Behind the Manuscript: The Psychedelic Renaissance and Treatment-Resistant Depression with David Feifel, MD, PhD

Journal of Clinical Psychiatry: psychiatrist.com/jcp/

Dr. David Feifel: https://www.linkedin.com/in/davidfeifel/

Kadima Neuropsychiatry Institute: https://www.kadimanp.com/

Ben Everett, PhD, is the Senior Scientific Director for The Journal of Clinical Psychiatry and Psychiatrist.com, where he oversees editorial strategy, content development, and multimedia education initiatives. He is the creator and host of The JCP Podcast, a series that brings together leading voices in psychiatry to explore the latest research and its clinical implications. Dr. Everett earned his PhD in Biochemistry with an emphasis in Neuroscience from the University of Tennessee Health Science Center. Over a two-decade career spanning academia, publishing, and the pharmaceutical industry, he has helped launch more than a dozen new treatments across psychiatry, neurology, and cardiometabolic medicine. His current work focuses on translating complex scientific advances into accessible, evidence-based insights that inform clinical practice and foster meaningful dialogue among mental health professionals.

This transcript has been auto-generated and may contain errors. Please refer to the original recording for full accuracy.

0:00 – Dr. David Feifel and His Breakthrough Career

Dr Ben Everett (0:07)

Hello and welcome to the JCP Podcast where we explore the science and stories shaping mental health care. Today I’m your host, Dr. Ben Everett, senior Scientific Director with Physicians Postgraduate Press, publisher of the Journal of Clinical Psychiatry. On this podcast we speak with clinicians, researchers and thought leaders advancing the field of psychiatry with a focus not just on what’s new, but on but what’s meaningful for our listeners in clinical practice. Today’s episode is part of our behind you’d manuscript series where we take a deeper look at a paper recently published in jcp. It also marks the beginning of our new theme, Psychedelics in Psychiatry, where we’ll be exploring the emerging science and clinical potential of psychedelic treatments in psychiatry. My guest today is Dr. David Feifel, a psychiatrist, neuroscientist and Professor Emeritus of Psychiatry at UC San Diego. He is the founding president of the Kadima Neuropsychiatry Institute in La Jolla, which specializes in advanced treatments for mental illness and conducts pioneering clinical research and novel approaches such as psychedelics. After earning his MD and PhD in Neurobiology from the University of Toronto, Dr. Feifel completed his psychiatry residency at UC San Diego where he rose to full professor and in 2008 established the world’s first ketamine infusion program for depression. Dr. Feifel has authored more than 150 peer reviewed publications and his work has been featured in the New York Times, Time Magazine, Rolling Stone, Scientific American and CNN among others. Through Kadima’s Project Africa, he’s working to bring ketamine and psychedelic therapy to Rwanda. He also contributes to national expert committees including the National Network of Depression Centers Task Force on Ketamine and Psychedelic Therapy and previously served on the board of the Clinical TMS Society. Today we’re going to be discussing your recent paper results from a long term observational follow up study of a single dose of psilocybin for treatment resistant episode of major depressive disorder which appeared in issue one of JCP this March. So Dr. Feifel, with that long introduction, this is a pleasure to have you with us today.

2:13 – How Early Curiosity Led to Psychiatry Instead of Neurology

Dr David Feifel (2:13)

Thank you Ben. It’s a pleasure for me to be here.

Dr Ben Everett (2:15)

All right, so we start out every episode with kind of a couple of icebreaker questions. Try and get people to know you a little bit better for you. Did you know from a young age you were going into science and medicine or was it something you got to a little bit later in life or what drove your passion in this area?

Dr David Feifel (2:32)

For me, science, yes. Medicine, no. I was. Gosh, I as a Child, I went through a series of immersed myself in different fields, thinking I was going to pursue careers. The first one was wanted to be an aeronautical engineer. I was fascinating with planes, then astronomy, and all the while as a. It was a kind of a debate between that and being a hockey player because I was born and raised in Toronto, Canada, so that’s sort of, you know, every child’s primary option. But by the time I had gotten to high school, I became enamored with the field of physics and quantum mechanics, which, as many of your listeners may know, brings the mind into the construction of reality. And that led to me being interested in the mind and the brain. And that’s how I decided to go into medicine and then psychiatry.

Dr Ben Everett (3:26)

Did you go directly into an MD PhD program or did you do one before the other?

Dr David Feifel (3:31)

No, actually like a combination of something in between the two. I actually didn’t know about an MD PhD program when I started medical school in the first year at the University of Toronto, they announced that people could apply from first year into this MD PhD program. And I was already interested in doing research. That sort of was my goal in going into medicine. I looked into it. I decided at the end of the day to do my own MD PhD program because I felt that I could be more efficient than the way that it was structured. I asked for a pause in my training. After my second preclinical year, I went out and did the majority of my PhD work and came back to finish my last two years of the medical degree. I did it in an integrated way, but created my own program.

Dr Ben Everett (4:17)

So you mentioned quantum mechanics and physics drove your interest in maybe cognition and reality and those types of things. So when you went back in and finished your clinical rotations, you knew you were going to do psychiatry, as you had already done your Ph.D. in neurobiology. @ that point in time, I actually.

Dr David Feifel (4:33)

Thought I wanted to go into neurology in my mind. That was the brain specialty. But it’s interesting that when I got to my neurology rotation, I realized they weren’t that interested in the mind. They were really interested in the brain as sort of a kind of a organ with wires and connected to the peripheral nervous system. And I’ll never forget doing my neurology residency and we had a journal club and it was with the residents and it was my turn to find it article. And I went to the library. And back in those days, you had to actually go to the library and look through journals. An odd concept for some of the younger listeners. I kept looking in the neurology journals for something that I thought was really profound and had philosophical implications on consciousness and so forth. And I finally found something that had to do with aphasia and brought it to the journal club. And I remember the attending who was actually at the time chair of the department of neurology, berated me for that, like, what is this kind of, you know, it was like they had no interest in that. I said, I don’t think I would be comfortable in neurology. And then shortly after I did my psychiatry rotation and really loved it because I think there was, you know, we knew less, and I think it’s still true, we knew less about the psychiatric disorders and how the brain manifested the symptoms. And they were more open to non conventional thoughts about psychiatric conditions and normal cognition. So I just found it was more wide open. I found my home there.

Dr Ben Everett (6:03)

It’s really interesting and that’s a theme that I’ve actually heard from other people in terms of a lot of physicians or people that go to medical school, they like these very kind of cut and dry, okay, this is your presentation, this is your diagnosis. And psychiatry is uncomfortable for a lot of people because it’s not as quantitative, it’s much more qualitative, subjective. And it really takes someone who has that type of mind to think through that and want to spend time in that space. So that’s really interesting. It’s interesting to share a little bit about myself. But I only have the PhD one 1D degree was enough for me. But I studied dopamine and dopamine receptor signaling was in a dopamine lab. So I did biochemistry and emphasis in neuroscience. And even though dopamine’s implicated in all these different things, I was just really honed in on neurodegeneration for some reason. But we’ve made much better strides, I think, in mental health and psychiatry over the last, let’s say two and a half, three decades than neurology. Although it’s really a golden age for neurology now with all sorts of new therapies that are really life changing for patients. So I’ve come to mental health later in my career as well. But I’ve really found a home in mental health. Love this space and working with psychiatrists and researchers in this area. So now that you’ve done this integrated MD, PhD, when you finished, what was your plan? Did you still want to try and do research, clinical medicine? Were you hoping to find a job? You could do both because sometimes in academia they’re like, okay, this is A clinical position or it’s a research position, sometimes you can find a job that is a combination of the two.

