Rhonda: Hello, folks. Today's podcast guest is Dr. Roland Griffiths who is a clinical pharmacologist at Johns Hopkins University. Roland has authored over 300 publications on mind-altering substances ranging from caffeine to ketamine and their effects on behavior and brain function, as well as other things. But even more recently, Roland and his colleagues published a very interesting study that's made a big splash on the effects of psilocybin on depressive symptoms and anxiety in patients with late-stage cancer, which I know is very interesting to a lot of you folks, and this may be outside my usual wheelhouse, but I'm very excited to talk to Roland today.

So, Roland, thank you for allowing me to come to your lab in your office. Maybe we can start by talking about this new study that I just got done reading about the effects of psilocybin on depression and anxiety in patients that were diagnosed with terminal cancer.

Roland: Yeah. Well, if you don't mind, let me backup where I got involved with this research...

Rhonda: That'll be great.

Roland: ...and then we'll move up to the cancer. So, about 20 years ago...let's see. I am a psychopharmacologist in the departments of psychiatry and neuroscience at Johns Hopkins. I've been doing research with mood-altering drugs for over 40 years. About 20 years ago, I took up a meditation practice and that got me very interested in altered states of consciousness, spiritual experience, the whole idea of personal transformation. And in the course of that, became reacquainted with this older research with classic psychedelics. These are serotonergically-mediated classic hallucinogens, LSD, psilocybin in the magic mushroom, DMT, mescaline.

And we initiated a study then which was published about a decade ago in healthy volunteers receiving psilocybin. The very interesting effect from that study was that psilocybin under conditions in which people are very carefully selected, they're supported, they're prepared, has effects that are deeply and profoundly personally and spiritually meaningful to people. So there's a phenomenology that occurs in these experiences. And what's interesting with respect to other mood-altering drugs is these experiences are deeply valued well after the experience has finished. So, months later, people continue to reflect back on that experience and opine that it's among the most personally meaningful and spiritually significant of their lives. I mean, in the top five if not the single most, comparing these experiences to that of birth of a firstborn child or death of a parent. So these are profound experiences.

And having worked with many different psychoactive substances because my research program has been funded primarily by National Institute on Drug Abuse, so I'm accustomed to giving high doses of mood-altering compounds. In contrast to most drugs that you give, these effects are much more salient and people ascribe long-term changes in attitudes, moods, and behavior to them. So, if you give a high dose of morphine, or cocaine, or a sedative-hypnotic, or any number of other drugs, people will remember it after it's done. They may reflect back and have pleasant memories or unpleasant memories of it, but it's something that happened long ago.

In contrast, these drugs have this kind of peculiar attribute that people feel as though they have learned something very important to them personally, and that it has information value for them moving forward in their lives. And so that became absolutely fascinating to us and provided kind of a focus of our studies now, over at least one area of study, over the last decade. So what is the quality of that experience that people have? Well, one thing I should say is that this is one of the rooms in which these studies are conducted, and that the way the sessions are run is that volunteers come in and they spend at least eight hours of preparation with us in which we develop rapport and trust with them so that they can feel safe during a high dose experience with psilocybin.

On the session day, they take a capsule. This is synthesized psilocybin, it's not mushrooms. And they're invited to lay down on this couch with eye shades and headphones through which they listen to a program of music. And then they're invited to direct their attention inward on their inner experience. So this isn't a guided session. There are two people present here who just provide reassurance if it's needed, but really are there just for safety purposes and to make people feel that if anxiety or fear arises, that they can just be reassured that despite what they may be feeling, they're 3going to be back to consensual reality by the end of the day.

So this is the context, and it's very hard to pin down the specific nature of the experience because it can be really quite varied. There can be autobiographical features of the experience where people remember issues from childhood or they reflect on relationships in their own lives. There can be aesthetic experiences where people get involved with imagery or color or geometric shapes, but there is a component to this experience that interestingly enough maps on to classically occurring mystical-type experiences that have been reported by mystics and religious figures over the eons.

And as unlikely as it sounds, we actually have good psychometric measures of those experiences, and they've been really well described, and in the core features of those experiences are the following. The central feature is this sense of the interconnectedness of all people and things, it's a sense of unity. And that's accompanied by a sense of sacredness or reverence for that experience. There's something humbling about that experience. And also very important, the experience has authenticity to it, a truth value to it that people will often say it's more real and more true than every day waking consciousness.

