Jerrold Rosenbaum: Are Psychedelics an Effective Treatment for Mood Disorders?

Nancy Kathryn Walecki: Magic mushrooms are known by many names—shrooms, liberty caps, and philosopher's stones to name a few—but might they now be called the future of psychiatric medicine? Psychedelics, particularly magic mushrooms, are gaining traction in the medical community as a potential way to treat mental health disorders, raising the questions: what's the science behind this? How do magic mushrooms help, and who do they help? And will psychedelics soon leave the haze of the counterculture for the fluorescent light of the medical establishment? Welcome to the Harvard Magazine podcast "Ask a Harvard Professor." I'm Nancy Kathryn Walecki. Joining us for office hours today is Dr. Jerrold Rosenbaum, Cobb professor of psychiatry at Harvard Medical School and psychiatrist-in-chief emeritus at Massachusetts General Hospital, where he oversaw a team of more than 600 clinicians and researchers. Formerly president of the Anxiety and Depression Association of America, Dr. Rosenbaum now directs the Center for Anxiety and Traumatic Stress Disorders at Mass General. He's also leading a team of clinicians, clinical scientists, neuroscientists, and medical physicists at Mass General's new Center for the Neuroscience of Psychedelics. Their goal is to uncover how psychedelics enhance the brain's capacity for change, and to discover how they might be used in new treatments for mental illness, all with the aim of making treatment-resistant mental illnesses obsolete. Welcome, Dr. Rosenbaum.

Jerrold Rosenbaum: Thank you, it's nice to be able to talk to you.

Nancy Kathryn Walecki: So first of all, most people probably think of psychedelics in the context of the 1960s countercultural movements, when they were being used recreationally. So is using psychedelic drugs in psychiatric treatment a new idea?

