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Psychedelics, Depression, Psychotherapy, SSRIs, Human Clinical Experience of Psychedelic Medicine

Full auto-generated transcript below. Beware of typos & mistranslations!

Alan Davis 5:07

Certainly I'm a clinical psychologist, but I find myself training have trained in psychiatry as well as social work. I'm actually currently a director of the Center for psychedelic drug research and education, and associate professor in the College of Social Work at Ohio State University. I also have an appointment as a faculty member at Johns Hopkins in psychiatry, as well as in the psychiatry department at OSU. So I kind of find myself working largely in interdisciplinary spaces, mostly focused on the topic of psychedelic therapies, running clinical trials, examining the safety and efficacy of this treatment for people with depression, and most recently for veterans with PTSD, and looking to advance the work and underrepresented folks as well.

Nick Jikomes 5:53

Yeah, I definitely want to talk about psilocybin and psychedelic assisted psychotherapy. But I also want to sort of give people a foundation in terms of you know, why that research is being done, and how it compares to more traditional or widespread treatment options. So for something like depression, say, what, what are the major forms of psychotherapy that are used and and sort of how do they work and how effective are they.

Alan Davis 6:21

So for the current treatments that are out there, mostly people can think of them as within two camps, one being psycho therapies. So talking to a therapist about issues related to mood or behavior, and then there's also medication psychopharmacology. So there are largely antidepressant most people are familiar with, at least the term SSRI or, or some are known as SNRIs. But those two types of treatments are about equally effective on their own. So, you know, not everyone will respond to therapy, not everyone will respond to medications, some people find one a better path than the other, both are about equally effective, they work in about, you know, let's say 30 to 50% of people. However, they don't work for everyone there, they're better when they are used together. So someone who both is in therapy and on an SSRI is, is typically going to do better than if they're on any one of those treatments alone. But they're not meeting the need that people have. And I think in part, it's because both currently take an approach of kind of reducing down into, you know, kind of a theoretical component, what the understanding of a mental health problem is. So for SSRIs, you know, the idea is that, well, there must be a, an imbalance in serotonin. And so if we give this medication, it's going to correct this imbalance, and then we're going to, you know, make people feel better. Well, the reason that doesn't work is because that doesn't really take into account all the other factors that make people depressed, like, you know, living in a, you know, oppressive system and a society and environment that doesn't really lend itself well to, you know, promoting mental health being just one of those factors. So, so yeah, there's there's a number of things that kind of get in the way of how helpful they are, but they do work for some people. So yeah, it's kind of a starting point to try. But then we need to find more options.

Nick Jikomes 8:14

And when you say that, psychotherapy, and medication using something, something like SSRIs work in about 30 to 50% of people for each each one, what exactly does that mean? Does that mean 30 to 50% of people who try one of those are going to see some improvement, does that mean that they go into complete remission with their depression, what actually constitutes an improvement there.

Alan Davis 8:40

So typically, a improvement is going to mean just any kind of reduction in symptoms. So there's two ways that that is measured. One is called a response, a clinical response is at least a 50% reduction in the intensity of your depression symptoms, or any other kind of mental health symptom, or there's remission, where your symptoms dropped below the line kind of necessary for it being like a diagnosable condition. So, you know, the overall effect of SSRIs is, is kind of a moderate effect. So it's not big, it's not large, it's not small, but it various somewhere between that kind of, you know, 30 to 50, or 40, to 60%. But in terms of getting people all the way to a remission place where they're no longer able to be diagnosed, because you know, it's working so well. That's probably on the lower end of about 30%.

Nick Jikomes 9:32

I see. And are there any, like, Are there any clear patterns in terms of like, who that 30% is to do the 30% of people? Were they going to complete remission or they have very significant symptom reduction? Do they share anything in common or is it is it sort of impossible to predict ahead of time if someone's gonna respond that way? You know,

Alan Davis 9:52

that's a great question and I unfortunately don't know that level of detail about a depressant medication. I do think that it, there is some evidence to suggest that it's probably folks where the hypothesis about what is contributing to the depression, meaning that you know, with with giving a medication, the hypothesis is that there's a chemical imbalance in the brain that needs to be corrected, right? So that 30% of people that are able to achieve remission are probably people who are as close as possible to that hypothesis being accurate for them. And there are a variety of reasons that depression exists. And this chemical, biological basis is really just one of those factors. Like, as I mentioned earlier, the environment is equally important to why people have mental health problems as these biological characteristics. There are also a variety of traumatic and stressful things that happen to people in their lives that, you know, it's kind of broadly a part of that environment as well. So, so medications aren't going to treat that, you know, medications aren't going to take someone out of poverty, for example, medications aren't going to, you know, alleviate someone being in abusive relationship, right. So. So I would say that it's more likely the case that those 30% are probably kind of purists, so to speak, in terms of like, maybe they have a supportive environment. Otherwise, they have, you know, resources, they're probably probably more resource in terms of housing and food stability and other things, and are probably as close to possible as that chemical imbalance being like, maybe the most important factor for them would be my gas, I really can't speak to whether or not that's been like, rigorously tested empirically, but that would be my theoretical deaths.

Nick Jikomes 11:36

Yeah, I mean, two things come to mind there, one would be, you know, even if someone is close to this sort of theoretical serotonin imbalance idea, let's just assume that's true for some people. If, if a change in the balance of something like, you know, triggering a neurotransmitter, like, serotonin, is an important component of depression. And that sort of an outcome of the inputs that are causing it depression, you know, simply fixing that, but not taking them out of, you know, whatever, whatever environment is, is, is, you know, producing the inputs that cause the depression and the imbalance or whatever. Treating them with something like an SSRI might fix that sort of endpoint. But if they don't actually change their environment, you're just you're constantly having the same inputs that are gonna feed into that. So that, you know, if you go off the medication, or you stop psychotherapy, you're just gonna revert back. The other thing that comes to mind that I would just love to get your basic thoughts on is, I mean, the brain is obviously very, very complicated. There's, I don't think anyone you know, I don't think anyone seriously believes that, you know, depression is ever caused by only something like serotonin being out of balance. There's lots and lots of factors. And I think

Alan Davis 12:48

it's up to the pharmaceutical industry who would like to convince you of that?