7:33 – Balancing Clinical Practice With Research Innovation

Dr David Feifel (7:33)

I really wanted to find a job that’s a combination of the two. And I remember that being a liability because there’s a kind of ethos in the MD PhD world where you’re not supposed to spend a lot of time clinically, supposed to be primarily focusing on research. And I thought that was such a waste. I mean, I mean, the whole point of having this extensive training is to be able to especially do like, maybe the ideal target for somebody who has an M.D. ph.D. Is translational work. But it wasn’t the ethos. And I don’t still think it’s not the ethos. It’s doing hardcore preclinical work. And really the mix that is often described ideally as 80, 20, 80% of your time in the research, 20% in the clinic, but how good can you be in the clinic? And I would go to interviews for residencies and, you know, if I mentioned that I’d like to be 50, 50 saying, you know, that’s not feasible and not advisable, but I was like, I just started to say 80, 20, and said to myself, I’m still going to do 50, 50, and I think I was able to do that. And people would ask me, how much of your time do you spend? And I, you know, I was. When I did my residency at UC San Diego, it was a research track residency. They had one of the best research track residencies. And I came onto the faculty. The kind of ethos there was if, you know, you kind of get grants and buy yourself out of the clinical requirements for your salary. And when I started to get grants, I didn’t want to do that. I still wanted to see patients, and I was running the inpatient unit and doing trials. So I went against the grain, as I kind of done for much of my life. And I broke the mold and maintained a very, very active clinical role at UC San Diego, as well as had a very well funded active preclinical lab. It was great. It was great. It was a lot of work. And people would ask me, like, when do you sleep? Yeah. Yes. If you ask my wife, she’ll say, that’s the cost. That was the cost for sleep. That was before all the bad data came out on sleep. And I’m a big coffee drinker as well. And the data on coffee have swung my way. You know, it seems like, you know, if you’re, you know, kind of just like hoping the data on Sleep is going to swing my way eventually too, because otherwise, you know, two years, I won’t be coherent.

Dr Ben Everett (9:53)

The coffee stuff is interesting because I follow that some too. Kind of a one cup a day guy myself. My wife’s a dietitian and their. I can’t remember the name of the journal, but it’s the official journal of their society. Years ago put out a paper that said that most Americans get all of their antioxidants through their coffee because our western diet is so poor. And so that’s been. I’ve just stuck with that one paper. It might have been swung the other way, but I’m like, I remember reading this one like 20 years ago.

Dr David Feifel (10:20)

That’s right.

Dr Ben Everett (10:21)

That was all I needed for antioxidant.

Dr David Feifel (10:23)

That’s right.

Dr Ben Everett (10:24)

I do other better things, so. Oh, well, great. Thanks for the introduction. So before we dive in really to this paper, this is our first entree into psychedelics. So for listeners who may not be up to speed with psychedelics, I want to just spend a few minutes just talking about psychedelics and really not going to be too overarching. We don’t have a semester to go through this. But just set a few things up. We’re going to focus on psilocybin for this paper specifically for use in treatment resistant depression. But there’s certainly a keen interest in a number of other psychedelics. I know there’s at least five, at least that I’m aware of that are being developed by industry in collaboration with academia on paths for FDA approval that have received breakthrough therapy designation status from fda, which is pretty rare. Not all drugs get that. You’ve got esketamine for treatment resistant depression and for major depressive disorder with an imminent risk of suicide. That was the latest indication that they got. For Spravato, I mentioned MDMA or Medomafetamine for ptsd, psilocybin for MDD and also for treatment resistant depression. Two different companies, different development paths there and then LSD for generalized anxiety disorder. So it seems to be a very exciting time for the study of psychedelics.

11:41 – Psychiatry Entering a Transformational New Era

Dr David Feifel (11:41)

I think it’s an exciting time for psychiatry. I think psychiatry is in the midst of a kind of golden age revolution, paradigm shift or whatever you want to call it. And that was also a big factor in me wanting to go into psychiatry. I felt that psychiatry was behind the other fields because the brain is complex. It’s the most complex when you’re trying to understand how it interacts with consciousness, it mediates. That’s less complex when you’re Trying to just understand how it moves your limbs. I just felt that with everything happening with, you know, neuroimaging and so forth, we were going to have this tremendous, you know, revolution and golden era. And so I want to be part of that. And it’s interesting because probably 10 years into my career as a board certified academic psychiatrist, I started to doubt whether it would happen. I thought maybe I kind of, my timing was right because nothing was changing. I mean, neuroscience was advancing and really doing remarkable things in terms of new tools and so forth. But the treatments were the same. And I, you know, I found myself, you know, a decade past my residency, pretty much prescribing the same medications for all intents and purposes. You know, my mentors in, in medical school were prescribing when they were residents. And, you know, I thought it may be my residents that are going to be the lucky ones. But then things started to happen. You know, ketamine, the papers on ketamine came out. Tms, which is extremely exciting, was developed. And I jumped onto that very early, as I did with ketamine. And now here we are with all the psychedelics. And I just think this is great because it’s so needed, you know, it’s so needed. It wasn’t just that psychiatry treatments weren’t, we weren’t developing anything. It’s that, that they really weren’t up to the task. When you think about how prevalent and how deleterious mental illness is, you know, I would, I would facetiously say, I feel like every, you know, back in those days, I felt, okay, I was going to war with Godzilla every day with a peashooter. It was like, wanted, give me something, give me an M16 or something. And now I feel like we’ve got some real tools that we currently have and even better ones that are hopefully just around the corner.

13:51 – Why SSRIs Fall Short and TRD Demands Better Solutions

Dr Ben Everett (13:51)

Yeah, I think certainly, you know, if we look at like SSRIs for depression or treatment resistant depression, you know, you look at most meta analyses now, the effect sizes really aren’t great. I think at best we could say Moderate, you know, 0.3 to 0.5 effect size, it’s been the best thing we’ve had for decades and for certainly for most patients, not, I wouldn’t say most patients, but for certain patients, SSRIs, SNRIs, they really don’t seem to have any impact at all. About 100 million people worldwide are estimated to have treatment resistant depression. Such a huge unmet need. And I know recently there was a reanalysis of the STARD study that’s the sequenced treatment alternatives to relieve depression. It noted that about a quarter of patients experience remission of their MDD following their initial treatment with citalopram. So a lot of room for improvement.

Dr David Feifel (14:40)

I think a lot of room for improvement. And what’s not sort of parent in those statistics is TRD is defined as two or more antidepressant failures, where a failure is getting less than 50% reduction in your baseline symptoms. Now, a lot of those people who are considered responders are maybe getting 50, 55% reduction, but, you know, that’s still leaves a lot of impairment. And they’re considered to be success stories. They’re not in that TRD statistic. And so even when I see a new patient coming for one of our advanced treatments, I always ask them about their experiences with the antidepressants. And even the ones that say that they feel the antidepressants have helped will still say that there’s still significant residual symptoms that impact her quality of life. So very few in true remission. And we, and I think we’ve seen that with the reanalysis of this rd. And then on top of that, the side effects, one of the most common things I hear is that, yes, they help me stay out of the darkest parts of depression, but I also feel like my emotional range is constricted. I feel mountain. Even when it’s a success, it comes at a price. So on the whole, I really think that conventional antidepressants leave a lot of room for improvement. They really just aren’t cutting it, given the prevalence of depression. And that’s true for anxiety as well. And almost all of our treatments, maybe with the exception of adhd, I mean, stimulants are quite effective and they’ve got issues, but people really feel that the effect sizes that they feel is quite big. But when it comes to most other treatments, there was a lot that needed to be improved. And I think we’re finally addressing that.

Dr Ben Everett (16:26)

Well, cool. So that kind of transitions us to psilocybin and mentioned a handful of these different, and I’ll put in air quotes, psychedelics, because off air we talked about how, you know, their traditional psychedelics are more like, you know, LSD, psilocybin, really very potent serotonin 2A receptor agonist, which certainly kind of fits the model, right, with SSRIs, SNRIs, things like that. Different from like an MDMA, which I think intactogen is the right type of qualification there. Ketamine is really dissociative, so they all get lumped together as psychedelics. But they do work differently in the brain from a psychopharmacology standpoint. And they’re being developed and studied for different indications now maybe in 20 years we’ll look back and we’ll understand sequencing. Oh, look for this patient, you do this and then you give them, you know that, and you put them on this. We’re at the infancy of this stuff right now, so we’ve got a long time to figure that out. But what is it about psilocybin in your view, having done some of this clinical research, that makes it well suited for TRD or mdd?

17:27 – What Makes Psilocybin the Leading Psychedelic Candidate

Dr David Feifel (17:27)

Psilocybin as a classic psychedelic, it makes it well suited. Time will tell, but I don’t know if we’ll see replicable systematic differences between psilocybin and, let’s say, LSD or other classic psychedelics like 5 Meo DMT. There clearly is some differences in their duration of the psychoactive effect. One of the reasons that make psilocybin particularly auspicious is, let’s say, the brand it has compared, for example, to lsd. I mean, psilocybin as sort of mushrooms has a very benign public image compared to, let’s say, lsd, which a lot of people associate as acid. You know, they work on the same. It always surprises some of the patients that I tell them that they actually work in the brain very similar. Same receptor studies that look at the effects in blinded patients find that they have at the kind of equivalent doses, similar effects, even subjective effects. In the studies that we’re doing, they gravitate to the psilocybin much more than some of the other psychedelics that, you know. The DMT is less well known and when people look into it, they come across, you know, very short, intense, it scares them. LSD has got this reputation, but psilocybin has got this natural kind of thing to it. So we, we find that we have less, you know, less. I wouldn’t say convincing, but people are more comfortable with the idea of psilocybin. So it’s, it’s a good entry in this class. It’s a good candidate as, you know, a entry point for acceptance, I think, in the public.