Jerrold Rosenbaum: No, it's not a new idea. The discovery of the psychoactive properties of psychedelics goes pretty far back. The iconic molecule LSD was synthesized by scientists, Albert Hofmann in 1938, working for Sandoz. And it was really due to a inadvertent contact with the substance—he hadn't determined what it would be good for—that he actually absorbed some and had these remarkable experiences, visual and perceptual changes, and he knew he had something interesting. There was a fair amount of research going on with LSD really into the 60s as a serious exploration of what it might mean for patients with psychiatric disorders. And it was explored as a model of psychosis, as a potential treatment for psychotic disorders, and there was some recognition that it might play a role in treating addictive disorders. And so, serious scientists really in the early 60s at our National Institutes of Health, were looking at these LSD and related substances. The patent life for LSD ended and Sandoz stopped making it, but it turns out to be a pretty easy compound to manufacture. And so, home labs came into existence and LSD made its way into non-medical use and non-research use, and there was a fair amount of interest in the experience that LSD generated and it became sort of a hallmark of, as you pointed out, the counterculture population, particularly with disaffected youth in the 60s, triggered by political events, the Vietnam War and other frustrations with society. And, as you know, a Harvard professor or Harvard faculty member, Timothy Leary, was enthusiastic and was encouraging people to use it, that the reality or the alternative experience from day-to-day reality that these substances afforded was viewed as preferred. And so he encouraged people to tune-in turn-on, dropout, and many did, setting up alternative lifestyles. But it was also associated with the protest movement against the Vietnam War. Other groups were also using other drugs as a way of coping with the reality of society that made their day-to-day experiences burdensome and suffering. And this was, in a way an alternative reality that offered some escape. So it became very popular. You should know these drugs are remarkably safe in the sense that they're not addictive. What they do do is offer you an experience that you might prefer to the experience you have in daily life. So people may have used them in protest or used them as an escape, but they're really remarkably safe drugs as far as drugs that are in the pharmacopoeia, or accessible to people over the counter. Their ability to harm oneself or harm others is remarkably low. Nonetheless, despite their therapeutic potential that was being explored and their recreational use, they became viewed as a threat to government I guess at that point in time. Indeed there probably were some individuals that had bad experiences and were damaged in some ways by those experiences, but the vast majority of use was pretty benign. In recent reports, it's said that the Nixon White House recognized that they couldn't shut down, say, the Black Panther movement or the hippies from protesting their issues, but they realized they could attack them for their drugs. And so they moved to make these drugs what's called Schedule I, which means they're deemed to have no value, either for research or therapeutic use. As a result, they are criminalized and many hundreds of thousands of people spend probably many hundreds of thousands of years in the criminal justice system because of their use of these agents. Other compounds are recognized to be psychedelic in the same way. Psychedelic drugs alter for a period of time, depending on the duration of their efficacy, your visual, cognitive, and perceptual reality. You may have hallucinations, visions, meaningful spiritual experiences. People feel they've seen God or they've lost their sense of self or their identity for a period of time and have merged with the universe, and often return from that experience feeling changed in some way, usually with a greater sense of peace or a greater sense of connectedness to nature and the world, or a sense that there's another reality out there that makes our lonely individual lives more endurable. Anyway, other psychedelic drugs other than LSD include many plant-based or mushroom-based chemicals that have been used by different societies, civilizations, and indigenous populations for really thousands and thousands of years, often viewed as sacred and used for special ceremonial events, not treated lightly, but still to this day, are part of religious experience in different cultural groups. So among the psychedelics that are of interest these days that people are exploring potential therapeutic use, not only LSD, but substances from so-called magic mushrooms like psilocybin, and various compounds related to psilocybin, mescaline and peyote, DMT (Dimethyltryptamine), and another substances sounds like it but it's somewhat different, 5-MeO-DMT, ayahuasca, ibogaine. So there are a variety of these substances that all have these dramatic changes in emotion, perception, sense of self, relationship to others, that fall into the category of psychedelics. MDMA, also known as molly or ecstasy is sometimes included in the group of psychedelics. The classic psychedelics like LSD and psilocybin are sometimes called entheogens because they induce a spiritual experience and a loss of sense of self—with a high enough dose, you can actually experience being alive but without a sense that you are an individual person or who you are—whereas MDMA is sometimes called empathogen, because although you can have other psychedelic-like perceptual experiences, typically the experiences associated with a sense of increased connection to self and others, increased connectedness, sometimes thought to involve the hormone oxytocin, but a more loving and connecting experience as opposed to a more solo spiritual journey.

Nancy Kathryn Walecki: So in a therapeutic setting is the active ingredient, for instance, in magic mushrooms, is psilocybin extracted from the mushroom and made into an oral drug or our patients ingesting the actual mushroom?

Jerrold Rosenbaum: So in general, most use in society today is people who have access to the mushroom itself. The medicalization of the treatment, though, involves synthesizing the actual chemical psilocybin. And that's not available to the general public. That's in testing as you would a novel potential therapeutic with FDA-approved clinical trials, going through the usual process from Phase 1 to Phase 3 of drug development. So different companies have found ways to synthesize their own version of the chemical psilocybin and have patented their own synthesis methods. One such company is Compass Pathways, which has a form of psilocybin, which is a medicine that can be given by an oral capsule. Another company is called Usona, which is developing its own psilocybin, but those products won't be available to the public until they finish the FDA approval process, and they're now in late Phase 2, which typically means we're two to three years away. Assuming a successful Phase 3 studies that show efficacy, probably two to three years away from availability for therapeutic use. The indications for which those companies will be seeking approval is for treatment-resistant depression, which is condition meant to describe individuals with major depressive disorder who have failed a number of trials of available antidepressant treatments. The bar there is kind of low. I think, at least for Compass Pathways studies, it's where people who have failed at least two prior antidepressant trials are considered treatment resistant. It's also worth knowing that these drugs are not being developed in the traditional way of just being a medication that you take in a daily way. They're expected to be used once, twice or three times—and in the case of MDMA, three times—and then expecting the condition to remit and that improvement to be relatively durable. But they're also being prescribed or used, along with psychotherapy and a lot of psychotherapy. So they're actually studying what's called psychedelic-assisted psychotherapy, rather than saying they're studying psychedelics. And it's fairly intensive. It involves two therapists with the patient for eight hours before the administration of psilocybin, two therapists with the patient for eight hours during the experience with psilocybin, and two therapists for eight hours for what's called an "integration session" days after receiving psilocybin. So it's a fairly elaborate therapeutic process involving administration of the psychedelic, but with a intensive supportive psychotherapy presence.

