Dr. Victoria Maizes: Hi Andy.

Dr. Andrew Weil: Hi Victoria.

Dr. Victoria Maizes: So today we will be speaking with Dr. Chuck Raison about other ways to think about depression.

Dr. Andrew Weil: Yeah, he's a longtime friend and colleague, and I first became interested in this work some time ago, and I'm fascinated that he's now very involved with the psychiatric uses of psychedelics.

Dr. Victoria Maizes: Yeah he was here at the University of Arizona for awhile, and did a study where he put people in heat chambers. So he has a long history of innovative work

Dr. Andrew Weil: Great let's talk to him.

Intro Music

Dr. Victoria Maizes: Dr. Chuck Raison is a professor at the University of Wisconsin and serves as Director of Research for the Usona Institute. He is internationally recognized for his studies on novel mechanisms for the treatment of major depression, as well as for his work on the effects of compassion training. He was named one of the world's most influential researchers by Web of Science for the decade 2010 to 2019 more recently, Dr. Raison has taken a leadership role in the development of psychedelics as potential treatments for the major depression. Welcome Chuck.

Charles Raison: Thank you. Nice to be here. Let me start by apologizing. I'm in a little bit of an echo-y room because I was in a big psychedelic meeting talking about an upcoming FDA meeting.

So if I sound like tin can I am in fact, in a tin can.

Dr. Victoria Maizes: Well, we are certainly going to want to talk with you a little bit about psychedelics and who knows. Maybe you can give us some breaking news but, but let's just start with depression. It is common and while antidepressants could certainly help some people about a third of people don't respond.

So how do you as a practicing psychiatrist and an internationally recognized researcher in the field think about this?

Charles Raison: Yeah, well, that's a lot, a lot of way. You know, I spent a lot of time trying to find other treatment modalities. You know, anybody that works in psychiatry can tell you about all sorts of people who had, you know, really beneficial responses to an anti-depressant people who may have killed themselves that didn't. You know, sometimes they work really, really well for people, but what has really become clear in the last 15 years is that [00:02:00] we and me very much amongst this sort of overestimated their benefits and underestimated their harms. And there was something Andy's talked about a lot, but you know, if you look at the sum, total data available to us now, it really looks like for many people, especially people that have chronic depression, the agents we have don't make them fully feel well.

And so that's a big problem. Number one. I've gotten really interested though, in the problem of what do you do with antidepressants really do work well because then you get these situations going where somebody is doing much better on an antidepressant and you know, 10 -15 years ago, we would have just said, well, leave them on an antidepressant forever.

But the data that has emerged suggests that that is really probably not an optimal strategy, that the longer you're on an antidepressant, the more likely you are over time to develop what's called phylaxis. So you begin to see the response. There's some evidence that the longer you're on an antidepressant, the more likely you are to become resistant to antidepressants.

The more likely for sure you are, if you do decide to stop to get withdrawals, that can be painful. But the main thing that's distressing is this evidence that. Even people that have been completely in remission on antidepressants for a couple of years, if they stop the antidepressants in these studies where they, they, you know, you blindly switched from staying on the antidepressant to go into the placebo, the rates of crashing on the antidepressants are sky high. And some studies of the 80% of people will be all the way back where they started within a year. And so at the very least what we can say about current antidepressants is they don’t modify the course of the disease so that you only get the benefit when you take them. And when you stop, most people will kind of go back to their baseline.

The more concerning possibility for which there is some evidence is that they may actually kind of worse than the disease course. And make you more vulnerable to relapse. So that is kind of a devil's bargain. You know, that [00:04:00] once you're on them, you sort of bought the tickets. You might have to take the ride. And we certainly never thought that way 20 years ago and that, you know, but I think more of my colleagues do even folks who are hardcore pharmacologists.

So that's another wrinkle in all this is that, you know, there's maybe kind of no free lunch. And these agents that sit on the brain day after day after day cause changes in the brain that over time began to work against therapeutic benefits.

Dr. Victoria Maizes: So you have packed a lot into that. And I just want to direct a question first to Andy, which is Andy, you have in recent years, and certainly with your book mind over meds pointed to some of this very risk of chronic medications.

Dr. Andrew Weil: Yeah, I see this as a part of a larger general problem is that when we use suppressive, antagonistic medications over time, the homeostatic reaction of the body may get us into worse trouble than we had to begin. So in other words, if you give drugs that increase serotonin at neural junctions, the body over time is going to respond by making less serotonin than dropping serotonin receptors.