Dr Ben Everett (19:07)

I agree wholeheartedly with that and I think patience who don’t have often the scientific knowledge and background that you would have as a investigator going through informed consent with somebody. But anytime something’s natural, people just feel like it’s okay, even though, like, okay, well, arsenic’s natural, right?

Dr David Feifel (19:22)

There’s plenty of things that are, that’s Exactly. The example I give, it’s like, I would say, you know, like a rattlesnake venom is totally natural. You know, it’s a strange kind of.

Dr Ben Everett (19:33)

Concept, but people definitely like that. I mean, I spent a large part of my career working on omega 3 fatty acids, you know, which is fish oil, people. Oh, yeah, fish oil. You know, and, like, you know, okay, but this is extremely concentrated. It’s just. It’s different. But people are like, oh, I’d much rather take that than take a phenofibrate or a niacin or something like that for triglycerides or whatever it is. So. All right, so. So why now? I think maybe we kind of got to this a little bit earlier. But, you know, why do you think this is the right time? You know, this has been termed the. The psychedelic renaissance. I’ll say just from a. A study standpoint, it’s still difficult to do research with psychedelics because they’re all still class 1 DEA under controlled substances act, which makes it very difficult to do the research. But given that we’re doing it, we’re here, companies are figuring out how to do it. You know, what makes this the right time for this psychedelic renaissance.

20:25 – Why the Psychedelic Renaissance Is Surging Now

Dr David Feifel (20:25)

A decade ago was. Was the right time. Two decades ago was the right time. Why it’s happening now is probably a number of factors. One is, I think we’ve got to the point the bloom is off. The SSRI rose. When I look back and I read some reviews of the history of psychiatry, and they talk about, like, Prozac being a big milestone, a big breakthrough. And really, what was the breakthrough there? I mean, it was more tolerable because, you know, it was more selective and didn’t have some of the noradrenergic or the cardiotoxic effects of the tricyclics. But from a mechanistic point of view or a efficacy point of view, there’s never been any evidence that was more effective. We got very enamored with the monoaminergic medications starting in the 60s. And then, you know, when Prozac came out, it was thought to be another kind of advance. But then I think we got to the point where we’re realizing, like, as we were just talking, yeah, take a close look, they’re not great. And they had a whole slew of meta analyses really questioning are they effective at all, you know, compared to placebo. At the same time, on the psychedelic front, I think enough time was passing from the early 70s when, you know, they were scheduled, and basically research became almost impossible. And, you Know, places like Johns Hopkins was kind of bringing the research back. These two factors, the recognition that we don’t really have good treatments compared to most other fields, and we’re not going anywhere with these treatments. At the same time, this very, very promising class of medications that were being studied in the 50s and the 60s that then got shut down, there was an opening attitude to that. And I think that’s. Those two things came together. I still, I’m amazed that a federal regulatory body, a conservative body like the FDA gives something like psilocybin or LSD fast track breakthrough status. It just seems like, you know, is that really happening? You know, have we changed that far? But I do think it’s a recognition of we need something, we need to take a little bit more risks because it’s just not good enough for people with depression and anxiety and PTSD and OCD and all those things.

Dr Ben Everett (22:51)

So what are the big misconceptions among patients, other clinicians? You know, maybe when you set up that first ketamine infusion clinic, you know, where people are like, man, he’s crazy. What’s he doing? Or were people like, oh, this is really something?

Dr David Feifel (23:02)

Well, I think there’s misconceptions on both ends. I think that a lot of people, when they hear about this class, certainly I got a lot of that when I started the first clinic for ketamine, for psychiatry, was, you know, this is reckless. These are addicting drugs. People are going to get addicted to them and people are going to going to be spike in abuse. So people kind of lump old illicit drugs in the same category. But, you know, you’ve seen the. You’ve seen the careful analysis of the addiction, proclivity of different substances. And there’s a whole world of difference between sort of an opiate substance like heroin or even alcohol, you know, which probably has the greatest adverse effect in terms of impact on society. And drugs like psilocybin and ketamine, in terms of their addiction potential. I wouldn’t say that without any potential, it’s relatively mild and we very rarely see it. I think people don’t distinguish. These are all illicit drugs. I think that’s one misconception. And then on the other hand, I think there’s some people who are overly enamored with these drugs, especially the classic psychedelics, thinking that they are going to, you know, completely be the end of mental illness and maybe all the problems in our society. I laugh, and I really, truly respect Rick Doblin, but I always chuckle when he tells the story about how when he was young and became convinced that psychedelics could be the answer to all the ills of the world, that he had made some efforts to, or at least plotted of sending the LSD to the Kremlin in the Soviet Union, the White House. If we can only get world leaders on this, war would end. And I just think that’s just, that’s not going to happen. And that’s why sometimes people get disappointed in some of these results because, you know, they find that psychedelics, when you test them rigorously, you know, they don’t work for everybody’s depression and when they work, they don’t cure it. You know, you see that there’s a kind of a dissipation over time and probably need to redose. And when you think that you take one of these and you have one of these so called hero trips and you’ll never be the same and you’re going to be a sort of a much more pleasant person, tolerant and so forth, that’s not in a realistic approach. We’ve got some corrections to do on both sides to put people more into a realistic, moderate attitude towards these drugs.

25:42 – Microdosing Myths and the Power of Expectancy

Dr Ben Everett (25:42)

The way I like to think about these things is are we talking about a medical model or are we talking about a guru or something like that? I won’t make any more comments than that. You know, having worked at Maps and our public benefit side of Maps and Lycos. But you mentioned kind of a heroic dose. So that’s Terence McKenna’s, you know, old term for like the full dose of. And specifically psychedelic mushrooms. There’s a lot of buzz and that’s exactly what it is. I’m doing air quotes. We’re not on video or. Well, Dr. Feifel and I are on video, but we’re just audio right now for the podcast. So anyway, air quotes here on, on the buzz around microdosing, you know, what do you think about microdosing? I certainly have my own thoughts, but I want to hear from you.

Dr David Feifel (26:25)

You know, I’m open. I take a scientific approach, right? I’m open. I was fascinated about this concept. I thought, wow. I mean, first of all, it has a lot of if it’s true that you can. And we should take a step back and define microdose because the term has become so widely used that I have a lot of patients come and they will say that they did some mushroom microdosing and when I talk to him it’s like they had a full on experience. And I say no, microdosing is taking the drug at A level where you don’t really experience anything. You wouldn’t know the difference subjectively whether you’re taking a placebo or not, but you’re actually taking a dose that’s below the psychedelic threshold. We should make sure that the audience, we’re all on the same page about microdosing. I thought it would be fascinating and I thought, boy would have a profound impact on the debate of whether, you know, the psychedelic experience is necessary. But it turns out that on the whole it hasn’t been researched rigorously enough. But the research that has been done hasn’t substantiated the efficacy of the microdosing. In contrast, you know, the studies that have looked at psychedelic dose meaning doses that clearly produce what people associate with the psychedelic experience are very effective. So I think we need to really study that some more. And I think either way it turns out it’ll be very interesting because to that the whole debate of whether you need the psychedelic experience or not.

Dr Ben Everett (27:55)

Yeah, very interesting. I think in terms of. I’ll put some numbers in here. So what Terence McKenna would say was a heroic dose was about 5 grams of dried psilocybin cubensis mushrooms. And typically when people talk about micro dosing, they’re talking about somewhere between like 125 to maybe up to 400 milligrams. But yeah, I’ll read things, you know, or somebody say, oh yeah, you know, I had some kind of mild subjective effects and how much you take, I took a gram. I’m like, okay, well you’re, that’s not, you’re probably not microdosing. But I’ve yet to see any real randomized, clinical or even somewhat controlled peer reviewed literature studies that really show there’s any effect. But then we kind of back into this placebo or expectancy bias. And if it’s helping people with their MDD or their adhd, there’s actually one decent study out of Europe that looked at it for adhd. Yeah. And it was mildly effective for microdosing. Again, only one study hadn’t been replicated to my knowledge. It’s very interesting. So a lot more to come. But yeah, I think we need to let the science really guide us.