Nick Jikomes 12:52

Yeah. But you know, there's so many, you know, psychiatric illness, in particular, when you're talking about the brain, it's so complicated, that, you know, you can have the same thing and two different people say it's a major depressive disorder, and it could have, you know, a partially or even a completely different underlying, you know, biological cause. And I would imagine that that's also a factor here, you know, one person's depression might look on the surface like another's, but the, the biological causes of that could be very different.

Alan Davis 13:22

Yeah, and not only can the biological causes be diverse and varied, but obviously, the environments can be diverse and varied. And it the symptoms are can be interpreted differently, depending on one's culture, depending on one's insight of their own kind of physiological, you know, experience in life, the way that they think. And so the way that the kind of information that comes back to them when they talk about their experiences with people like loved ones, and others, and it's like each individual's experience of their depression, or their PTSD, or whatever the condition is, will be filtered through all of these different lenses. And so, it's really difficult, if not impossible, to really even have a, you know, a diagnostic category like, like major depressive disorder, and have any confidence at all that we're actually, you know, meaningfully diagnosing, and measuring and understanding a condition in any more than one person at a time, if that makes sense. Like, it's, to me, the whole the whole pursuit of a diagnostic classification system is a misrepresentation of the idiosyncrasies of of which mental health problems come up to begin with. Yeah,

Nick Jikomes 14:36

yeah, I mean, I think it's so hard to for anyone to even just speak about their feelings, their subjective experience, the way that different people talk about it, you know, they might be having the same phenomenology in their experience, but they describe it two different ways just because they have, you know, a different vocabulary and and if and it's so sort of, you know, these things are so sort of ephemeral and a more This just just intrinsically, you know, the other thing is, you know, I think for most psychiatric illness, right, there's no, there are no actual like objective tests, there's no, there's no you can't get bloodwork and know that you know, you've got depression or something like that is, is that something that you also think about or that the field of psychiatry and clinical psychology thinks about, like developing ways to assess someone's psychiatric condition without relying solely on their self, the words they use to self report?

Alan Davis 15:33

Yes, and not only has it been of interest, but you know, billions of dollars have been put into, into research looking at, you know, the biological basis of these conditions with frankly, very little outcome that's led to, you know, a clear ability to do something like a blood test or a genetic test and, and have any kind of understanding, I think there is some there's some benefit that's come from that research, but that research has largely been designed with this kind of, like reductionistic, you classification lens, right? Where they want to get to a point where they can say, Okay, well, now we've found the, you know, the biomarker for depression, as if that biomarker exists solely within the body, that it's definable, and that it will kind of apply cross culturally and even within culture across individuals. And to me, that's the same farce that has that has led to having a depressant medication as a, you know, a treatment for people, right, the medication is not actually solving the problem of depression, for some people who are in remission, who will take that medication for the rest of their life, who will deal with the side effects of that medication. And we'll deal with a variety of other things that come up because of having to take that medication for the rest of our lives. For some people, they're in remission. But that does not mean that like any of this approach is actually leading towards healing of what that depressed state is.

Nick Jikomes 16:56

And, you know, in, so, so if it's roughly 30, to 50%, give or take of people with something like depression will respond to some degree, from taking something like an SSRI, how many of those people have side effects that are either chronic while they're on it, or that persist after the medication stops? So, you know, even for the 30 to 50%, where it works, to some extent, doesn't work? And they're better to some extent, or do some significant proportion of them also have other things that go wrong? Because of the medication? Yeah,

Alan Davis 17:33

I mean, there's definitely a lot of people that have side effects of medication. That's one of reasons why people don't stay on them. It's one of reasons why the, you know, the efficacy rates are so low is because people will find them intolerable, you know, they deal with depending on the medication, it obviously varies on what people might experience as a side effect. But it's everything from nausea and vomiting and diarrhea to weight gain and feeling like you're empty inside or feeling, you know, more anxious, nervous, some people will have, you know, major side effects into their sexual functioning, typically as a reduction in sexual desire or difficulty orgasming. And people will have increase in appetite, which of course, contributes to weight gain. So there's just, you know, there's there's so many side effects for all these different medications that have been developed. And, and a lot of people really struggle with them.

Nick Jikomes 18:23

And are all of those like acute side effects that they have when they're on the medication? Are there any that can? You know, because there's a lot of people that are on SSRIs, for years, sometimes many years? And then if those people stop, are there any side effects that is there anything about their biology that changes that has an enduring change? That sort of never goes back?

Alan Davis 18:46

Yeah, I'm not sure entirely about that question. But I will say just anecdotally, from people that I've worked with, some of them who have come into the psilocybin clinical trials who have been on medications for a really long time, they do describe a kind of overall dampening of their emotional connection to things and I think that there is some emerging evidence showing that the you kind of the longer someone's been on an SSRI, you know, because there's also like a potential dampening of like things like the psychedelic experience, and which I think kind of goes to this notion that, you know, the brain, the brain might be, you know, I hate to use the word forever, it might be changed for a while, that persists beyond just discontinuing that medication. And just because of how long the brain has kind of been in this medicated state.

Nick Jikomes 19:36

And so on the psychotherapy side, so if someone goes in for talk therapy, what are the major sort of forms or strategies of psychotherapy, like I know that I know there's cognitive behavioral therapy, and there's other forms of therapy. What are the big ones there? And do they have different levels of effectiveness? Why are some more popular than others? Like what what are the major forms of psychotherapy?