And then when you try to reduce the dose or get off the drug, you're left with a worse situation than you had to begin with. And I think this is a common observation now, and it's not just standby depressants. It's a whole range of our chronic medications.

Charles Raison: Absolutely benzodiazepines it's been called oppositional tolerance.

And then exactly what the brain begins to sort of fight against another way of thinking about it. It pushes back against the changes that are when you have a drug chronically on the synapse. And it's, you know, it's very concerning, but it does fit, you know, why should we think the antidepressants be different than say in a benzodiazepines, like valum, you know, you know, that have to take valum for a couple of few days in a crisis it can really be beneficial. But if you take it for months. [00:06:00]And if I had to stop it, the brain overreacts and over shoots.

Dr. Andrew Weil: Or PPIs, Chuck, the same thing happens when you suppress stomach acid production. There's so many different drugs. You can see the same pattern with, let me ask you a question, I think first became interested in your work when I was researching my book, Spontaneous Happiness and writing about depression and I came across the cytokine hypothesis of depression, which just interested me because it seems to me we had all our eggs in the serotonin basket and suddenly there was another way of looking at depression. How did, how do you feel about that now?

Charles Raison: Well, I think that it's really interesting. My mentor, Andy Miller at Emory has just been such a world leader in this space and what we know now, I think incontrovertibly is that inflammation is a pathway to depression. Not all depressed people have elevated inflammation, depending on the population is probably about a third of all depressed people. I mean, when we say, you know, when they say that depression is associated with increased inflammation, what we really mean is that average is higher, but that it's not that every depressed person is a little bit more inflamed.

It's that there's a subgroup of depressed people that are considerably more inflamed. And we now know that they have different patterns of brain function. They have very specific symptoms that tend to be more elevated things like anhedonia, loss of pleasure, and they respond differently to antidepressants.

And interestingly, they're the only folks in the depressive sort of cohort that show an antidepressant response to anti-inflammatory. So, yeah, so basically inflammation is one of the ways people get depressed. There is a subgroup of depressed people that have this chronic inflamed sort of chronic inflammation.

And those people have, have a different types of brain functioning and other depressed people, and they probably respond differently to treatments. So, yeah, I think that has really now been pretty well established.

Dr. Victoria Maizes: So given that anti-depressant in the long run might do more harm than good. And yet, for some people who are terribly depressed, they still might be an essential treatment. Is there a way to discern who actually benefits, whether you have serotonin at the root cause or inflammation as the root cause or something completely different at the root cause so that we only treat the people who are most likely to benefit.

Charles Raison: Man that is the holy grail of psychiatry, right?

We've been after that for, you know, since I was knee-high to a grasshopper, I mean, not as a psychiatrist, I mean, as a kid, I mean, been way, way back. And it's been very, very difficult to do because depression is such a heterogeneous condition. And because, you know, you've mentioned it it's so common. I think the other thing about depression is not only is it probably a whole bunch of different sort of biological conditions that we don't understand.

It's also a fairly normal human reactions with adversity. And so you're kind of swimming upstream against sort of how evolution built us. So there's a lot of reasons, I think why it's difficult to find that sort of, you know, precision medicine or predictive biomarkers. Interestingly, interestingly, at this point, I think the most promising predicted bio-market is not a brain chemical.

It's actually an inflammatory chemical thing called C-reactive protein. And there have been several small studies suggesting that people with elevated CRP, which means that their inflammation is elevated, do not respond as well to serotonin antidepressants. So the part of SSRI is like Prozac and Paxil don't work as well in people that have elevated inflammation. And if you're going to stick with standard antidepressants agents than have more norepinephrine a dopamine effects, like there's an old drug called nortriptyline for a more recent drug called Welbutrin appropriately on those agents actually seem to differentially work better in people with elevated inflammation. So again, you know, the big, big study that's directly testing. This is going on at Emory in Atlanta right now. And we'll see. But like I said, there's about four studies that have sort of pointed to this. It's not going to give you a hundred percent certainty, but even if it helped a little bit, I think that that would be very useful.

Dr. Victoria Maizes: Well that is interesting because certainly depression has been an empirical diagnosis where we haven't necessarily had much blood work that we could look at. Are you suggesting perhaps that for any doctor who's listening, that they check a CRP before they prescribe an antidepressant?