Nancy Kathryn Walecki: What do we know so far about what happens in the brain of someone with these disorders when they use psilocybin?

Jerrold Rosenbaum: Well, it's pretty dramatic. You know, our understanding of it at this point is pretty primitive, and we know some things. We know where these chemicals bind initially in the brain, in which receptors. All psychedelics bind to the 5-HT2A receptor, which is one of the subtypes of the receptors for the neurohormone neurotransmitter, serotonin. So interestingly, you know, it's at least initially engaging with the same system that many of our traditional antidepressants do like the SSRIs, like Prozac, or Lexapro, and so forth. But it also binds to other receptors, not as avidly as to the 5-HT2A but 5-HE2B, 2C. But that doesn't really tell you much, it just tells you where it's engaging. It doesn't tell you, you know, what's happening downstream and what genes are turning on or turning off as a result. And that's more or less the focus of our center at Mass General, which is to try to understand that really, the the downstream neurochemistry of what's happening. There have been some imaging studies of individuals, not patients, but volunteers who have received, say, psilocybin, and a whole bunch of things are happening in the brain. One of the pioneering researchers, Robin Carhart-Harris, calls it the "snowglobe effect," where it looks like, you know, someone's taken your brain and shaken it up, and all this, you know, all these things are happening for a period of time. And whether those connections and disconnections that are going on, you see parts of the brain communicating with each other, transiently, that rarely talk to each other. You see, you see, disintegration of key networks, so like the default mode network, which is a network in the brain that is thought to be particularly important for a sense of self and self reflection and identity. And the disintegration of the default network may be part of that experience of what's called ego dissolution or loss of sense of self. What's interesting is all these changes happen for a relatively short period of time, depending on the substance you're using. With psilocybin, it's several hours, with shorter-acting agents, like 5-MeO-DMT, you'd expect it to be very brief. And so it's not a durable effect. It's a transient effect. But after that happens, and whether it's because of it, or despite it, people feel some kind of profound, or often feel some kind of profound change: a loss of depression, or anxiety, or a sense of calm or peace they've not known in the world. The classic studies about reflecting and that are LSD and psilocybin, which have both been used in the past for individuals who had received medical death sentences, you know, terminal diagnoses, and when exposed to these psychedelic agents have lost their depression and anxiety or fear of dying, or at least that's what the reports indicate. And that those who had survived for several months, six months, retain that, that sense of peace, that somehow they felt a different connection with the universe. I mean, I guess for those who have read "Slaughterhouse-Five," Kurt Vonnegut's book, they say, I think they became Tralfamadorians they, you know, that "so it goes" and you know, "I didn't live then I live here, and I don't live there, but it's all okay." So maybe that, anyway, so those studies have been particularly influential. It's estimated 30 million people have used psychedelics, and probably 10 million people alive today have used them. So there is a trove of testimonials of people who feel either transiently or sometimes in a more sustained way, changed for the better because of having use these in appropriate way—appropriate way meaning, they took it seriously, they paid attention to the the time and place and who they were with, and when they went through these experiences they tried to use it to address issues. So we talk about terms like set and setting, which is your preparation for the experience, what you hope to get out of it, and having a comforting and peaceful setting to minimize the possibility, which is real, of a terrifying or a distressing experience. And, you know, when I got into this effort to start a center at Mass General, I began hearing from people all over the country, both those who suffer and want help, but those who have used these agents, all telling me how life-changing they were. So there have been hundreds of studies with psychedelics and the challenging part is that most of those studies would not be considered ones that provide definitive evidence, because many of them were open studies of just studying people having the experience or small studies without the power to really test for efficacy. Most of the people studying the agents were passionate advocates, and most of the volunteers had high expectations. So having been, for most of my career, a clinician and a clinician researcher who often had ideas about innovations and advances to help people with depression and anxiety disorders, I you know, I often found that things that I discovered that work dramatically well stopped working when I studied them. So it you know, one has to be a little circumspect, you know. The dry weight, if you will, of all the evidence, whether it be testimonials, small studies, open studies, and now, a couple of controlled studies, the evidence suggests that these agents will be therapeutic tools, that they will work for some people who have struggled to have benefit from other treatment approaches. So that makes us optimistic. I think from the point of view of our center, we consider the current psychedelics as forerunners. They just happen to be the ones that are, you know, widely used, and we're taking advantage of them. But there have been hundreds of startups, some of them now with billions of dollars of valuation already, that are pursuing variations, either variations in how these drugs are packaged and delivered, or tweaks to their molecular structure to seek certain advantages, like shorter acting. Or there's even a company that that just announced a very successful $70 million series A that believes that you can eliminate the entheogenic experience, the "trip" if you will, and still have a therapeutic agent. Because the other thing we gather about these drugs, which is actually not unique to psychedelics because it's also true of the antidepressants we now use is that they have neuroplastic effects. We've been able to see this in laboratory animals, and these drugs induce the brain to form new neuronal connections and synapses in the same way older antidepressants did but often after some latency. So neuroplasticity means that the brain is given the capacity to change. Neuroplasticity is associated with resilience, with adaptation. You can induce neuroplasticity through a variety of means, such as meditation and mindfulness or exercise or antidepressants, but these drugs seem to turn it on very dramatically and quickly. Now whether that can explain why they're therapeutic is not entirely clear, because neuroplasticity means that, you know, you're forming new synapses, maybe there are newborn neurons coming into play in certain regions in the brain. For those who want to picture this we talk about, you know, when you're under stress or you're in a depression, your neurons look a little bit like your tree branches in winter, and when neuroplasticity is occurring—typically associated with certain chemical changes, the increase in chemicals like BDNF—your neurons look like it's springtime, and there's buds and branches are growing and so forth. So if that happens, it may account for, you know, some of the sustained well-being or resilience that people report. Whether that could explain what happens, often dramatically—that you go in and have a session and come out feeling changed in how you think, feel and behave—it's hard to attribute that to neuroplasticity per se. But, again, as I said, we're still at a pretty primitive level in understanding how these things work. But again, some people, some companies are trying to see whether they can block the hallucinatory experience or that trip, which would make these agents much more, I think, acceptable to more people who might be vigilant about wanting to go through something like a psychedelic experience.