Alan Davis 20:00

There are several, there's, there's been kind of waves of psychotherapy development over time. Some of the early treatments that are that are pretty effective are called behavioral therapies. One is called behavioral activation. And in particular for depression, which is really about kind of getting active, getting the body moving, that kind of just engaging in behaviors that can reinforce, you know, physical activity, kind of things like working out, going to the gym going on a walk, things that can activate one socially kind of getting engaged with, you know, friends with a community that, you know, this type of behavioral activation has been shown to be an effective strategy to help with depression. Since then, you know, things like cognitive behavioral therapy, which really just adds into that behavioral component. Also, this understanding that the mind that you wants, thoughts also affect one's emotions. So it's not just behavior, its behavior, thoughts and emotions as like a triad can kind of, at any one of those places can kind of create a chain of depressed thoughts or anxious thoughts that they can also give kind of a place to intervene at any of those levels. So something like you know, someone having a depressed thought, you know, there's there's strategies that can be used to kind of help deal with that. There's a newer wave of treatments that are also available now called mindfulness based therapies, there's one called Acceptance and Commitment Therapy that is that has gained quite a bit of popularity, all of these, what we're calling third wave therapies. All of these third wave therapies really aren't integration of mindfulness, understanding more of kind of an Eastern approach to mental health and well being things like meditation and awareness of breath and body. And that these approaches when you combine them within this kind of CBT space, that the combination of these things seem to be helpful for people. But what we know from decades of research on any of these treatments, especially those treatments, where they're actually compared to each other, is that they're all about the same in terms of how well they work, they work, you know, for some, they don't work for everyone. They're also, you know, pretty expensive to get into therapy to have the type of resources that allow one to do this for months, typically, or if not longer. And so they're about as effective as is the antidepressants out there. They're more effective. If you're doing both at the same time, there's a there's kind of an added advantage there. But probably, what's the biggest thing that we've learned from the research on psychotherapy is it's about fit, it's about the fit between what's the right person? What's their approach? What kind of therapists are they working with? Is that therapist? Is that a good approach for them? How well does that fit together? That match is what typically is going to be shown to be effective for an individual, which is hard, because there's a lot of therapists out there that are doing a lot of different things. And people don't often know that they can go into a therapist and like, interview them, right and kind of want to assess like, as a customer want to assess the fit and want to assess the treatment that's being you know, offered to them. And some, for some reasons, because people just don't know that there are different treatments or there are, you know, different approaches, but but it is about that fit. And it's also about the relationship. So we know from a lot of research that the what we call the therapeutic alliance, or the kind of safety and the connection that people feel, with developing, you know, trust in a provider with developing trust in a therapist, that kind of becomes a safe space for them to explore the darkened squishy parts of themselves, that they don't necessarily feel comfortable sharing with everybody, that that relationship is also really effective in and of itself, regardless of what treatments being provided to somebody, that just having that safety in that space in that trust can also help people feel better.

Nick Jikomes 23:54

And so psychedelics and psilocybin assisted therapy, been getting a lot of attention over the past few years, I know that you've been involved in some of those trials. Can you just kind of give us a state of the art for psilocybin assisted psychotherapy for things like depression? What is the totality of the clinical research say today? It would you say it's proven that psilocybin is effective at some level? Where are the clinical trials out in terms of, you know, phase 234? And all of that sort of just where are we today with that?

Alan Davis 24:26

So we are, I would say, at the late stage of all of the research that will need to take place before the FDA will have enough information to decide whether or not should be made available to the public. That phase of research that we're in is called phase three. And that's the last phase where a treatment is explored typically at multiple sites around the country or the world, in hundreds of people as opposed to these smaller studies that are only done in in dozens, excuse me, and that research is largely pointing towards a The likelihood of approval by FDA and probably the European Medicines Agency as well, within the next, I would say 1218 months. So we are we're pretty close. Of course, nothing scientifically is ever definitive. So, you know, I can't say for certain whether, you know that data will lead to approval, but it seems it seems like there's, you know, the writing's on the wall to some extent. And the reason I say that is because of not only the preliminary evidence that's, that's being published, you know, over the last few years, but also because, you know, the FDA has signaled to the Biden administration, that the likelihood of approval for psychedelic medicines is, you know, strong, and that they're not too far in the future. And so because of that, there's actually been a federal task force that has been initiated at this point to, to bring together all the different stakeholders at the federal level, who would be involved in overseeing this type of dissemination of a treatment. So people at the DEA, obviously are involved in this conversation, the people at Department of Health and Human Services who oversee things like Medicaid and Medicare, and overall kind of guidance around treatments that should be covered by those nationalized health care system. People at the VA, there's a lot of stakeholders involved in these conversations. And and my guess is that those conversations would not have been initiated if we weren't, if we weren't, at some level of certainty that there's enough evidence already just suggests that psilocybin therapy is is going to be at least an effective option for some people.

Nick Jikomes 26:34

And what basic results have people seen so far in trials for psilocybin assisted psychotherapy for depression in terms of, you know, what are the effect sizes? Is it working for a similar percentage to like the 3030 to 50%? We see for SSRIs, is it working for more people? Is it working for people who SSRIs didn't help their depression, like were like, what kind of what kind of effects are we seeing?