Dr David Feifel (28:58)

It’s interesting that you have like swaths of people completely convinced that it’s having effects on them. Most often you hear about, you know, folks in Silicon Valley, very common there, and square by it and so forth, and then you do the studies and you go, well, that’s interesting. When you do a placebo controlled studies, there’s no Difference. So you start to wonder, all these people, you know, just what you, as you were saying, Ben, the effect of expectancy, the placebo effect, which I think is one of the things, you know, in, I was going to say in psychiatry, but in medicine in general, we have had such a wrong attitude towards, you know, we have looked at the placebo effect as sort of like unwanted noise that you have to kind of separate from the bioactive effect of the medicine. Whereas it is perhaps the most potent healing approach or phenomenon that perhaps we have. Getting back to tapping into the mind, Western medicine has kind of labeled it as some sort of unwanted freeloader that you need to kind of extract in order to really get to real medicines that have an effect. And you know, a lot of times, you know, in studies, the relative difference between the placebo, even when they’re statistically significant and the active drug pales compared to the overall placebo effect. Let me just editorialize for a second here. Our whole approach by the FDA as well. If you know you didn’t separate from placebo enough and we’re not going to approve you, even though everybody got better, the folks in the placebo got better, the folks who got the active drug got even more better, but not more better enough, if you will, to meet that. P05 and so we’re not going to prove this. The only problem with that, Ben, is that our baseline in the field, whether it’s psychiatry or another specialty of medicine, isn’t giving the baseline, isn’t giving the placebo. This is not like, well, this isn’t really making a difference. It isn’t making a difference in the controlled laboratory context where you have a placebo. But if everyone got this level of improvement, it would make a huge difference. And you’re not going to let this get approved because of the placebo, but we’re not allowed to give people placebos. Right. It’s making decisions about efficacy that really don’t take into account there may be no good treatment for something at all. You know, consider a condition and you’ve got something that dismisses statistical significance from placebo. But, and that’s because it was a big placebo response. Okay, well, we’re not going to prove it, but now nobody’s going to get those kinds of improvements because nobody’s getting the placebo to start with. I think it’s a wrong headed approach to thinking about making people’s lives better.

Dr Ben Everett (31:50)

It’s certainly complicated. And like when Dr. Brandon was on a couple of weeks ago, he’s a clinical Trialist by, you know, his career. And we spent a lot of time talking about placebo effect, especially in schizophrenia, where we’re seeing these drugs perform really well in phase two and then they get to phase three. And it’s not that, you know, the drugs in phase three, larger settings, they’re performing about how they did in phase two, but the placebo effect in these phase three studies is nearly identical. You know, I think there’s gotta just be something this expectancy bias. And for people who haven’t done clinical research, when you go through informed consent with a patient, you’re going through all of these different things, side effects, potential positive effects, all these different things. So you’re teaching the patient so much about what to expect. And these patients have been suffering for so long for whatever the disease, whether it’s a oncology type of disorder or schizophrenia, you know, serious treatment resistant depression or something like that. People are, they’re in these trials or they’re looking for these trials because they’re looking for hope. And hope is very powerful. It’s a very tough egg to crack. And I don’t think we figured it out yet. So let’s come back to the topic at hand here. So the, the psilocybin that’s been done at least for, for clinical research with the compass pathways, the sibin therapeutics or pharmaceuticals, they’re using a synthetic version. And so the doses are a little bit different. So let’s just kind of set that up. So, and this actually is a dose ranging study, the phase two study that we’ll get into, but we’ll talk about 25 milligrams is gonna be the highest dose. I know there’s been research up to maybe 40 milligrams of these synthetics. And that’s probably somewhere on the order of your 5 gram heroic dose that like Terence McKenna would have agree with that.

Dr David Feifel (33:32)

Yes, I think that’s about right.

Dr Ben Everett (33:34)

And then for people that are completely naive to psychedelics or what we’re going on, this is very different from your traditional clinical trial where you come in, you know, you do some baseline labs, you know, so here’s your bottle of whatever you’re getting, you know, placebo or, you know, it’s double wine, we don’t know. And you’re just going to take this every day and then we’re going to check in with you in two weeks or three weeks or whatever it is, Correct?

33:55 – How Set and Setting Shape Psychedelic Treatment Outcomes

Dr David Feifel (33:55)

Yeah, very different.

Dr Ben Everett (33:56)

You’re bringing patients in and because patients are going to be in an altered state of consciousness, we need to do a lot to ensure safety of the patient as well as the staff in case something untowards were to happen, like can happen with PTSD patients or acute anxiety with psychedelics. And so we talk about set and setting a lot. Can you talk to us about set and setting?

Dr David Feifel (34:15)

I think that’s one of the most interesting aspects of this class of medications. The traditional medicine concept is that the treatment, let’s limit it to drugs. The drug carries the treatment. In other words, the patient is just a passive object that needs to be. Some organ, needs to be remediated. And so the drug has been designed to go in and do that. And, you know, and the job of the patient is really to put it in their mouth, put it into their body, or come to the clinic and get an infusion or whatever it is. There’s never been really much attention paid to the patient, their state of mind or the setting that the drug was given. And comes along these medications, starting with ketamine and these psychedelics. And we realize that the patient’s state of mind and the environment that they’re getting this treatment plays a huge role in the outcome. And the example I give to patients is, let’s say I usually use ketamine because most of the people are coming to for actual treatment to our clinic or getting ketamine just because it’s available, rather than those that are being recruited into clinical trials. So I say to them, so imagine you’re walking, let’s say, in the mall, and I see you, and I run up and I surreptitiously, when you’re putting down your water bottle, I put ketamine in your water bottle. And this could be psilocybin or LSD or any of this psychedelics. I’ll tell you what would happen. It would be a horrible story, a horrible experience. You wouldn’t know what’s going on. You would think you’re losing your mind or having a stroke. And on top of it, the noise and the people around you would just make the experience even worse. You’d be kind of embarrassed and trying to hold it together, wishing this would. Would end. At the end of that, you know what it would be if it was ketamine, maybe an hour. If it’s psilocybin, maybe six hours later, you’d probably be sitting down somewhere with your head in your hand saying, that was horrible. What was that? That was horrible. If I came up to you and I said, listen, I have to be honest, that was ketamine, and I put it in your Water bottle, you want to throttle me, number one. And number two, you’d say, well, if that’s ketamine or psilocybin or whatever it is, I never want to do that again because that was horrible. And you certainly are unlikely to have an improvement in your mood or your anxiety. Now, I tell people, you come to Kadima knowing that you’re coming to get this treatment and we prepare you for it so we, so that you know exactly what’s going to happen. And you know, we put you in a room that is calming, it’s got plants, you’re listening to music, and we have a staff around you that understand this process, make you feel at ease, you feel like you’re safe. That same drug, that same dose, that it would not be at all surprising if you came out. And a lot of our patients will say something to this effect like, that was the most incredible experience I’ve ever had. You know, I just feel, you know, my depression is gone. This is what it’s like not to be depressed. It’s remarkable. Same drug, same dose. What’s the difference? Same person. The difference was the person’s state of mind, the knowledge they had of what’s going on, how prepared they were for it, and the setting. Stimulating, noisy setting versus a calm setting with a feeling of trust and safety. If you’re interested, Ben, you had mentioned before, some people like cut and dry aspects of medicine tend not to go into psychiatry. So if you’re sort of a. Well, I don’t want to be, I don’t want to be pejorative, but if, let’s say you’re an orthopedic surgeon, he gives you a kick, is the fact that you can do some drilling and pop out somebody’s worn out knee and pop in a new one and it’s cut and dry. And that’s kind of what gratifies you. You’re not going to like the messiness of, of this where you have to make sure that, you know, a person’s kind of appropriately prepared and, and you’re setting, where you’re doing that surgery is just conducive to it. But if you’re somebody like me who is really fascinated, the complexity of this marriage between this psychopharmacological agent and the person’s pre existing consciousness, brain state. It’s fascinating. It’s, it’s really fascinating and it brings a whole new dimension. There’s now a triad between the provider, the drug and the patient, all of which have to be optimized.

Dr Ben Everett (38:43)

Yeah, absolutely. The Therapeutic alliance is so important for this that you don’t have to have for, okay, you know, your cholesterol’s a little high. Here’s a statin, you know, fill it, take it. I’ll see you back in 12 weeks. We’ll see if your LDLs come down. It’s very different. So set and setting is very important for this. And that also gets into, you know, the idea of psychotherapy, which is we have not figured out at all. Right. So in this study that we’re going to talk about, psychotherapy was provided with the MDMA for ptsd. There was a lot of psychotherapy kind of in phase three. Some of the companies are kind of moving away from psychotherapy, at least as a prescribed, regimented part of the protocol. And I think some of that’s because of what happened for the MDMA for ptsd, adcom, where the FDA just really struggled with are we weighing the efficacy of the drug or the psychotherapy? If you’re doing both at the same time, it’s like we need to have a different type of comparator, you know, like almost like a two by two factorial design or a different type of trial setup. So it does get very complex. But just for that, what do you think about the role of psychotherapy? You know, with psychedelics?