Nancy Kathryn Walecki: So right now, in these clinical trials, are patients taking, you know, a microdose? Or are they hallucinating, taking a large dose?

Jerrold Rosenbaum: Yeah. There's some interest in microdosing, I would say. Microdosing is a dose of a psychedelic that does not have a perceived effect on perception. It's a dose that you could take and not know you're on anything. So there is some interest in it, because there are testimonials of people who use these very low doses, these doses that are below your ability to perceive that you're on something, and taking them daily or sometimes three times a week. And they say that over time, it's improved their, you know, their mood, anxiety, attention, what have you. There's not any evidence at all for microdosing, other than testimonials. There was one study that attempted to do a controlled trial of microdosing in England, where placebo and microdosing came out, everybody did better, but placebo did just as well. So the studies that are being done are all full doses, and they're done in controlled settings. In fact, for some of the trials that are being planned, where they're not certain what dose will be adequate, they will give a second dose at a higher dose to make sure a person has a intense entheogenic or spiritual or emotional experience. So you want to have that for the clinical studies that are being done. Again, there are some companies that are planning to study microdosing, but there's no evidence for that. It's full dosing, you have to have the experience, and as I said, the first studies that are being done, the ones with MDMA and psilocybin, have a fairly elaborate psychotherapeutic support along with the treatment.