Charles Raison: Yeah. You know, I've actually begun to tell people that, and I'm very conservative, right. But the thing is, you know, CRP is a standardized lab set that we get. And if the larger studies turn out not to support this, I don't think you've done any worse. So I have actually started sort of talking to you about the other thing I've talked about is that there are, there are also data to suggest that anti-inflammatory strategies may not be universally beneficial for depressive people.

So for instance, if you look at the literature on omega three fatty acids in studies, there's some evidence that people that are very depressed, but have low levels of inflammation actually do better with placebo and have to have the higher levels of inflammation to begin with the benefits from the mega three fatty acids, which fits with this sort of idea that it's the people that have the increased inflammation would benefit from having it dampened.

We did a study now about oh God, eight or nine years ago where we gave medically healthy, depressed people who had failed other edit depressants, a couple of infusions of a very, very powerful anti-inflammatory agent infliximab, it used to be marketed as Remicade for GI problems. And, you know, it's very specific and very powerful it just turns off inflammation. And we found that in the group of depressed people as a whole, it was no better than salt water, which was the sea salt water work a little better, but in the people that had elevated inflammation, it worked as an antidepressant compared to the placebo, but the peak was low inflammation they did better with saltwater a lot better. There's a really interesting little story that's beginning to emerge here. And one way of looking at it, I think the conservative way of looking at it would be that inflammation is really relevant only for people that are depressed with high inflammation, my contrarian view, which is a sort of my view probably is that there may be something in here worth understanding around inflammation where there's some depressed people that clearly blocking inflammation does not help them. So it's inflammation…if it's low, is it doing something that we need, something that might be beneficial, so that in fact, the immune kind of systems are involved in a wider range of depressive conditions, but in different ways. And I can give you a little example from a study that we did at Arizona. So, you know, as you know, we did this hypothermia studies where we looked at heat and we had this very strong finding that if you put people in the hypothermia machine and really cook them up, one of the classic inflammatory molecules called interleukin six, go shooting up.

Now interleukin six is increased in depression it's bad if you're elevated, you're more likely to die of cancer and more likely to die of dementia. You know, it's, it's a bad actor, but hypothermia just jacks it up like crazy and the more it goes up more un-depressed people are over the subsequent weeks.

It's short, it's time limited. But it's really interesting. And so clearly something there's, there's complexities in these systems. And I have this little pet theory that. I cannot endorse because it's just theory, but that there may be some depressed people that actually would benefit from just a little time limited jolt of inflammation, perhaps to do the opposite of what you talked about Andy, you know, where something's chronically on the brain, the brain sort of weakens, right. You know, why work out if you've got a body suit that does all the movements for you. So maybe you get a little bit of an adaptive stressor that's time limited. And the body responds by in some way, building up its resilience and building up some sort of immune resilience.

Again, I can't prove that, but that's one of the things that we're trying to use the hypothermia to study.

Andrew Weil: And what about novel treatments for depression? Things that are on the horizon?

Charles Raison: Yeah. Well, you know, so, so if we go back to something you said, Andy, which is, you know, why psychiatry decided to follow a sort of Edison model as opposed to surgery model is interesting, right? So why did we think that, you know, so, you know, if you've got high blood pressure, you just take a high blood pressure medicine every day. If you get diabetes, you take insulin every day. If you got depression, just take an antidepressant every day.

Where did we, where did we fall into that larger sort of schema of how these things are treated? I don't know, but we certainly did, as we all know, we can talk about that. What's interesting, is that in the last half a decade or so, there's been the emergence of these treatments that in addition to having kind of novel mechanisms of action, having novel administration schedule.

So, you know, if we start with, with ketamine, you know, the shocker route with ketamine, when people first started studying. Okay first off, people felt much better, very rapidly, and you give people a single dose it's in the body for a couple of hours and they still feel better a week later right. So that, you know, kind of what's up with that?

What's going on with that? And then there's this drug called brexanolone which is same thing, you know, you can give it to people over a certain period of time and then they stay on depressed for kind of a longer period of time. And then the granddaddy of these sorts of agents are the psychedelics.

Right, So I was just on the phone with rolling, which is why I'm speaking to you from the tin can, you know, you know, he and the guys at NYU showed that you give people that are depressed and anxious and have a potentially lethal cancer, a single treatment with a high dose of psilocybin. And, you know, the vast majority of them feel completely in remission six months later.