Alan Davis 27:01

So it does vary a little bit by study. So I'll try to do my best to summarize, but in general, what we're seeing is that there is a larger proportion of people in these studies who are in complete remission from depression. In our study that we completed at Johns Hopkins, which was the first randomized controlled trial looking at comparing psilocybin therapy to a waitlist, no treatment group was that 50% of the people that were in that study, were in complete remission at one month after the treatment was over. Now, keep in mind that, you know, 50%, it's still larger than the 30% in remission, you know, from any depressants or psychotherapy. But it also only took, you know, two doses of psilocybin in conjunction with about 13 hours of therapy. So one treatment package two doses of a medication, and 50% of people were in remission. What was really interesting is that at one year later, after the treatment was over, that 50% of people were still in remission. So these are folks who often had been on a variety of other medications had tried psycho therapies had had been through the gamut, so to speak of other approaches, and either found them to be not as successful as they needed them to be. So maybe they had some benefit, but not completely, or they were dealing with side effects that they didn't like, or for some, you know, the treatments never helped. So, so that's pretty remarkable in and of itself, just to kind of see that, on some of the other larger studies that had been that had been conducted now comparing both to placebo as well as other treatments like SSRIs, we see that in one of those studies, there was a on almost all indications, all indications of, of looking at the variety of ways you can measure depression, almost all of them, they showed that psilocybin therapy had a favorable treatment profile compared to SSRIs. With the exception of this one measure that was kind of their official measure of symptoms, which subsequently now there's been some interesting studies looking at whether that measure was actually appropriate to use as that comparison. And yeah, but in any event, so the reason I bring that up is because there's likely to be some diminishing effect. As we get into these bigger studies. As we compare to placebo, as we have hundreds, if not 1000s of people that are eventually treated in these studies, I think we're going to see that it's maybe not as high as 50% remission, in part just because you know, those studies that are so small, they're so selective to get into them. You know, it's very narrow in terms of the type of people that are in those kinds of studies. And so similar to how we have people who don't have just like a purely biological basis of depression, right, and we've kind of as you disseminate treatments out into the real world, to real people who are not so selectively chosen, we're likely to see some diminishing in that. It's likely though, that it's still at least as effective as other options, if not probably more effective than other options.

Nick Jikomes 29:57

Yeah, and I imagine that tip Alright, as as the, as you progress with the, you know, phase 123 trials, they're getting bigger and you're casting a wider net. And that's probably common, right that the sort of effect size is probably diminished somewhat as you go through the solution.

Alan Davis 30:15

Absolutely. So so it's definitely expected with every treatment as it reaches a broader and broader sample of people that have been tested. And again, even when it goes from testing to implementation, you're certainly going to see some diminishment of effect there as well as it gets to like the biggest potential population. At the same time, you know, even if we even if we end up in a place where we can say statistically, or scientifically, that it's the same effectiveness as other treatments, it still only takes two doses of the substance, it has a much more favorable side effect profile, it leads to other really important things that people will talk about in terms of their identity development, and understanding their relationships better moving towards things that are important to them in their life. So even outside of symptom reduction, these, this treatment provides a whole range of other types of enduring effects that people find desirable and important. And I think that it that's, that's very unique to this, this type of treatment. So even, even if it's only as effective as other treatments, it still seems like for some people, that might be a much better option.

Nick Jikomes 31:22

Yeah, I mean, it is remarkable that you see this kind of effect from just two doses of something in the context of several weeks of psychotherapy are so for the trials that have been done, or that you've been involved with, are the people that are willing and able to do the psilocybin assisted psychotherapy are these typically people that have tried other things, and it hasn't worked. So they're just really hoping that something new will work, or, and sort of the other thing that's related to that, I guess, is how many of these people are completely naive to psychedelics, and have never tried them before? How many of them had previous experience with psychedelics, and you know, what's your sense for what chunk of the patient population is going to be excited to try something like this if other things have failed, and what percentage might be intimidated and won't wouldn't want to go through something like this.

Alan Davis 32:12

So most of the studies that have been completed, have been completed specifically with folks that are considered treatment resistant, which means that they've tried at least one, sometimes two or more, other treatments and treatments have not been successful. That's not the case. For every study, like our depression study at Hopkins, we didn't require that they had that background. But I think because of the nature of this kind of these studies, right now, the nature of them being highly experimental, they're using a psychedelic, which has a whole, you know, stigmatized background in people's minds about what psychedelics are. Because of all of that we're still typically seeing even when it's not a requirement that most people in the studies have had several medication trials in the past, it has not worked for them. And so they kind of they find their way into these studies. It's kind of like a last hope, you know, of trying to find something that will work for them. And so, but in terms of the, you know, the, the kind of the folks that this sorry, I'm kind of losing track a little bit on what the second part or third part of your question was. Yeah, maybe you could repeat it if you'd like.

Nick Jikomes 33:15

Oh, yeah. I was just asking, yeah. Are there differences between people who have previous experience with psychedelics versus those that don't? And, you know, What's your general sense of, you know, how, you know, what percentage of people say, are going to be interested in trying something like this, versus those that, you know, might be intimidated by the nature of of a psychedelic assisted psychotherapy.

Alan Davis 33:36

So most of the studies have a requirement that people have to have limited exposures to psychedelics prior to coming in to study. Usually, what that means is that no exposure to psychedelics in the last five years, and there's a preference for really none ever, ideally. But if it's more than five years ago, and it you know, it was kind of like more like a recreational experience, it wasn't really done for the intention of a therapeutic experience. Or if it even if it was, but it didn't lead to like any kind of measurable important changes or something like that, then we then people would can get into the studies, but it really is trying to minimize, you know, knowing that this is potentially the first time someone has been exposed to a psychedelic.

Nick Jikomes 34:18

So in general, it sounds like the majority of patients that have done have gone through the trials that have been done so far, are often treatment resistant. So they have tried other things, at least one of the things before and the majority of them are also have limited to no history with psychedelics.

Alan Davis 34:35

Typically, that's probably a typical profile, or if they have had experience with psychedelics, it's been, you know, in their, you know, years if not decades ago, it was kind of like a blip of experimentation or something like that, but it wasn't like they were continuing to use psychedelics into adulthood or things like that. So, so typically, that's, I would say, a pretty common profile in the studies. However, there are some folks who Who, especially with the on the history of depression side, there are some folks who have not tried treatments before, especially in our study at Hopkins, as I mentioned, you know, that we had several people in that study who had not tried anything in terms of treatments before that. So it's not the entire, you know, encapsulation of folks. But that's, that's a good general swath. So I think in terms of like, the latter part of your question about, you know, are there gonna be people who are afraid of this treatment? Or who are going to have thoughts about I mean, absolutely, I mean, people have thoughts about it. Now, for sure. There's people who, you know, are out there who I'm sure have, you know, for the last, you know, four or five decades, been, you know, living in a misinformation campaign about psychedelics, you know, from all levels of government and education spaces. So, you know, that, unfortunately, that that misinformation campaign has done a lot of damage to helping people understand what these substances are, their history, you know, their their long term, in most cases, history of abuse, and in indigenous communities. For things like treatment and rites of passage and a different parts of the developmental trajectory, and people's lives that these these medicines have been used, you know, far longer than the Western research has been going on. So, but that information and that understanding and that contextualization, and really the absence of any cultural container or context, in the US for psychedelics, as a result of that has led to people being afraid of the substances and people worrying about the potential risks that might be involved, there's been, you know, there's been just like, like, like fabricated lies told to them for so long that you just start to believe the lies after a period of time.