Nancy Kathryn Walecki: So is there a risk of psychosis with taking these large doses? And then how do psychiatrists mitigate that during the therapy session?

Jerrold Rosenbaum: So there is a psychotic-like experience that attends the experience and interestingly, varies with the substance being used. For example, there's a characteristic report with DMT of people encountering creatures from another dimension, which they've called "machine elves", and whether that's suggestibility, that people have read about it, and and now, you know, have that experience, but different individuals have different experiences. So they're psychotic-like and that you are having perceptual distortion, sometimes hallucinations, and visions, and so forth. But again, they're transient, and often the outcome of the experience is a positive one. Because it's psychotic-like, people are very cautious about administering these agents to people who have a history of a psychosis—whether it's schizophrenia, bipolar illness, or even family history—because certainly people have had psychedelic trips and come into emergency rooms, and either have had transient psychotic experiences that were distressing, or in some cases, people had onset of a psychosis. Now, given the numbers of people who have had these agents, you know, they may well have triggered a psychotic episode in somebody who had a psychotic disorder, or it may just have been that people who were vulnerable to psychosis happened to be using these agents. So it's not clear yet. I mean, there are some people who hold out the belief that the right use of these agents may be therapeutic, but for now, it's considered to be a contraindication, and researchers are cautious about administering these agents to anybody who has either had a psychotic disorder or has a prodrome of a psychotic disorder, or a family history of a psychotic disorder. But truthfully, we don't really know whether these drugs in the end are dangerous for people with a history of psychosis. But that remains for, I think, very cautious research approach, maybe starting with microdosing and a very controlled environment to see whether they could have therapeutic benefits in the end for some people, but we, we really don't know that.

Nancy Kathryn Walecki: So are these mainly being studied as a potential treatment for depression? Or are there other disorders that psychedelics could be useful for?