So, you know, you got a drug that's in the body for eight hours. You got people saying they feel better for this extended period. And, you know, so what's on horizon that I'm most excited about is not just these individual agents, but the potential, there may be pharmacologic interventions that don't fall into that, taking it every day is on the brain and you're weakening systems, but rather really kind of treatments that might be like adaptive stressors where boom, you're there on the body for a short period of time in the brain for a short period of time. And they set in motion downstream changes that we'd come to some degree self-sustaining, right.

You don't need to do the psilocybin every three days it may not last forever. But you've, you've set in motion as sort of internally generated and sustained resilience sort of function or pattern. And, and that to me is what I think is going to be the sort of hope for the pharmacologic treatment of at least some of our psychiatric conditions.

And you know, my fingers are crossed because I really think that it will help us avoid exactly what you articulated. The fact that, you know, when, when, when the drug is always doing what the body should be doing, the body quits doing,

Dr. Victoria Maizes: You know, you said it could be an adaptive stressor, but I'm just wondering so much is being written now about the psychedelics.

Do you have a sense beyond that of the mechanism of the what is actually happening as you rewire the brain?

Charles Raison: Well, that's a great question. And I can tell you about one of the wildest things that I know of trying to look at this… So the big question in psychedelics is the big theoretical question is, well, how do they work?

Right? How is this possible? There's two schools of thought there's two camps and they're heading off in these sort of different commercial directions. The more sort of standard school of thought is that, that these agents must be essentially purely biological agents. And so what we really want to do is to take something like psilocybin and tweak the molecule until we find one that doesn't have psychedelic effects that you could take it home and that would miraculously make you feel impressed for six months, right? I mean, that is the holy - and they actually, two months would even be better maybe two weeks because he had to work for bills, but you know that essentially there's a way to distill out the experiential effects for the psychedelics. And, you know, I, I never say never did anything.

Dr. Victoria Maizes: Well, that's kind of what people have been doing with cannabis, right? They've been playing with the, with the plant. So the molecules to try and create a mix that doesn't make people stoned, but still gives the beneficial effects.

Charles Raison: I mean, that's, that's the history of the mechanistic perspective on the west. And, you know, it's given us all sorts of things that are very valuable and they may succeed in doing that. If you look at currently available psychedelics, most studies suggest that there's something about the acute experience that predicts the longer-term outcome.

And so, and not just anything about the acute experience, but the psychedelic experiences that have certain elements seem to be more beneficial. And then those there's a little bevy of those elements. So one of the ones has been most studies, but some of it's called the mystical experience with and people getting this profound bodily felt sometimes inability to explain sense that they're deeply connected to all sorts of things. They didn't think they were connected to before God, other people, the planet, you know, that their life fits into a larger pattern in some meaningful way. And you know, people all of a sudden feel like it makes sense in a way that it did before.

When that happens people tend to get a lot happier. They get tend to quit. smoking and tend to quit drug. And the other thing that happens seems to be useful is people will often go through very difficult experiences…with psychedelics, this goes back to the kind of maybe adaptive stressor idea that, you know, it's like you see all your demons in, in an hour and a half, right.

And people will have these really difficult emotional experiences. But folks have shown in small studies that if that happens and a person through the psychedelic experience feels like they've either accepted those things or they're going to change those things or that they've somehow dealt with them that also strongly associated with good therapeutic outcomes right?

So trying to understand what is it about the conscious experience acutely that sets people up longer term is I think one of the places to go looking and so one of the things that we're doing is looking at whether in fact the conscious experience is required for psychedelics to have an edit depressant effect.

And when you begin to think about consciousness, you know, it really means at least a couple of things. One is, you know, you, you're pretty convinced you're conscious right now. But, but you know, a year from now, you're not going to really remember much about this podcast, unless I say something horrible that gets us all in trouble…but your conscious, right? But the other part of consciousness is that sort of memory, right. That we take with us. And so we've actually started to study at Wisconsin where we are in the sort of piloting phases of giving people in this case, psilocybin, but co-administration with medasalam, which is at, at, at a certain dose, it gives people kind of a blackout.