39:51 – Do Psychedelics Really Need Psychotherapy to Work

Dr David Feifel (39:51)

It’s fraught with controversy, but I think that I have to be really honest, psychotherapy, the large effects we are getting with this category of drugs, is not reliant on a very specific psychotherapy. I think psychological support is important, education is important, but I don’t think there’s a term psychedelic assisted psychotherapy or ketamine assisted psychotherapy, which I really think is wrongheaded, which suggests that psychedelic is facilitating augmenting the psychotherapy. But it’s a psychotherapy that’s really doing the yeoman’s work when it comes to the improvements in symptoms. And we know from studies that, for example, the first ketamine studies done, you know, just have somebody on a gurney and IV put in them and given the drug, there was no psychotherapy, probably not all that much. And people showed remissions at 24 hours. And I know that I talked to many psychotherapists who have been using ketamine and psychedelics in their practice. Just had a hard time believing that. It sort of goes back to the era when medications, antidepressant medications came about. And previous to that it was psychiatry was all psychotherapy. And people couldn’t believe that you can improve somebody’s depression with a six week Course of, you know, something like Elavil, because it believed that these were deep personality structures that were due to, you know, childhood develop and things like that. So I don’t think we need very complicated psychotherapies. As one patient, I had a young lady said to me, you know, doing ketamine is like doing psychotherapy, but you’re both the psychotherapist and the patient at the same time. You know, while I do think the experience is, I’m not a believer in purely the, you know, neuroplastinogen aspect, where we can extract the experience and just go and make psychedelics. Just like the traditional concept where it’s all about the mechanics of what it will do in the brain without the patient being important. I think that’s going to fail. I think it’ll probably separate from placebo, those neuroplasticians, but they won’t have the profound effects that we see with, you know, with some of these psychedelics. But on the other hand, I don’t think that it requires a very systematic, structured psychotherapy. I think it just needs support and education. It’s almost like auto psychotherapy. You know, insights are produced, new perspectives are produced and it doesn’t require a lot of extraneous therapy. That’s my opinion on it. Time will tell.

Dr Ben Everett (42:35)

It’s an active area of research for sure. All right, so and then lastly, at least for psilocybin, again, very different from your traditional SSRI type of drug where the patient might not feel anything right away. How long do these dosing sessions last? And it’s kind of the last one to set up the phase two study here.

Dr David Feifel (42:51)

I believe in the phase two study for psilocybin, patients had to stay eight hours before they could not see or at least they could be discharged. But it turns out that probably based on the kind of the results, probably six hours is going to be adequate for most people.

Dr Ben Everett (43:10)

And this is very different depending on the drug, like LSD is more like 10 to 12 hours. Ketamine is pretty rapid and goes away pretty quickly too. So it’s not like that now when you’re doing infusion, you can kind of make it last a little bit longer.

Dr David Feifel (43:24)

Ketamine is, it lasts as long as you have to continue to give it because it is that short acting. And then on the other end of things, we have like 5 Meo DMT. You know, there was just a phase two study published on that where the average time to recovery was two hours and got really good results.

Dr Ben Everett (43:41)

Yeah, very quick.

Dr David Feifel (43:42)

It’s Great, because there’s so many unanswered questions that will be answered in the next few five to ten years about these. One of them is, you know, does the duration, you know, of the experience matter? My suspicions was that it was. But then you have these recent results of these very, very short acting psychedelics, you know, the 5 Meo DMT for as a best example, performing at least as well as the longer ones.

Dr Ben Everett (44:08)

A lot to be determined. And you know, there was a paper just out, what, not even a month ago, I think, out of David Olson’s lab and he’s at UC Davis, I believe, that did look at this. Do you have to have the subjective effect essentially, do you have to have the trip for the therapeutic effect? Which has very much been an open academic question. And at least in his animal model study you did not. And that’s the first evidence we have. Obviously it’ll have to be replicated and looked at in a bunch of different ways.

Dr David Feifel (44:34)

But I did animal models of psychiatric illnesses for two decades at UCSD and I’m sorry to say, but I don’t think we can extrapolate something like psychedelic experience and depression from animal models. But if you look at the indirect evidence in human studies, for example, you know, there early on there was a compound called GLICS 13, it was a NMDA receptor that did not have the dissociative, the psychedelic effects of ketamine, but acted on the receptor. And this was a drug that, you know, was being touted as being a, you know, a rapid antidepressant that wasn’t going to have any of the, you know, subjective effects. And that would have been real. It would have, it would have settled the debate. And phase two looked reasonably good. And phase three, they had to stop the study because it didn’t work. And then there was a study recently at Stanford where they gave ketamine to folks under anesthesia and the ketamine did not separate from placebo.

Dr Ben Everett (45:45)

Yeah, that was an interesting study.

Dr David Feifel (45:46)

That study had that. It was complicated. And in the studies that we’re talking about, this paper and its Predecessor, the Phase 2 randomized trial, the COMP001, there was a strong correlation between certain subjective effects, namely something called oceanic boundlessness and the efficacy. But the strongest correlation in terms of whether somebody got a good response across all the doses to a good therapeutic antidepressant response to the psilocybin was with something called as the score on the Emotional Breakthrough Inventory. So a lot of people experiencing these psychedelic treatments, you know, in a therapeutic context, will feel that, you know, something clicked, they came to some resolution. They kind of, they saw things in a different way that made sense and gave them a different way to have a relationship with their past, with who they are. And these are broadly classified as emotional breakthroughs. That was the strongest factor in predicting, you know, whether people’s depression would get better. So I, I think that at the end of the day that results will show that they do contribute. It may not be all of the therapeutic effect, but I do think it’s a major contribution. And when we finally have drugs that truly, or, or studies that can truly extract the experience from the pharmacological effects, we’ll see that we lose a significant part of the therapeutic effect.

Dr Ben Everett (47:20)

Well, my bias, or I should say hypothesis, is to agree with you. I think the trip is necessary. And I’ll just say two things. One is that a lot of the work that was done at Hopkins with Roland Griffiths and others does show exactly that, like the oceanic boundlessness among others is very important for the people. And these were mostly like a end of life anxiety studies. So patients have like a fatal cancer or something like that. And they’re given, I believe they used LSD in those studies, but very tight correlations there. And then at a session at a conference years ago, it was the first tar one and it didn’t work. And it was. Dr. Leslie Citrome was the panelist there. And the promise for this had all been these rat models and looking at the circuits and, and I just remember him saying very succinctly at the end, you know, he was like the facilitator, I guess, was, why didn’t it work? And he was like, well, you know, it turns out we’re a little bit more complicated than rap. And I just love that. It was Dr. Citron that stuck with me. All right, well, look, we spent a long time kind of setting up the psychedelic landscape a little bit, so let’s really get into this phase two study again. I remember when it came out, huge news for the field. New England Journal of medicine publication in 2022. And we’ll put the show notes, the link for that and everything is open access. So just, you know, for brevity, I’ll set this up a little bit. So this was a very typical randomized control trial. Multi Site International studied patients with treatment resistant depression. Inclusion criteria. The diagnostics were very similar to what you mentioned earlier. Typical for treatment resistant depression, at least two substantial courses of antidepressant at an appropriate dose and length, not more than.

48:58 – Inside the Phase 2 Study and How TRD Patients Were Enrolled

Dr David Feifel (48:58)

Four I believe so. It excludes extremely resistant subjects.

Dr Ben Everett (49:03)

And in terms of, you know, if we look at sort of like baseline inclusion exclusion criteria, you know, male, female, over 18 MDD without psychotic features. We still worry about that with the psychedelics. I think in most patients had had unresolved major depression for at least a year going into this study.

Dr David Feifel (49:23)

Right. They couldn’t have it. It was their only depression episode. I believe they couldn’t have it for longer than two or three years. So they didn’t want folks who have been depressed their whole lives kind of. There’s a feeling that that might kind of be a different category of depression. But if they’ve had episodes, it could be longer. And the average was what you described? Yes, correct.

Dr Ben Everett (49:44)

And then if patients were on any, you know, psychotropic medications, did they need to discontinue those before they went in?