Jerrold Rosenbaum: Yeah, there'll be, they're going to be developed and tested for really everything. So right now, we're furthest along in trials for treatment-resistant depression, and PTSD. PTSD, there was quite a good study that was published in a quality journal, "Nature Medicine," sponsored by the MAPS Foundation, which has been, for a long time been raising funds to develop MDMA as a therapeutic and is beginning their studies with PTSD. And that study was very positive. But there are studies in addiction, harkening back to the early studies that showed promise with alcoholism, some you know, people were able to become in recovery after using LSD. And so that's being pursued. There are people using ayahuasca for addiction and other disorders. There are people, and actually a number of veterans, going into Mexico to use ibogaine for addiction. So that I know there's a small study about to take place with eating disorders, there's been a study with OCD at an academic medical center, there is interest in LSD, particularly microdosing for anxiety disorders. So basically, these substances are being looked at, really, for all the important psychiatric disorders. And it makes sense because, you know, the psychiatric disorders are not disorders in the classic sense, where we really, you know, understand the specific biology. Although we call these things disorders, they often occur with other disorders. So you know, if you have anxiety, you have depression. If you have depression, you have anxiety. If you have OCD, you have anxiety and depression. If you have bipolar illness, you have psychosis, and sometimes depression, sometimes mania. The genes that underpin these disorders are multiple hundreds of genes, create a genetic risk profile for these drugs. And they overlap. So the genes that you find in populations with schizophrenia are also found in bipolar illness, and depression overlaps with bipolar illness and ADHD. So they're there, we're really not talking about discrete disorders. And the agents that we use now, which we call antidepressants, are used for OCD and they're used for anxiety disorders, they're used for depression, they're used for pain. So it really, really gets back more to this notion that these are conditions where, for whatever reason, people are stuck in states they can't get out of that are distressing. The brain does have the capacity to recover from these but it needs help from these therapeutic molecules, some of which we call antidepressants, but they're more aptly called psychopatholytics, because they work for so many different conditions. And they're not treating depression, we don't even know specifically what causes depression except it's a brain state with changes in neural networks. Some patterns of connectivity in the brain are associated with good response to antidepressants, some with good response to psychotherapies, like CBT. So there's difference in brain networks. But it's, it's like the brain is stuck in a state that needs to change. And it may be that, you know, when you induce neuroplasticity, you give the brain a chance to recover. Or it may be with the psychedelics, you know, you basically disrupt the network and it allows it to reboot the same way that when you restart your computer, it has a chance to kind of, you know, the software has a chance to kind of work better, and so you switch from one state back to another. The underlying principle that got me involved in psychedelics, I'm a, you know, although I'm a child of the 60s, I have not actually used any of these substances. But, you know, when I was coming to the end of my "use by date" as chief of psychiatry, and I was trying to think of, you know, what am I going to do in the afterlife, as always, I was led by my patients who, you know, you just sort of, you know, you're looking at this, the same, same conditions and many times, same patients, for years, and then suddenly something strikes you. And what struck me was how the burden of all the disorders that we were trying to treat, whether it was depression or anxiety or addiction or OCD, was carried by a form of stuck repetitive thinking, which is termed "rumination." And, you know, psychologists have studied rumination, but it's interesting, it's not been a major part of our nosology in psychiatry. The DSM-5 categories of psychiatric diagnoses hardly mentions rumination at all. And yet, when you talk to depressed people or anxious people, mostly, you know, they're in this stuck mode of, of dwelling on disparaging thoughts or things they feel they did wrong or things they wish they could change, and they make no progress. It's sometimes called faux-problem-solving. And it's very burdensome, and distressing, and absorbs a lot of energy, and when people are very depressed, it's tormenting. But what I also noticed was that when people recovered from depression, it didn't go away, it just got a little lighter. So there was something about the process of rumination that seemed fundamental to a lot of the suffering that went with psychiatric disorders, and in my oversimplified notion of rumination, I knew that people who have done neuroimaging studies of rumination show increased activity in the default mode network. And so when I saw the the first studies about changes in default mode network with psilocybin, I