Nick Jikomes 36:48

And, you know, in terms of the the subjective experience, when people go through these therapy sessions, that that are assisted with psilocybin, obviously, everyone's going to have their own unique experience. And no, you know, no two experiences are going to be identical or even similar. But you know, in terms of the people that go into complete remission, you know, six to 12 months out, and those that don't really see response, are there any kind of common threads in terms of how they report their experiences being to the people who are going to remission like report, a better, less terrifying experience or a stronger experience? Are there any patterns there?

Alan Davis 37:26

So there are some patterns that have emerged. I mean, we know that, that some of the acute effects of psychedelics things like the Insight component, you know, getting a new understanding a new realization, or awareness of something about yourself, about things that you've struggled with about relationships or things in your life that are difficult, you know, that those insights that in those new understandings can be incredibly powerful, and are often correlated pretty strongly with mental health improvements. The mystical or spiritual experience is another acute effect, that there's evidence to suggest that these these spiritual moments in the psychedelic experience can also be helpful that can be impactful for some, you know, it's described as, you know, one of the single most or top five, spiritually significant and psychologically insightful experience of their entire life. And so the the impact of that type of experience can certainly not only math, you know, mathematically or statistically be related to outcome, but it's I think it's just in general related to why people's perspectives have shifted and changed in terms of how they view themselves, how they view the world around them. And also, you know, how their mental health shifts and changes as a result. But there's also you know, a variety of biological things that are happening in the brain, we know that, that for people who are depressed, you know, the part of the brain that that is kind of interacts with that depression, that that you will like over react when it sees negative emotional things in the environment that will kind of reinforce this like depressive state, this depressive kind of attitude because it's lighting up when it sees, you know, someone frowning on one side of the street, as opposed to like someone smiling on the other side, like it gets a taking that inflammation in the brain is like, like, it's like, it's substantiating their depression, right? Like, oh, yeah, like it is, life does suck, because look, this person's not happy, right? That part of the brain, when you have exposure to psilocybin therapy, that part of the brain reacts differently after the therapy is completed, it does not respond as strongly to that, that negative emotional information in the environment. And so, you know, the just the fact that the brain is changing and how it responds to things going on around the individual, you know, helps us to see that it's not just it's not just someone's you know, trip, although the trip seems to be important and helpful for people. But it also seems to be there's just like biological changes happening at the level of the neuron and the synapse in the brain that might also be contributing to this benefit so, and there's a lot more that, you know, we're just starting to better understand there's, there's experiences of difficult physiological experiences that people sometimes feel is like a release of some kind of energetic release of some kind. Some people talk about emotional catharsis and ego dissolution and, and a variety of other things that we're really just starting to tap into to better understand how it's related. But, but any of these types of things, any of these types of experiences seem to be potentially helpful for people.

Nick Jikomes 40:31

In terms of the enduring effects, so you mentioned that in some of these studies, people, they followed up with patients six to 12 months after they did psilocybin assisted psychotherapy, and a significant proportion of them were still in remission, which is, which is great news. What's the longest anyone's ever looked out? Is it 12 months? Or is it even longer?

Alan Davis 40:53

My understanding is that the study that we did Hopkins with a 12 month follow up is the longest that's been published so far on, folks with depression. I do believe that there are some studies that are trying to look beyond that. Now. We're actually at Hopkins, we're trying to do a four year follow up of all of those people who participated in that study, just to see it, you know, three to four years out, you know, how does it look now, this far out? So we'll kind of know, hopefully, by the end of this year, or early next year, what the results are from that. But as far as I know, that 12 months is the farthest out that studies have published on the topic of how enduring those effects have been. And in that study, we found that, you know, still about half were in remission. And we also found even at 12 months out that people were reporting that, you know, that experience was still one of the most personally meaningful experiences of their life. And so I think that, you know, it's it led to a lot of other things besides just, you know, for some an antidepressant effect for some it also led to new meaning and purpose.

Nick Jikomes 41:56

And so, what, are there any, are there any enduring or lasting side effects? Do people report any type of physiological change or anything else, that that outlasts the treatment itself.

Alan Davis 42:15

So some of the most common side effects are things like transient anxiety that can happen during the especially during the onset phase of the psychedelic experience. For some people that can be really difficult, there can be panic, there can be fear and anxiety, it's really reasons why we do so much therapy ahead of time, and why there's trained professionals in the room with someone when we do this treatment, is to help manage some of that. One of the other really common side effects is headache that comes usually later in the day of the session, sometimes over the following night or evening. But outside of that, there are very few. And as far as I can tell, no serious side effects for people. Now, that's also taking into consideration, you know, very careful selection process into these studies. And so when you look at just people using psychedelics out in the real world, outside of therapeutic context, there is a small, but still, you know, meaningful risk for, you know, enduring problems related to, you know, you've probably people have probably heard of like people having a bad trip, people have probably heard that there are people who struggle with, you know, some of the psychedelic effects that come back, even after they've come down from the trip. And sometimes those those lingering effects, like still seeing things moving in the visual field or still feeling kind of unsettled, or kind of feeling some of the things they felt during, you know, that panic or fear place of the psychedelic state. Sometimes for those people, there are some people who develop what's called HPPD, which is this kind of long term, ongoing, kind of continued experience of these like, kind of negative psychedelic effects. It's a really rare condition, it's it's estimated, it's less than 1% of people who have developed this type of complication. And so far, that has not happened at all, it's been 0% in the clinical trials, but in part because we're screening people out who might potentially be at risk for that. So people who have like a history of you know, psychosis and their family who have, you know, potentially like a predisposition to having some of those challenges are weeded out of the study. So, you know, overall, there's, I think, very few, you know, risks involved in actually, you know, if you're carefully screened, if you're carefully prepared, if you're working with trained professionals, but there are risks that are that are that are there, and they're some of the risks that are there, even when we do such careful selection and screening are, you know, there's risk to kind of being vulnerable to suggestions of being vulnerable in a in a, in a psychedelic state to, to things that people might not, you know, otherwise consent to, you know, so there's been some studies that, you know, there's been some question about, you know, what kind of therapy was provided whether or not the providers of those therapies were acting in unethical ways in terms of things like touch during a session or kind of how they engage physically with an individual. And there's even been some cases reported, you know, in some studies of sexual abuse, and so they're absolutely, you know, I'm not just talking about psilocybin, I'm talking about just like psychedelic therapy, generally speaking right now, you know, there are risks involved with with people being in a vulnerable state that don't necessarily have anything to do with the side effects of the medication, but just have to do with like, being in this kind of really intensely vulnerable space with with other people.