Dr David Feifel (49:51)

Yes, yes. They had to be completely discontinued at least two weeks before the dosing or the baseline, which was a day before dosing. So they, those if they needed to be titrated, you know, they would be titrated so that two weeks before dosing. And all of that had, I think had to occur within six weeks. You know, starting, you know, starting tapering to baseline was this six weeks. They had four weeks to taper my medications.

Dr Ben Everett (50:15)

So really all pretty standard for a psychotropic type of study. And we know, look, depending on the class of atypical the patients are on, some of them you can get off pretty easily and others, yeah, you really need a clinician guided taper to do it safely. So we don’t want, you know, rebound psychosis or anything like that. And I think, see, the only other thing I’ll mention, sex was well matched. It was predominantly white, like, you know, 90% white in this study, about 30% moderate MDD bad madris and then 68% severe MDD bad madras. So and this is really what’s interesting and unique about psychedelics. So the patients come in, they have their baseline on that kind of, you call it day zero or day, you know, minus one, depending on how you look at it. And they come into the clinic and they get a single dose of psilocybin.

Dr David Feifel (51:03)

Exactly. At that stage, the fda, this compass sponsored study was still very early in this whole development program. One of the first. And so the FDA really wanted to see what happens with a single dose. Both in the main randomized part of the study, the 12 week study, but also then in this, in the paper that prompted this discussion, the 52 week follow up, they Wouldn’t allow, you know, additional. The investigators really were advocating for incorporating a, you know, an open label, but the FDA really just wanted to say, what happens if you take one medication, one dose? We want to see it followed through. I think things have loosened up now so that even in phase two, they’re allowing like open label components, which would have been really nice because one of the big challenges in these studies, Ben, is that patients, the functional blinding is all knows, kind of difficult for this, but patients tend to know or tend to be able to kind of predict whether they’ve had certainly like the. The high dose versus a placebo or low dose. And then it’s very hard for them to stick out a long study unless there’s the prospect of getting an open label at some point, getting the real deal. And at this stage of the whole psychedelic development, this wasn’t allowed. It was just one dose. And we’re going to follow you all.

Dr Ben Everett (52:27)

The way through and dose ranging study. So it was 1mg, 10mg or 25mg of placebo and then double blind, so people don’t know what they’re getting.

Dr David Feifel (52:36)

25 milligrams of psilocybin. You missed psilocybin.

Dr Ben Everett (52:38)

I’m sorry, I’m sorry, I didn’t know what I said. I said ketamine.

Dr David Feifel (52:42)

You said 110 and 25 milligrams of placebo, which I think would be interesting. Yeah.

Dr Ben Everett (52:46)

We don’t need different doses of placebo, do we? That’s a good catch. Sorry about that.

Dr David Feifel (52:51)

Well, I guess it’s different doses. I mean, you know, different doses of expectations set up. Right.

Dr Ben Everett (52:56)

Yeah, there you go. Well, you just mentioned these psychedelic studies can be difficult to blind. What all constraints or trial protocol things were in place to try and protect, you know, the blind. And this one, again, there’s not a placebo arm, just the three active arms, but the one milligram is really kind of, my understanding, was intended to be sort of the null comparator, but maybe there’ll be some minor subjective effects in the patient if they’re naive to psilocybin, which most patients were. It was only a handful of patients had ever done psilocybin before, which I think is another really good point about this study, because that was an FDA concern about some of the MDMA studies, was a lot of the patients had.

Dr David Feifel (53:33)

Done MDMA before the raters were blinded. I think the fact that we had a spectrum of doses I think helped maintain that equipoise to some degree among subjects. Because, you know, I think if you sit in a room, you know, for eight hours, there are moments where you can feel a little bit convince yourself that no, your thoughts are different, your perception might be a little bit different, especially if, you know that you might be on. So I think that, you know, people, let’s say, who got placebo experience, that they may say, I wonder if I’m on the low dose, the 10 milligram dose, you know, So I think that kind of helped with the whole equipoise of the study. It really was just the standard things you do in a double blind, randomized control study.

Dr Ben Everett (54:17)

And then you mentioned at Kadema, because I know this was part of this study as well, was there’s a playlist of music and then patients wear eye shades. Right. So the experience is really designed to have the patient focused inwardly.

Dr David Feifel (54:29)

That’s right. That brings up a good point. A lot of people believe when they think about a therapeutic psychedelic experience, they believe that, you know, the standard practice is to kind of be talking to a therapist and therapist somehow guiding you through this. And this is when I started, you know, get into this field. This is sort of like, you know, what I was hearing. And the truth of the matter is I don’t know what the practice was at one point, but today the best practice, these sort of, the manuals that are put together by the experts don’t encourage that at all. In fact, they encourage facilitators to guide the patients back to not talking if they’re excessively talking to the facilitators, to turn inward and just experience this. So it’s really a time for the patients to be with their internal experience, not doing any kind of, you know, therapy or, or so forth.

Dr Ben Everett (55:22)

Yeah, nice.

Dr David Feifel (55:23)

And the facilitators are really there during that time just for emotional support if they’re. If the subjects experience a challenging moment, you know, to help them, kind of comfort them through that, but not to really add something to the inherent effects of the drug.

Dr Ben Everett (55:38)

All right, so in terms of results, so primary endpoint was, even though it was a 12 week prospective follow up, the primary endpoint was at three weeks. So they get the psilocybin on day one and then the blind and independent raters do madras on a number of different days. Like I think the first one was either 24, 48 hours later. That’s right, 24 hours, 24 hours later. So the day after. But the primary endpoint they set at three weeks. So what would we find?

56:04 – Why 25mg Psilocybin Delivered the Strongest Clinical Results

Dr David Feifel (56:04)

We found that there was an Improvement in all the groups in terms of the, the modulus, which was the primary efficacy measure. But there was a difference and it followed the dose response. You know, the greatest reduction in moderates, when I think it was like 12 points, was in the high dose group to 25 milligrams. I think it was around eight point drop from subjects baseline in the 10 milligram group and about five and a half in the 1 milligram group. And that turned out in terms of statistically that the 25 milligram separated from the control comparator which was the 1 milligram but the 10 milligram didn’t. It was, you know, 8 versus 5.5 versus 12 versus 5.5. It was similar in terms of the, you know, the secondary measures which was response and admission. Response being how many, what percentage of patients actually had a 50% or more reduction in baseline symptoms and remission being, I think an absolute score of less than 10 on the mad risk. So basically there was a consistency where the 1mg group improved, as you would expect, even if it was not very psychoactive. We see placebo groups improving in depression studies all the time. But there was clearly a signal where there was something to the psilocybin because 10 milligram improved more. Not enough to separate statistically to, you know, convince that this was not by chance, but the 25 milligram did.

Dr Ben Everett (57:35)

So 25 milligram is really the dose that they’ve taken forward into the phase three study?

Dr David Feifel (57:39)

That’s correct, yes.

Dr Ben Everett (57:41)

And looking at the people who did the 50% response, 25 milligrams, about 37% of patients did get that, that 50% response at week three. And then looking at remission, which was a MODRA score of less than 10 total, about 29% of patients in that 25 milligram group got that. And again, this is not head to head study, so we can’t say, oh well, compared to. But if we think about what we get from an SSRI in the same patient population, I think this looks really good.

Dr David Feifel (58:12)

Absolutely, yes. As I said, I know that there was some disappointment and I remember being called by some investment groups to speak to their investors on this because they were panicking and I was like, just so you know, those of us on who’ve been in this field and are actually treating patients are drooling. We would love this. I don’t know what you were expecting, but gosh, I wish this week I could give this to my patients. It’s all relative in what perspective you’re coming from.

Dr Ben Everett (58:45)

Yeah, I remember having those same conversations with a number of different people. And I just thought, you know, maybe people have too much hope on psychedelics. But I was like, this is a really good scientifically objective finding for patients that have been suffering. And it’s not fair to think that any new treatment is going to be a panacea for every single patient. It’s nothing’s right for everybody and provides full therapeutic benefit for every single patient.

Dr David Feifel (59:08)

And when you know how challenging and most of these folks have had, their current episode may not have been years and years and years, but they’ve had depression for years and years. That doesn’t surrender very easily. I have to tell you, you know, it’s very hard to change somebody’s wiring as an adult if it’s kind of pathological. So getting these kinds of results was really great. And this is one. This is one dose, right? And, you know, now we’re, you know, in the phase three studies, the design has become more complicated where we were able to give repeated doses, repeated administrations of the same dose to see what, you know, what happens when you’re able to kind of do more than one dose. And I think that’s where ultimately that’s the paradigm that’s going to be the one that makes it into clinical world. We’re not going to just have patients come in one time and say, well, you’re good for life. Enjoy. You know, we’re going to understand that they need to. We may even load it like we do right now with ketamine, where we just know that, you know, if you do one, it’s gonna be gone in two weeks. So we do an induction phase where you’re coming in even if you’re already starting to feel benefits. We’re just coming in and doing typically, you know, six to eight treatments in a fairly short period of time to kind of induce that more durable therapeutic effect.