simply said for our studies on rumination, which we were starting to do—we had developed a measure to be able to look at how it can change in the short term with different therapeutic approaches, and we were trying to develop a treatment protocol for rumination—I thought, "Well, gee, it would be interesting to study psilocybin because look what happens to the default mode network." Now, there's a lot of, you know, more sophisticated neuroscientists than I who feel that the efficacy, or the therapeutic value, or the characteristic response to psychedelics is not entirely explained simply by changes in default mode network. There may be important other systems or regions of the brain involved, like thalamus and so forth. But at that point, you know, that was enough for me to go on, and I reached out to one of the founders of Compass Pathways to just see if I could source psilocybin to study in people with severe rumination. I had no idea first of all, how hard it is to get from having psilocybin to being able to do a study, getting through all the regulatory barriers. But that said, the person I spoke to, whose name is Ekaterina Malievskaia, one of the founders of Compass Pathways, not only was willing to provide us with psilocybin, but through a foundation and other sources of philanthropic support, kind of underwrote the project. So we were able to fund now two basically neuroimaging studies of psilocybin in treatment-resistant, depressed patients with severe rumination. So that's how I got into the business. And then, in talking to her one day, she said, "This is a good project, but can you think of something bigger?" And I said, "You mean, like a whole center to study psychedelics?" And she, because she's pretty sophisticated, she's a physician-scientist herself, and she knew the resources that existed at Mass General, which I don't know if you know, is the nation's largest hospital-based research institutem with $1.1 billion a year of funding, etc. But then, you know, one of the jewels in the crown is MGH Neuroscience, or Mass General Neuroscience. And so, she said, "Yeah." So I said, "Well, that's interesting." So I just made some phone calls to some of our most brilliant, distinguished scientists like Bruce Rosen, who runs the Martinos Center for neuroimaging and basically, his team invented fMRI and designs and creates all the newest tools for neuroimaging. And when I called him, he said, "You know, I've always been wanting to do this, but I didn't think I could say anything. But if you say it," because you know, I was an old timer, "I'm in." And then I called one of the most brilliant researchers on neuroplasticity who's a member of my department in psychiatry and also neurology, Steve Haggarty of the Haggarty Lab. And it turns out he had a lifelong interest in this stuff and had been, you know, his Bible was "Plants of the Gods", and he, as a teenager, read Richard Evans Schultes collections of Amazon plants, and he was just always wanting to do this. But again, same idea, you know: would he be taken seriously? And so when Bruce was in, and I was in, he was in, and then he brought along Jacob Hooker, who is as far I know the most brilliant neurochemist that has been created by evolution, and then in the Department of Psychiatry, we had, you know, people with lots of experience in clinical research. And my partner in the rumination study was a junior faculty member that had been one of our residents who, by chance, when she did her MD-PhD at Yale, her PhD was on rumination. So she became the lead on the rumination project and then crossed over to become the associate director of the Center for Neuroscience of Psychedelics. Her name is Sharmin Ghaznavi. So we had a team, and then the team kept growing, you know, lots of people wanted to be part of it. A cardiologist, Jeremy Ruskin, who founded our Cardiac Arrhythmia Service decades ago, and is now Director Emeritus, he wanted to look at cardiac effects of psychedelics, and he's joined our team, and just you know, a volunteer, newly retired brilliant biostatistician. So the team just started growing. And, you know, we as I said, we had some funding to start with and our goal was to, you know, raise significant philanthropy, to be able to answer the questions that we started with, which was what is really happening in the brain, not just where do things start? But what is fundamentally changing? What are the neurochemical pathways? How are they influencing changes in networks? And then the goal would be to, if you can understand that, you probably can come up with novel therapeutics that may be easier to use, less burden by historical things like Schedule I, that might be able to be safely given in more traditional clinical settings. And so that would be the goal: to try to understand how these things work and then to continue the advance of our knowledge of psychiatric disorders and therapeutics. And that's going to require a lot more funding, which we thought was going to require that we do better at philanthropy than we have done. We've raised about $8 million so far for different components of the center, but we really, as far as I can tell, need somewhere between 50 and 100 million so that it becomes sustainable, and I can get out of the way and get somebody younger and mid-career to take it over.