Nick Jikomes 45:36

And in terms of the psychotherapy side of psilocybin assisted psychotherapy, there's several weeks of therapy that that are surrounding the usually two doses of psilocybin that people get, is this a new form of therapy that's very specific to these studies? Or is it is it basically one of the standard forms of therapy like CBT, or something, what does the actual talk therapy side of this look like?

Alan Davis 46:02

So the therapy that's provided is, in some ways, kind of unique, because part of the therapy is preparing someone for a psychedelic experience. So, you know, that certainly is something unique to this type of approach. And we spend many hours with people talking through kind of all the different types of things that might happen during the psychedelic experience, and also helping to prepare them with skills, things they can use, and do to navigate that psychedelic space. So that is obviously unique to this approach. But there's, there's other things that we're doing as well, that are not unique to this approach, you know, connecting with people in the therapy also means, you know, talking about things like their emotions and their behaviors and their thoughts and, and talking about things like mindfulness and things that, as I mentioned earlier, are kind of a featured in a variety of different therapeutic approaches. So for some studies, they're actually tying together the the components that are specific to psilocybin therapy, and, you know, measurable components of, you know, official other therapies. So there are some studies that are using a Acceptance and Commitment Therapy approach. And there's some studies who are using motivational interviewing or cognitive behavioral therapy, and they're really doing a full therapeutic package that you would otherwise see kind of in a in a study just of that therapy. And they're kind of tying that embedding that within, you know, this other kind of psycho educational component for, for preparing people for psychedelic experiences. And, and there's a lot of studies that aren't, you know, tying a specific therapy that they're kind of, they're kind of maybe doing a little bit more of an eclectic or integrative approach, but I would say that most studies are using some, you know, mix of both kind of what we already know is helpful from other therapies and kind of tying that into this newer approach for psychedelics.

Nick Jikomes 47:56

And, I mean, there's a lot of different psychedelics, and other psychoactive is being investigated for all sorts of different stuff now, depression, addiction, other things, I know that you've, you've done some work sort of comparing contrasting some of these drugs. So I know that you've looked at psilocybin versus things like five Meo DMT. And so what have you seen there so far, in terms of what are the major differences there, both in terms of subjective effects, the length or duration of the effects? And what do we think might be relevant there in terms of, you know, therapeutic potential.

Alan Davis 48:30

So, you know, there are a variety of differences with psychedelics, you know, they're, they're broadly classified in the same group, but they can be very different depending on the context that people are in and the type of substance they've consumed. For something comparing something like five Meo DMT to psilocybin, the one of the biggest differences is the duration of effect. So five Meo DMT, typically lasts somewhere on average of like, 20 to 40 minutes, depending on the, how it's consumed, or how it's put into the body. When it's smoked, or inhaled, it's much shorter duration, when it's injected intramuscularly, or kind of evaluated in a slower way into the body, the effects are longer, but it's still, you know, less than, you know, 45 minutes compared to psilocybin, which is, you know, four to six hours. And that's compared to something like LSD that's, you know, 10 to 12 hours. So, there are obviously a variety of the ways in which the duration of these effects can be different, because of that duration and the way in which things you know, there's the time course that people have in these experiences, there's also differences in the way that the the kind of effects will fluctuate, that people might have a variety of different types of experiences with psilocybin, that kind of ebb and flow, you know, as the substances moving its way through the, through the, through the body. But, you know, with five Meo DMT there's just such a narrow window of time to have any experience that it often just like comes on, there's like one experience and then it kind of comes down as opposed to psilocybin where, you know, it might come in way It might be like an overall wave of effect that kind of reaches a peak and subsides. But there might be like, kind of additional waves that kind of come and go, especially throughout the latter hours of the experience. In terms of the differences in the acute effects, I mean, those vary so much just we even within substance by everything that relates to the individual who's consumed it and the environment that they're in and the preparation that they've had and their cultural can you know, contextualization. So there's so much as inter drug differences. So it's hard to compare them directly in terms of the subjective effects. Although one of the biggest differences with something like five Meo DMT is that it doesn't seem to have as much a visual phenomenology as other psychedelics. So it seems to be potentially more emotional and psychologically psychedelic as opposed to visually, but seems to have equal if not greater intensity of reported effects and other ways in terms of the emotional catharsis that people report experiencing, or these really deep, you know, mystical and spiritual or insightful experiences that people report. So. So yeah, there's some overlapping things across these substances, but also, a lot of you noticed a lot of differences.

Nick Jikomes 51:14

And so based on your experience with some of these trials, and and everything that you've done, there's a big question. You know, in in the field of psychedelic science, generally speaking around, you know, whether or not the subjective effects are therapeutically relevant or even, you know, potentially unnecessary, or whether they're just, you know, basically a side effect. And there might be this, there might be an ability to create derivatives of existing psychedelics that have the benefits around, you know, generating the clinical outcomes we want, but that don't require tripping at all, or at least less than something like psilocybin or DMT, or whatever. Based on your clinical experience on the clinical side here. Do you think it's likely that such drugs will be created? Do you think that the subjective effects are likely involved in the therapeutic outcomes here? Or are they are they, you know, plausibly irrelevant.