They're awake, they’re experiencing, but they don't remember afterwards. And, and so we're kind of curious to see, can we kind of peel the onion and if we give people a psychedelic experience they cannot remember, does it still have that therapeutic effect? And it might, or it might not, you know, it's interesting if it still does than that suggests that you don't have to remember it to get the benefit that it maybe it's something to do with the experience while it's happening or the brain activity while it's happening.

And of course, if on the other hand, if you don't remember you’re like well, I don't know, you know, that was nothing then, you know, then you don't need to go further than trying to understand what is it doing to memory and to the consolidation of memory that is inducing these, these do sort of therapeutic benefits.

Now what the biology, what the neurobiology of that underneath is…you know, we've got fancy EEGs and all this stuff, that's a thornier issue but one of the things that psychedelics let us do is they really do serve as probes for the causal power of consciousness to see does conscious experience as we typically understand consciousness does it, or the brain activity that, that produces it or serves it,  does it really have a long-term causative effect, the ability to change us? You know, if we want to be optimistic, I think that's a really nice human story. I that's, I'm voting for it.

I'm hoping for it, but we're actually trying to test.

Dr. Victoria Maizes: I don't know, it, it rings to me of our society's discomfort with psychedelic medicines that we're going to say, okay, we'll give you a psychedelic, which we think will lead to an improvement in your mood, state, and resolution of your depression. But we won't let you remember it because we don't want you to have had a psychedelic experience that you remember.

Charles Raison: Well, so interestingly you know, my bias is towards, I'm hoping that will actually show that if you don't remember it, it doesn't happen. That would be consistent with, but, you know, I had to jump through some hoops to get approval to do this. And [00:24:00] the, the gentleman who finally made the approvals kind of a hardcore biochemist.

And he said, exactly what you said, Victoria. He said, this is a great study 'cause, you know, you can sorta knock people out and they wouldn't have to have a psychedelic experience. So you're right. There's that again, that the folks that are, that are doing a much more sophisticated thing of trying to find a pill that doesn't give you an experience that is totally what they’re after, whereas the vantage point because of my own biases, I really rooting for the experience. I hope very much that it turns out that the, the neurobiology of consciousness turns out to be integral to how these agents do their deed, because that would you know, that wouldn't perhaps allow a psychiatry to have some kind of remarriage for psychotherapy, which would be, you know, very positive.

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Dr. Victoria Maizes: Andy, we are witnessing such a dramatic increase in depression, anxiety, and mental health disorders. I mean, the CDC said that a 13% of adults over 18 used antidepressants in the last 30 days that was before the pandemic that was 2015 to 2018 data. What is happening in our society? Why are we in this crazy position?

Dr. Andrew Weil: You know Victoria I wrote about that in Spontaneous Happiness. I think the reasons are complex. One is how much of this is real. How much is the creation of the pharmaceutical industry? That's been very successful at convincing people that ordinary states of sadness are matters of disordered brain biochemistry that require treatment.

We're not supposed to be happy all the time. There also may be some value in depression. You know, there's a strong correlation between depression and creativity. You know, many of our greatest writers, artists, musicians have suffered from depression. Many have used alcohol or drugs to deal with that.

Some have committed suicide. But they're linked. And there has been some very interesting writing by evolutionary psychologists about the value of depression that it may, that people who were genetically predisposed to depression might do better at problem solving. Because you have a state of inward concentration and focus.

And so in as our species was developing, those people might have been the ones that were successful at dealing with very difficult situations. Then you look at all the things that are, that are, have changed in society compared with hunter gatherer societies, where depression is almost non-existent, you know, when you look at how our diets have changed, they're much more pro-inflammatory, we're disconnected from nature.

We have disordered cycles of sleeping or exposed to all sorts of noise. There are so many factors. We, we have had a breakdown of social relations, much accentuated in this time of pandemic. You know, so I think there are just so many factors that enter into this.

Charles Raison: What he said.

Dr. Andrew Weil: But also Victoria, one thing I pointed out, which I think is interesting is that when I asked people, you know, why, why are so many people depressed? The common answer I get is we'll look at the data of the world, look at the state of the economy. And, my parents lived through the great depression, which was much worse than anything we're experiencing.

They lived through World War II, which is the most horrific experience of the 20th century and all the indications were that mental, emotional health was better in those periods than it is today. So I don't think you can use those kind of facile explanations as to why there is this epidemic of depression.