Dr Ben Everett (1:00:28)

So we covered efficacy. What about safety? You know, we always have to balance efficacy and safety. So any major safety findings from the study?

Dr David Feifel (1:00:35)

Headaches was probably the most common, mostly on the day of dosing. I think there was maybe only one person who needed, like, a rescue medication during the dosing that was in the high. That’s not surprisingly, in the 25 milligram group, I think they needed lorazepam for a panic attack. But when you consider the Overall numbers, over 200 subjects, I think that the side effects were kind of comforting, if you will, for such a powerful drug. There were serious adverse events, but including Some suicidal ideation in the, in the 25 milligram group. But I think that it wasn’t. Given the nature of the population, I don’t think it was anything that was really alarming.

Dr Ben Everett (1:01:20)

Patients that have a history of suicidal ideation, it’s consistent with what we’re seeing in other psychedelic studies.

Dr David Feifel (1:01:26)

I’ll say things out good.

Dr Ben Everett (1:01:28)

I felt the same thing when I read it.

Dr David Feifel (1:01:29)

I think it was maybe two. Two participants in the 25 milligram group had changes in their suicidal ideation at some point in the, in the study.

Dr Ben Everett (1:01:39)

Yeah. And then you mentioned over 200 patients. I forgot to mention the power of the study. So about 75 to 80 patients per arm across three arms. And at the time, I think this was the largest randomized controlled trial of psilocybin that had ever been undertaken.

Dr David Feifel (1:01:53)

It remains the largest one that’s been conducted. There are bigger ones that are in phase three now that are going on sponsored by Compass and Usona. But this one being concluded is right now is the best we have in terms of power and size and so forth.

Dr Ben Everett (1:02:11)

Yeah. And then I’ll just mention briefly that there was one other really small study. It was just 19 patients, open label, and it was 19 patients also with TRD who were on a maintenance dose of an SSRI. And then they got the single dose of, in that study, 25 milligrams. Yeah, they only did 25. That’s what I thought.

Dr David Feifel (1:02:30)

Yeah. It was an open label. It was a two site study. It was Qedema and a site in Dublin. And the idea here was to address the issue of whether patients need to get off SSRIs before doing psilocybin, other classic psychedelics. Because that’s sort of a, the current wisdom of concern that, you know, the SSRIs might inhibit the effects of the serotonin 2A agonist. In that study we had 19 patients that were given on a stable dose of an SSRI, I think for at least four weeks, but still had significant symptoms of depression. And they were given 25 milligram open label, the high dose. In the other large phase two study, basically their, their improvement, although there’s no built in comparator like a 1 milligram. But the magnitude of the improvement was quite comparable to what we saw in the large 200 plus phase two study with the three doses. So at least it suggests that you may get similar efficacy even while on an ssri. The expectation was that we might see much, much lower improvements because of the blocking of the therapeutic effect by the ssri, but that didn’t seem to have that graft. It’s a very small study. The controls weren’t built in, but nevertheless, it was an important first step, I think, into scientifically addressing what had been assumed to be going to be a problem and that of adding psilocybin to patients on SSRIs.

Dr Ben Everett (1:04:04)

All right, so we’ve got these two studies, the bigger study, the smaller study, and patients that were in these studies were allowed to go into this long term follow up study. And that’s the subject of the paper that was published in JCP here recently and I’ll mention. So when they first started the larger phase two study, they had not thought to do this long term durability study. So not all of the patients were invited to participate in this. And that’s actually not uncommon in clinical research. Sometimes it just happens this way. I like this because you’re able to get some durability data and long term safety data from a phase 2 study, which a lot of times you don’t have the opportunity to do.

Dr David Feifel (1:04:45)

It was a bit of an afterthought. You’re right, Ben. A lot of the subjects in the main phase 2 study didn’t have the opportunity to enroll in it because they had already completed their 12 weeks. But nevertheless, I’m glad that this was incorporated in time so we could follow folks up to a year after whatever dose that they got.

Dr Ben Everett (1:05:04)

All right, so it looked like about 58 patients. Excuse me, it’s larger than that. I’ll read it this way because I’ve got it written down so.

Dr David Feifel (1:05:11)

Well, there was, I think 58 from.

Dr Ben Everett (1:05:13)

The, from the 25 milligram or no, 50.

Dr David Feifel (1:05:16)

It was actually 58 from the main study and then I think 8 from the, that small study that you mentioned. So there was something like 22 people in a 25 milligram and something close to that from the 10, and I think 17 from the 1 milligram group. They’re relatively small numbers, 58 in total from the phase two randomized control trial.

1:05:39 – What Long-Term Follow Up Reveals About Relapse and Durability

Dr Ben Everett (1:05:39)

Thanks for breaking that down. All right, so in this 40 weeks of follow up now, no additional study drug. What about, you know, can they drop in or add on something or what are you looking at?

Dr David Feifel (1:05:51)

The main outcome was, you know, looking at the number of depressive episodes, sort of like relapses. We want to see like, you know, okay, what happens now? You know, what’s the course of this therapeutic effect? And so a depressive event could be defined a number of ways. For example, if somebody you know, had to be hospitalized for worsening depression or suicidal ideation if the principal investigator felt that they needed to go on an antidepressant, which was allowed already in the phase two study. After the primary endpoint, if they felt clinically they couldn’t stay in the study without going on an antidepressant that was considered sort of a depressive event. If their Madras score had increased by a certain amount, that was another way to be classified as having a depressive event. Or if they’re suicidal, their SI score met a certain threshold, you know, that also I think those were the main criteria for classifying a subject in this long term study as having a depressive relapse.

Dr Ben Everett (1:06:56)

Okay, so what was the main finding?

Dr David Feifel (1:06:58)

The main outcome I think followed what we saw in the 12 week study, that folks in the 1 milligram and 10 milligram actually had more depressive events especially needed to start antidepressants than the 25 milligram and they also had them earlier. So antidepressant interventions were required more often in the two lower doses and were usually time wise required earlier. In the long term follow up. This study just didn’t have the numbers to do a statistical analysis. So that wasn’t even done. It did kind of demonstrate that there was in the long term a sort of consistency or some sort of continuity with what we saw in the 12 week study where the 25 milligram really kind of distinguished itself from the, from the 1 milligram comparator but not the 10 milligram. And the same thing really happened in, in terms of the number of relapses. There were fewer and took longer than the 1 milligram and the 10 milligram was closer to the 1 milligram.

Dr Ben Everett (1:08:06)

Again, I invite people to go look at the paper, but yeah, if you look at the paper, the Kaplan Meier plot, you know, it’s pretty clear. You can just glance at it and see that there’s a nice dose response curve, you know, the power like you said and quite there. But again from a phase two study, you know, you’re really not trying to power this for like a new drug application so that you can get any durability effect. And again, I don’t think anybody is really thinking of psilocybin as a, oh, you’re going to take this one time and you’re going to be cured in air quotes forever. I like the data. I think it’s a good proof of concept for, you know, it’ll probably be interpatient dependent but you Know, maybe in the fullness of time, we’ll have some people come in once a quarter for a treatment. You know, maybe some patients can go a little bit longer and some patients need to, you need to speed it up a little bit quicker. But still, if given the choice, and this is what it’ll end up being, you know, it’ll be another tool in the tool belt, you know, if someday approved, let’s say another two plus years from now, it gets approval, another tool in the toolkit and then another option for patients. Right. Okay, we can start you on a daily oral, you know, or maybe we can consider this. I like the idea of the different tools.

Dr David Feifel (1:09:10)

I think once they’re out on the market, there’s only so much you can learn about the best way to use these drugs in the clinical trials. On the one hand, I mean, it’s the strongest, most rigorous evidence that the answers that you do get. But because these studies are so complex and expensive and long to do, you know, we only can ask so many questions and then they get approved. And then once they get approved, then they get into the hands of real world clinicians with real world patients, then we kind of, kind of learn the best ways to deploy these new tools. And I think you’re right. I think it’s going to be repeated treatments that may over time require less frequent and less frequent readministrations. But certainly I think it’s at this point it’s probably safe to say that it’s unlikely that the concept of one and done, which was a concept when I started, you know, we started doing these studies, is pretty much dead. But just how many readministrations on average and what the interval is going to be and for how many years, that still remains to be determined.