Alan Davis 52:14

You know, as someone who's provided this treatment to people and seen firsthand the importance and the relevance of those subjective effects, it's hard for me to imagine that stripping those away, would otherwise still make it effective. At the same time, as a scientist, I wouldn't rule it out, I just know that I haven't seen that work yet. So it'll be curious to see what some of those studies, you know whether or not they're able to demonstrate that it can be as effective, I still think that people should have the, if nothing else have the option and the opportunity to choose the fit, that's the best fit for them, it might be the case that maybe for those people who aren't in remission, you know, from the typical psychedelic therapy approach, perhaps those people, maybe the the acute effects were distracting or, you know, otherwise, were confusing and led to, you know, difficulty in integrating the experience, you know, we've had some people who could make no sense of what happened to them in the psychedelic experience, and it was kind of distressing and difficult. And so, you know, for those people may be a better fit would be to then try a psychedelic without, you know, the acute effects and to see if that was helpful for them. But for others, you know, there's such important meaning making that comes from these acute experiences that, you know, I would hate to see that stripped away from from the model completely. So hopefully, it's a both and situation in the future, there's going to be some people who are just terrified of psychedelics and the experiences that they've heard people have and, and for those people, it might be better that they have an option that that still potentially brings them relief but obviate some of that, that anxiety. So yeah, I hope to see a place for both approaches. But my current experience seeing people, you know, with these experiences, is that to remove that completely would be missing the point.

Nick Jikomes 54:05

And what's your What are your thoughts around microdosing? Have any My understanding is that for for psilocybin, and most other things that have been studied clinically, typically, or pretty much every time we're talking about large or fully psychedelic doses? Has anyone done clinical trials for psilocybin or anything else at very low doses? And just what are your thoughts generally around this increasingly popular phenomenon of micro dosing?

Alan Davis 54:32

Yeah, it's really interesting. I think that the, the idea is a fascinating one, you know, that somehow sub perceptual doses of a psychedelic might still contribute to improvements in mental health and just overall well being. It's really intriguing. And I think that there's enough anecdotal reports out there of people who are reporting benefits in this way, that it certainly deserves, you know, really, you know, robust scientific and experimentation to understand it better. However, the current studies that have been done on the topic have largely shown that it's probably a placebo effect, that it's that they haven't been able to discern, again, it's only been a couple of studies. So there's more needs to be done. But at least in these early studies, they've shown that like, there really is no difference between placebo and people who are getting the microdose. That being said, you know, there are, there's something to be said about the placebo effect is not a bad thing, right. Like, like, there's a lot of things that affect people's experiences in life. And if you told me that, like, I could take a micro dose of something, and I had, you know, let's say a 30% chance that it was going to improve my life. And it might just be because my brain is really powerful and might be driving that change, like, okay, like, if there's no risks involved in like, why not, you know, because that's still, that's still an improvement in the betterment of someone's well being in life, because they're, you know, engaged in this behavior. But whether it actually means that like micro dosing is effective for that, I think, you know, the science is so far pointing to like, maybe not, but again, we haven't been able to do because there hasn't been funding to do it, yet. There hasn't been like large studies on this topic that have really started to dig into this experimentally. So I think we need more studies to know for sure, but, you know, it's Yeah, question about whether or not it's actually working.

Nick Jikomes 56:22

And, you know, around the question of placebos here, you know, when we're doing trials for things like psilocybin, where, you know, we're using a full dose, so the, the effects are quite, quite potent, and very noticeable. What are the placebos that are actually used? And how does? How does the question of placebos and blinding? You know, how do you think about that, when you're when you're talking about something like a psychedelic, where the effects are just like so obvious, subjectively obvious that? You know, it's difficult to think about what a true placebo would even look like here?

Alan Davis 56:56

Yeah, it's, it's, it's a concern for this type of research. It's something that is has been touted as, as almost like a deal breaker in terms of really understanding from the kind of gold standard scientific lens of really understanding the true efficacy of this approach. Because it we it's very difficult to mask people to condition it's very difficult to be blinded, both as the person receiving the psychedelic or the placebo, and as the experimenter, right, it's hard for us to be blinded as to what people have gotten, although I will say, not impossible, there are there's absolutely been times where people have been given a placebo. And it's fooled, that people thought they got the drug. And also the experimenters thought they got the drug. And it wasn't revealed till later that they didn't. So that expectation that expectancy of what people think is going to happen, the placebo effect, like is real with this drug as well. But most people are functionally unblinded. Most people know they haven't gotten the psychedelic, most most therapists know the therapy participant hasn't gotten it. So it's an issue it but to me, it's actually the bigger issue that this brings up is not whether or not we'll be able to, you know, have enough evidence to determine whether or not made available to the public. I mean, I think I think the writing's on the wall in that regard. I think regardless of this issue with blinding, you know, the placebo controlled studies are still showing that there's, you know, an effect of the treatment, unlikely that will be enough for FDA approval, I think the bigger issue that it's bringing up is actually the inadequacy of our scientific system. And the inadequacy of thinking that the placebo controlled trial is shouldn't be the end all be all of experimental manipulation. And I think that actually, this is a really good example of us needing to as scientists and as and as a culture that kind of revolves around sciences as a way of knowledge formation, that we actually need to think about what other ways of knowing what other ways of understanding things is equally or potentially just in this case, better suited to help us understand the questions that we're asking in these studies? And so I think it just for me, it just calls into question the adequacy of the system that we're in, and how we need to probably find better and just Yeah, better alternatives for this type of study.

Nick Jikomes 59:14

And approximately how many phase three trials are ongoing for psilocybin assisted psychotherapy, and what are the key next steps that need to happen to trigger the FDA issuing an official opinion and approximately how long do we think that's going to take?