Nancy Kathryn Walecki: So are these studies mainly right now using brain imaging and kind of combining that? Okay.

Jerrold Rosenbaum: Yeah, so the first two human studies are psilocybin in treatment-resistant depressed patients, one focused more on rumination, one focused on other cognitive variables with lots of neuroimaging, five neuroimaging sessions with each study with a single psilocybin therapeutic experience, but done the same way it's being done in the clinical trials with the 24 hours of therapeutic support. We are talking with other potential collaborators for other psychedelic studies that may involve some of the other psychedelics that I mentioned, like LSD and 5-MeO-DMT. And there has been some significant philanthropic support for the basic laboratories, the Haggarty Lab and the Hooker Lab. There have been some sponsored research agreements with the leading psychedelic companies, like Atai and Compass Pathways, who are supporting some research efforts in some of our CMP labs.

Nancy Kathryn Walecki: Okay, I suppose, kind of wrapping up, do you think this could ever become as widely used as other psychiatric pharmaceuticals or what's sort of the end goal?

Jerrold Rosenbaum: You know not in the near term. I think there'll be a lot of barriers to widespread use, even if they turn out to be powerfully effective. They're going to be expensive, you know, to develop a therapeutic agent is, hundreds of millions of dollars of cost. If these are treatments that are going to be used once, twice, or three times with the expectation there'll be a durable benefit, my guess is they'll have to be very expensive for the companies to justify their investment. And then in particular, if it turns out, they're not that durable, because we don't have a lot of long-term data to show how long these benefits last, then it's going to get complicated. And then if you're going to have to have two therapists for eight hours before, and then during, and then after, and then if you need a special setting that is conducive to a positive experience, you know, with, you know, music and headphones and quiet and, you know, there are not a lot of current clinical settings that can provide that. There are entrepreneurial efforts to create centers that might be able to do that. They're focusing now on ketamine, which is prescribable and available and cheap, or at least generic ketamine is cheap. And with the idea that they'll transition those centers to be sites for psychedelic treatments when the time comes. But still, even if they're powerfully effective, I think it'll it'll be a long time before they are first, second, or third line and not reserved for, say in the same way we use ECT today for you know, for people who have failed lots of treatment and are quite ill. So my guess is it'll be a while before these medications are accessible by patients as first, or second or third line treatments. What I think is going to happen, and some of the people who are skeptical or cautious about this worry about this, is that when they get medically approved and the process of decriminalizing possession of these substances decreases, that you'll see more widespread access through what is now called the underground. Given that LSD is easy to manufacture and mushrooms, you know, can be obtained, there'll be more people using these substances outside of the medical system, encouraged by the approval of them as medications.

Nancy Kathryn Walecki: Okay. What is ECT that you mentioned?

Jerrold Rosenbaum: Electroconvulsive therapy, also historically called shock therapy, but it's a treatment whereby an anesthetized patient has an induced seizure in a hospital setting. And a series of those treatments, usually somewhere between six and 12, will typically, 80% of the time, allow a patient who's been resistant to treatment to recover. It's typically used for severe depression, suicidal depression, psychotic depression. Ketamine infusions is a another, sometimes more preferred, alternative for that population now as well. It seems to be particularly helpful for very severe anxiety and depression and suicidal depression. Infusions of this anesthetic or pain medicine, or party drug, depending on your perspective of ketamine, that seems to be sort of a forerunner or as, you know, kind of a stalking horse for the psychedelics. It's sort of a model for that, in that patients come in, they get an infusion, they're in the setting for several hours while they have that experience, and they may get two or three over a one-to-two-week period, and many times get remission from a depressive condition that had not responded to traditional treatments.

Nancy Kathryn Walecki: Okay. And final question, are there any anecdotal experiences you've encountered in your research that have been really compelling to you in thinking about the potential reach of these drugs?

Jerrold Rosenbaum: So our human studies are starting later this year, so I can't say that I've observed anything in our research, but I have had lots of conversations, lots of outreach from individuals, some pretty, you know, serious people, academics that I've known over the years who have reached out to me because they have heard of our interest and have talked about their personal "journeys," they would sometimes call them because they weren't necessarily using them for therapeutic purposes, but to treat lifelong anxiety or impairing symptoms. And, you know, they're, again, they're testimonials. I mean, I'm not hearing, I haven't heard from people who have said, "This was the worst experience of my life where I'd never do it again."

Nancy Kathryn Walecki: Right.

Jerrold Rosenbaum: But the weight of all these stories is, you know, compels you to pursue understanding of what's happening.

Nancy Kathryn Walecki: Right. Well, thank you very much for joining us today and for such a great conversation. Dr. Rosenbaum.

Jerrold Rosenbaum: Thank you, Nancy Kathryn.

 This episode of Ask a Harvard Professor was hosted by Nancy Kathryn Walecki and the season is produced by Jacob Sweet and Niko Yaitanes. Our theme music was created by Louis Weeks. This fourth season is sponsored by the Harvard University Employees Credit Union and supported by voluntary donations from listeners like you. To support the podcast, visit harvardmagazine.com/supportpodcast. If you enjoyed this episode, please consider rating and reviewing us on Apple Podcasts. Contact us with questions at harvard_magazine@harvard.edu.