administering Ketamine with Psychotherapy,” by Jennifer Dore, Brent Turnipseed, Shannon Dwyer, Andrea Turnipseed, Julane Andries, German Ascani, Celeste Monnette, Angela Huidekoper, Nicole Strauss, and Phil Wolfson (J Psychoactive Drugs, 2019).
- “MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials,” by Michael C. Mithoefer, Allison A. Feduccia, Lisa Jerome, Anne Mithoefer, Mark Wagner, Zach Walsh, Scott Hamilton, Berra Yazar-Klosinski, Amy Emerson, and Rick Doblin (Psychopharmacology, 2019).
- “A Review of 3,4-methylenedioxymethamphetamine (MDMA)-Assisted Psychotherapy,” by Ben Sessa, Laurie Higbed, and David Nutt (Front Psychiatry, 2019).
- “Early Phase in the Development of Cannabidiol as a Treatment for Addiction: Opioid Relapse Takes Initial Center Stage,” by Yasmin L. Hurd, Michelle Yoon, Alex F. Manini, Stephanie Hernandez, Ruben Olmedo, Maria Ostman, and Didier Jutras-Aswad (Neurotherapeutics, 2015).
- “The origin of MDMA (ecstasy) revisited: the true story reconstructed from the original documents,” by Roland W. Freudenmann, Florian Öxler, and Sabine Bernschneider-Reif (Society for the Study of Addiction, 2006).
- “Antidepressant effects of ketamine in depressed patients,” by Robert M. Berman, Angela Cappiello, Amit Anand, Dan A. Oren, George R. Heninger, Dennis S. Charney, and John H. Krystal (Biological Psychiatry, 2000).