Dr. Victoria Maizes: Andy in Spontaneous Happiness, you actually point to a whole array of lifestyle changes that people can make that potentially would help resolve at least let's say mild, maybe moderate depression. Where are you with that now? And Chuck as a psychiatrist, how do you see, or what effect do you see from the range of changes people can make from physical activity to nutrition, to potentially having different kinds of light exposure, especially if you're in a place where there's long winter nights

Charles Raison: Like Wisconsin, let's let Andy ask because he's going to say the same thing.

Dr. Andrew Weil: There are so many possibilities. There's practicing gratitude. There is not letting the pressing things into your consciousness. Now don't read sad novels and listen to sad songs or be around sad people. You know, moods are contagious and we have very good data on how mood spread through groups, just like infectious diseases.

You know, if you have a happy friend that lives within a half mile, you're more likely to be happy. And if the distance increases beyond a certain point, the effect falls off. I mean, so those are simple steps you can take. And then there's, then there's you know practicing meditation. As I said, practicing gratitude.

I think that there's so many things that people can do before you resort to medication.

Charles Raison: Yep. Agreed. And of course, physical exercise, you know, I mean, I literally just now horrible, but I finally got myself back on the treadmill in the morning and it's really striking. I mean, I feel better and, and I am in Wisconsin.

I have really good seasonal affective disorder. You know. I've got my light, I've got my light in the morning. It helps. And then the other thing is, and I have troubles with this guy. I hate vegetables, which is just, I I'm, I am really convinced that it's what you eat, you know, if you're, if you're horribly depressed and you change your diet, you're not going to get undepressed in a week.

But the data that if you just eat healthier day, then over time that you're less likely to be depressed and that it's going to make a difference. The data really powerful. I mean, I think, you know, what you eat, how you exercise and the social stuff that Andy was talking about, I mean, those are three just key areas that that can have a big influence, especially if they're done consistently over time. I think they have a lot of protective potential.

Dr. Victoria Maizes: So good as prevention, but maybe a little bit more limited as treatment.

Charles Raison: Perhaps when people get really, really depressed, but even there, even there. Yeah. Even there, man, I, I would not suspend those there. I think that, I think in a better world, these things would be the bedrocks of how we treated non-psychotic depression.

And psychotherapy the thing. Yeah, the good psychotherapy. I mean, and there's a caveat there of course we don't put FDA approval on individual therapists, but psychotherapy is really helpful for people very often. So that's another, it, all these things, of course, the psychotherapy there's challenges with finding a therapist and the cost and stuff, but some of these other things are, are sort of even easier to implement.

And, you know, I mean, I just, I talked about heat, hypothermia, you know, with now there's several studies, like four or five that suggest that periodic episodic exposure, you know, basically sauna, but like I hate exposure for, for some people like everything more than others to really be an antidepressant. I mean, in our study, we did in Arizona we gave people a single treatment and they felt better for weeks afterwards.

So, you know, just another little trick that, that is something that showing hot baths now there's actually a study showing that it has, you know, a modest but appreciable antidepressant effect. So there's another little thing that many of us could sort of implement one degree or other

What [00:32:00] are the things that you see on horizon? That you're really interesting in?

Dr. Andrew Weil: Well, I, you know, I think the mainstreaming of integrative medicine is, is preceding a pace and that's very gratifying.

Victoria, how, how do you see progress in psychiatry? What's happened with our integrative medicine and residency there?

Dr. Victoria Maizes: So integrative medicine in residency is a program that our Center has, which is about a 200-hour curriculum that gets embedded into existing residency programs. So it's not a separate or a different program.

We have four different psychiatry residencies that are now embedding that into their general psychiatry residency education. And that's terrific. We've also had a lot of psychiatrists come into our fellowship over the years. I think we're close to a hundred. So folks who are just saying, you know, there's a broader role that they want to play then being the prescribers of pills and having very short visits with their patients.

Charles Raison: Yeah, absolutely. I mean, no place needed integrative approach more than psychiatry. Every place needs but God almighty it’s so.

Dr. Victoria Maizes: I think the other thing that is on the horizon, but we haven't talked about still confusing is the microbiome and you know, the second brain, how do we alter the gut so that we improve mental health. And clearly there are many studies suggesting that that's doable, but I don't think that that's a clear path for everybody.