Dr Ben Everett (1:10:18)

And I’ll just mention, you know, safety, obviously there’s no additional giving of study medication. So, you know, they report safety, but it’s exactly what you would expect. It’s a depressed patient population. There’s again, there’s some suicidal ideation, you know, headache, nausea, but essentially in the course of a year, who isn’t going to have some of those things? So that really wraps up the paper. Congratulations to you and your study co authors on the paper. I do know just in preparing for this, I did look at where Compass was in their phase three program and they did put out a press release about a month ago that their first phase three is done and it met its primary endpoint. I’m sure they’re waiting on full data set law and working on a Manuscript, but I’ll be looking forward to that.

Dr David Feifel (1:10:59)

Right.

Dr Ben Everett (1:10:59)

All right. I want to be cognizant of your time. We got, like, two more questions or we can shut it down.

Dr David Feifel (1:11:03)

Oh, let’s go for it.

Dr Ben Everett (1:11:04)

Okay. All right. Let’s translate sort of research to clinical reality. As I’ve said, you know, none of these are clinically available, approved by the FDA outside of research right now. But, you know, you did establish the world’s first ketamine infusion program for depression. So you have some firsthand experience in bringing some novel therapy into clinical practice. If people listen to this and they’re like, oh, wow, I would definitely want to offer this in my clinic, you know, when it’s available. What can providers be thinking about or doing now to get ready for two, three, four years from now? We’ve got a couple of different psychedelic options approved.

1:11:38 – How Clinicians Can Prepare for Psychedelic Medicine Adoption

Dr David Feifel (1:11:38)

I worry a little bit because I don’t think that residency programs are fully cognizant of this tsunami of change that’s occurring in psychiatry and preparing trainees for this. So if you’re a resident and you don’t feel like your program is really giving you enough preparation for this new type of psychiatry, it’s not just psychedelics, it’s neuromodulation, then I think you need to seek out experiences. Because if you’re not going to be prepared for it, and I think this is true for practitioners early in their career as well, is you’re going to find yourself practicing an obsolete kind of psychiatry. I don’t think there’s a lot of historical examples. I’m not an expert on the history of medicine, but, you know, where. Where there’s. There’s such a paradigm shift occurring so quickly. If you’re out there and you’re starting a career and you’re expecting that you’re going to be prescribing traditional antidepressants for your career, I think you’re going to. You’re going to struggle, because I really think that these are going to supersede those. I don’t think the SSRIs and the SNRIs are going to go away overnight, but I think that they are going to be shrinking in terms of their footprint overall for psychiatry. What makes it difficult, I think, for a lot of more established psychiatrists is, you know, they already have a practice in place and they’ve been doing it for years. And it’s not like just, oh, here’s a new medication. You need to learn how to dose this and so forth. This is a whole different paradigm. And Also has different physical requirements. Right. You need the space to have patients in your facility or office for better part of a day. You need to have a team of people who are going to be, you know, facilitators trained to deal with psychedelic experiences and the challenges that can come up. You have to at very least collaborate with people with those skills and in those disciplines. Sometimes it’s funny, it comes down to some very small things. For example, when these studies started to appear, the traditional clinical trial places had a hard time accommodating them. And that was one of the reasons that, you know, Kadema, we were able to kind of get in early with these studies because we already had the physical setup, having done ketamine and something just like having bathrooms inside the suite rather than sort of the public bathrooms, if you’re not saying in a medical building, which just won’t work for a patient who’s in the middle of a ketamine or a psilocybin experience. So we already had those, and those are kind of like de rigueur for clinical trials. And how many psychiatrists have that in their office or have a room that can accommodate somebody comfortably for eight hours? There is going to be, you know, a shift. And I think psychiatrists are going to have to decide whether they’re going to be providers or at very least they should become very familiar with it so they can appropriately, you know, refer patients and then follow them. I think there’s also this emerging concept, I don’t know if it’s going to be if this concept is going to stick, but of interventional psychiatry, where psychiatrists like myself don’t continue to follow the patient all the time, but they get involved during the acute treatment episodes, like, you know, for a dosing, for example, for a course of tms, and then kind of hand them back to their primary psychiatrist for follow up. And then, you know, the primary psychiatrist follows them and says, you know, I think you might need another dosing. Why don’t we send you back to Kadema? You know, I’m going to call Dr. Feifel and see what he thinks if we should kind of schedule another dosing for you. So I think that’s one way psychiatry may accommodate this new change, is have centers of excellence that are populated by people trained in these advanced treats. And then keep in mind, I mean, there’s lots of things coming down the road, aside from the psychedelics, technology that’s really cool with, you know, the ultrasound is looking very promising for neuropsychiatry, believe it or not. Near infrared light, photobiomodulation. I think we’re in the midst of what I call the Cambrian explosion of treatments, which is a reference to the evolutionary record where Cambrian era, suddenly there was this massive explosion of life forms, most of which went extinct. But, you know, just proliferation of all these strange new life forms. And I think that’s what’s happening in psychiatry. We’re having this sort of Cambrian explosion of treatments after a long time of stagnation. So I think early on at least, it’ll be relegated to centers of excellence that have the capacity to do these and sort of the open attitude to kind of taking on new things. A lot of psychiatrists are. This is what I’m familiar with, prescribing these medications, and they’re not comfortable in stretching to these new concepts.

Dr Ben Everett (1:16:32)

Great. So as we start this new series or one of our themes on psychedelics, you’re really tied in with the research on this. What excites you the most in the next, let’s say, five to 10 years? Is there something you think we’re really going to learn about the brain? Is it going to be circuit development, we’re going to understand more, or what is it you’re thinking about?

1:16:53 – Why the Future of Psychiatry May Rely on Harnessing Placebo Power

Dr David Feifel (1:16:53)

I think that the big paradigm shift in psychiatry, and this may not be just around the corner, is going to be a relinquishing of the reductionist idea that how we feel, how we think is all just how our chemicals and neurons interact. I came to this field as a very hardcore enamored by the whole biological revolution. I’m seeing its limitations. And we talked about the placebo effect. And I think actually the placebo effect might hold the secret for not just psychiatry, but all of medicine. The fact that we have to have placebo treatments, arms, because people get better just by when certain expectations are set up. And so we have to stop thinking about the placebo effect as this tainting, this impurity in our studies. And say, this is probably the most interesting thing. How do we leverage that? How do we leverage that? People can actually in some ways be healed just with, you know, changes in what they expect, what they think is happening. You know, a few years ago there was a study that showed that a long standing knee procedure that had just been sort of grandfathered in and was assumed to be the standard procedure for, I can’t believe was for what injury was no better than a sham surgery. This is not just in psychiatry where we’re dealing with the mind, where it makes sense that expectations. This is even when it comes to certainly in pain. You know, it’s been so difficult to develop pain drugs because there’s such a large interaction of expectation and context that has caused so many development programs to fail. I think that’s really when we are going to get into the next level of effective treatment. That’s sort of my opinion.

Dr Ben Everett (1:18:58)

Well, look, you’ve been very gracious with your time today. I appreciate it. A lot of good stuff in this episode today. So want to thank you again for joining us on the JCP podcast. This conversation has really given us an in depth look kind of behind the manuscript as well as psychedelics and psychiatry and kind of what at least one avenue of the future potentially holds in psychiatry. I’ve been a real pleasure to hear your insights in the field where it may be headed. Continue to look forward to watching this stuff. And look when that phase three study comes out, I might be calling you again.

Dr David Feifel (1:19:32)

Absolutely. It was a pleasure talking to you, Ben.

Dr Ben Everett (1:19:34)

Look, I want to invite our listeners to tune in next time. My guest will be Dr. Michael Halasa. He’s professor of neurobiology and psychiatry at Tufts University. Dr. Halas Research is focused on connecting neural circuits to cognition. Additionally his clinical responsibility in the inpatient setting at Tufts. We’re going to be exploring multiple topics, but I know he’s got a lot of early experience with xanomeling trospium in that inpatient setting and I think that’s going to be interesting as well. But really we’re going to talk about his paper and cell reports developing algorithmic psychiatry via multi level spanning computational models, which is a mouthful, but it’s a really interesting read. So this has been the JCP podcast, Insightful, evidence based and human centered. Thanks for joining us. Until next time, stay curious, stay informed and take care.

Episode Resources & Full Transcripts