Alan Davis 59:30

So as far as I know, there are two and possibly a third, but for sure two, phase three trials that are either underway or soon to be underway. One is being led by the Sona Institute here in the US they're pursuing psilocybin therapy for major depressive disorder. There's another one being pursued by a company in the UK called Compass. Compass is pursuing it as psilocybin therapy for treatment resistant depression. Both of those, both of those Studies and both of those trajectories of studies have already received what's considered a breakthrough therapy designation by the FDA, which means that a few years ago, based on the evidence at the time, the FDA already said this is already something that should be fast tracked. This is something that needs to have special FDA oversight, because the evidence of the time was already so strong, which is why these studies have progressed, the way that they have with additional FDA oversight by the FDA is also signaling that we're getting closer to them being ready to make a final determination and ruling, my guess is that we will probably be in a place of having some type of ruling by the FDA, probably in late 2024, early 2025. We my best guess we're probably closer in terms of when MDMA therapy for PTSD will be approved, that's likely to be probably in the first half of 2024. So we're probably gonna see the door open with MDMA therapy, and then within a year of that, probably psilocybin therapy for depression.

Nick Jikomes 1:01:02

What so what kind of studies are you currently working on? What are the are you just sort of doing bigger versions of things you've already done? Or are you doing like new new types of studies answering different types of questions?

Alan Davis 1:01:15

So I'm more on the ladder. I'm, I'm interested in a couple of different areas of research. The first one that that we've done that we've started now is, we've launched a psilocybin trial for veterans with PTSD. There has not yet been a study of psilocybin and PTSD in general yet, and specifically not one yet in veterans. And so we're working on that trial right now at Ohio State University, we also just got funding to launch a comparison study of five Meo DMT and psilocybin therapy in lung cancer patients. And so we're going to be launching that trial in early 2024. And then, in addition to that, I have several pilot studies that are underway right now that we've been working on for last couple of years to start to bring together, minority and underrepresented populations more closely into psychedelic therapy research. And so we're likely in the next year or two, we're going to be launching trials in gender and sexual minority individuals looking at minority stress and the effect of that on mental health and using the psychedelic therapy as as as treatment for dealing with stigma and and the negative outcomes of being in a marginalized group. We've also been working on translating all of the psychedelic measures into Spanish so we can reduce the barrier of language for people getting into these studies. So it's been predominantly English language studies. And so that's hopefully going to increase access and availability people. And then we've also been doing studies looking at bipoc and other people of the global majority and kind of racial trauma and the way in which just being in kind of a racial or ethnically diverse group kind of confers its own type of depressive, or depressive and traumatic kind of reactions to, to being marginalized in society. And so in all three of those different areas, we're hoping in the coming years with funding to be able to launch studies.

Nick Jikomes 1:03:11

And so you mentioned the study using psilocybin and five Meo in patients with lung cancer is that to treat like end of life anxiety,

Alan Davis 1:03:19

yeah, so that'll be treating end of or kind of the anxiety and depression that's associated with receiving the life threatening illness diagnosis.

Nick Jikomes 1:03:27

And just for those who don't know, what sort of results have we seen for that type of thing so far?

Alan Davis 1:03:33

Yeah, so the cancer, there are life threatening illness in general, were some of the first large trials that were published with the kind of looking at psilocybin therapy. They were published in 2016, by researchers at Hopkins and New York University. And those studies were really the first out there that showed in this population of cancer patients that the psychedelic therapy helped to reduce and in some cases, kind of completely put into remission, anxiety and depression and was increasing the quality of life among folks that had these, these life threatening illness diagnoses for some kind of helped them live more meaningful lives with whatever life they had left. And yeah, and kind of deal with things like death, anxiety and existential distress and, and other you know, phenomenological, you know, things that occurred, just getting that diagnosis. And so it's in fact, some of the reason why there was a push to then pursue it more and just depression in general as opposed to just depression that shows up, you know, related to this very, you know, unique type of medical condition, but just to see whether it can be helpful in general with depression and anxiety.

Nick Jikomes 1:04:49

Is there anything that you want to reiterate for people about what we discussed today or any final thoughts you have about psilocybin assisted therapy or psychedelics as assisted therapy in general?

Alan Davis 1:04:59

You You know, I just I like to say to people right now that there's a lot of momentum building in this space, there's a lot of really exciting studies that are being published, you know, seems like every day lately about the potential benefits here, it's important for you to remember that all of these studies are using psychedelics in the context of, you know, highly selectively chosen people in they're all getting extensive psychotherapy and preparation and integration. And so, you know, while we're still in this place of having to wait for FDA approval, and having this treatment available, you know, in someplace local to you, there's still a lot of interest, and people are really wanting to get access to this as soon as possible. And unfortunately, that's led to, you know, unscrupulous and unethical providers out there who are, you know, willing to give people drugs without any other type of support and preparation and screening and oversight. And so people are being harmed by that, in, in part, because of all the demand that's being generated from this work. So I would just encourage people to, you know, take take some time to let this play out, let let let, let's get through FDA approval, let's get kind of closer to this being available for people. Or if people are going to, you know, pursue it because they don't want to wait or things are too difficult to wait longer than please, please, please make sure that you're working with trusted folks that you're working with people who are engaging, who have protocols in place to screen you to to make sure that you're a good fit, that have protocols in place to provide preparation and integration support. And you still look the good places out there that are doing this. Now, before it's legal in the US. They're still implementing a lot of the same things that you see or hear about in the trials. They're implementing preparation, even if even if it's only a couple of hours, they're still meeting with people ahead of time to ask them questions to make sure they're still a good fit. Like all of those things are just really good elements of harm reduction and benefit enhancement. So I just encourage people to to still seek out if they are going to still seek out those elements and make sure that they're they're working with trusted folks.

Nick Jikomes 1:07:09

All right. Well, Dr. Ellen Davis, thank you for joining me today.

Alan Davis 1:07:13

Thanks so much.


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