Charles Raison: Yeah, that's right. I mean, I don't think that, you know, that's my read on it because I've kinda taken a little dive back into that lately. We actually did a study in Arizona where we gave older adults dogs looking to see if it would enhance their microbiome, interestingly, not so clear to enhance their microbiome of the lower third inflammation, but, but yeah, you know, the, there's a bit of a needle in the haystack problem with that. I mean, that is, [00:34:00] they say the second most complex ecosystem for our brain and that we know universe, you know, which probably is why it's able to contribute to our thoughts and feelings.

But I agree. I mean, I think the data that to some degree, the organisms in our guts are getting a vote on who we are. Yes, it's really becoming pretty clear, you know, and then figuring out, you know, how do we, how do we engage with them in ways that offer a win-win scenarios for them and us? Right. I mean, I was saying this back 15 years ago, that, that how we think about our relationships with the microbial world is going to be a major player in the 21st century.

Long before COVID, COVID really brings that home. You know, we are the scorched earth policy that we've had towards the microbial world in the 20th century is probably not going to be sustainable. Right, I mean, we always think about bacteria, but even with viruses, right. Trying to figure out how do we, how do we enter into peaceful relationships with that world is going to be really, really important for our mental health, because, you know, clearly as I say they get a vote.

So that's actually one of the most exciting areas that I know of that I kind of flirted with it and very quickly saw that. You know, complex beyond my capacity to do more than be sort of an armchair guy on it. You know, the mathematics really intense, but it's really interesting. And I do think that will unlock more there over the next.

Dr. Victoria Maizes: So as the director of research for Usona, can you give us any insight into how far we are from FDA approval for psychedelics, for depression and anxiety?

Charles Raison: Yeah. With, with caveats. So I think that it is fairly likely that, that in fact, this is not Usona, it's actually Multidisciplinary Association for psychedelics – MAPS- And they had a very positive phase, three trial for MDMA for post-traumatic sort of phase three of the large studies. You need two positive ones to get approval from the FDA. They are more than halfway through with their second one. And they have just recently done some financial deals that are gonna give them I think the funding to actually be able to commercialize it.

I think it's very likely that MDMA assisted psychotherapy for post-traumatic stress disorder may see approval in, they say 23, but I don't believe, but I think 24, you know psilocybin you know, there's, there's several organizations that are in this space now. So you, Usona is between two thirds and three quarters of the way done with a first a hundred person, a phase two study and major depression.

There is a large commercial entity called Compass Pathways. They are not, they're actually looking at treatment resistant depression, they published their results, and we can talk a long time about it's very interesting. It suggests that for people that are chronically depressed and psychedelics are not going to be a miracle cure, but they do have a single.

Assuming that these studies show positively in phase three, I would think it's psilocybin for, for depressive disorders is I don't, you know, we don't say ever, but 3, 4, 5 years away, something like that, maybe, you know, things go well. So I think certainly by the end of this decade if the studies bear it out, I think there'll be several psychedelics on offer.

And then the other thing to keep an eye on is the things like the Oregon initiative, right? So. I may not know about this, but Oregon passed this. What seemed to be incredible initiative at the time to basically allow people to use psilocybin mushrooms in a site, in a psychological setting so that in a therapeutic setting.

So you got to come up with the and you got to go to serve a trained therapist. I think that there's, you know, people people are buying up swaths of land retreat centers in Europe are buying up swaths of land to set up large centers in Oregon. I think Oregon is to become, you know, if this really goes forward, it's going to be this place where.

You know, if you say to me, Chuck, you know, I've got my, you know, my son-in-law's so depressed and you know, I failed stuff. I wanted him to try on a psychedelic. I'll probably say, go to Oregon, you know? And so this is really interesting because this, this is a way potentially, it kind of gets around the FDA a little bit, which is why Usona doesn't take a position one way or the other, but, but it's happening and it's interesting and it's something to watch for sure. And so that is slated. I believe it's the 23 start. So, so there, we may begin to see things even sooner. So I think by 2025, there's to be a couple of options in psychedelics for folks that are struggling with mental illnesses in the United States.

Dr. Victoria Maizes: Well Chuck, it is always interesting to talk with you. Thank you so much for being on our podcast. Thank you for your truly innovative research and for all your thoughtfulness about these challenging issues.

Charles Raison: Thank you so good to see you guys be well and you know, I'm going to come out at some point.

Dr. Victoria Maizes: Well let us know. It'd be great to see you

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