In addition, there's a sense of positive moods, sometimes hard opening or love, transcendence of time and space, the past and the future collapse into the present moment, and the experiences are said to be ineffable. People, among the first things they say on coming out of an experience like this is, "I can't possibly put this experience into words." But the feature of that sense of unity, the interconnectedness of all things, and the truth value of that experience, I think, are the features that underscore this reorganizational component for many people. And so, it's not unusual for people to say months or even years after the experience that they think of this experience almost every day if not every day. It's reorganizational to how they hold themselves and other people in the world. There is a existential component to this that gets people looking at the mystery of consciousness for lack of a better description. What's really going on here that we're conscious beings, we're aware? That we're aware?

There's a huge mystery behind that that is so inexplicable at many different levels and so profoundly moving, and it's an experience for which most people feel deep gratitude when we allow ourselves to reflect on that because we're human after all. We get caught up in our life stories. So, we have pursued that line of research. We've done several different studies in healthy volunteers. We've looked at dose effects. We've had controls for expectancy. We're absolutely convinced it's a very robust and replicable effect. And so, that's opened up a fantastic number of really interesting research questions. We can do reductionistic neuroscience. Whether we're doing brain imaging work, we can ask questions about pharmacology, we can ask questions about biological and genetic dispositions or behavioral interactions or set and setting conditions that modulate those experiences. And to bring this to your question, we can look at therapeutic effects.

And so, one of the first studies that we've conducted looking at therapeutic effects is to look at cancer patients who are experiencing very significant anxiety or fear in face of a life-threatening cancer diagnosis. And it turns out that this kind of very disquieting existential anxiety and sometimes depression very often accompanies these life-threatening cancer diagnoses as you might expect that it would. And our treatment options are quite limited, so we do have our classic antidepressants and our anxiolytics. And there are different kinds of psychotherapy approaches, but for many people, these interventions are not very effective and they can really experience a very degraded quality of life and a sense of hopelessness and depression that really diminishes their whole experience in the latter parts of their lives.

So, it was this population that we were interested in treating with psilocybin to see whether there would be therapeutic effects. One of the reasons we chose that population is that there were studies back in the 50s and 60s that produced suggestive evidence that compounds from this category of the classic hallucinogens like LSD and some other psilocybin analogs might be effective in this regard, but these trials were not conducted under the rigorous clinical standards that would be expected today. And just a footnote, of course, work with these classic hallucinogens really came to a standstill in the late 60s with the psychedelic movement and the cultural reactivity we had to that which placed these drugs into schedule one. They became very difficult to obtain. There was no funding that was available, and the media surrounding the surge in use of these compounds back in the 60s led people to conclude incorrectly as it turns out that the risks of exposure to these compounds were greater than any possible benefits. But functionally, what happened was there was a period of several decades where no clinical research was done with these compounds.

So, people had made observations previously that there might be a signal here. There had been one pilot study published a couple years ago with a low dose of psilocybin out of UCLA. And then we undertook our study at Johns Hopkins. A group at NYU ran a somewhat smaller study and we co-published just this last week, in fact, our results. And the results really were quite striking. They confirmed everything we had seen in the healthy volunteers that is these very vulnerable cancer patients who had very significant anxiety or depression experience the same types of...experience is very often classified as this mystical-type experiences, but they were deeply moved by these experiences.

And interestingly, these people experience very large and sustained decreases in anxiety and depression, and the effects occurred really quite promptly after the administration of the drug. And although the design of the study was such, it was a crossover design so people were crossed over between essentially an inactive dose of psilocybin to an active dose or vice-versa. So the strongest conclusion we can make comparing our placebo condition and our active condition is this effect lasted out to five weeks, but in fact, we followed people out to six months and there was no evidence that there was any significant rate of relapse over that period of time.

So, in other words, most people who demonstrated a large therapeutic effect remained having low levels of anxiety or depression out to six months. So there's suggestive evidence that there's a long duration of that...

Rhonda: After one treatment.

Roland: ...after one treatment, yeah.

Rhonda: That's pretty amazing. I have so many questions to ask you, but just something that I'm very interested in is depression and the effects of the immune system on depression, inflammation on depression, and vice versa, depression also affects the immune system. And knowing what we know about how the immune system is also important for cancer, I'm just kind of curious if any of these patients, if there's any information on their actual cancer prognosis, whether or not, I mean, indirectly or directly, psilocybin may be affecting the immune system via making...I mean, if you're feeling better, if you're not as anxious, then surely, your immune system is going to be...stress depresses the immune system, anxiety depresses the immune system.

So it would be very interesting to see whether or not there's actually a direct or an indirect effect on the immune system, and possibly on their cancer progression.

Roland: I mean, it's a very interesting and important question. We did not collect data that specifically addressed it, and we were very reluctant to imply in any sense to these individuals that this was a cure for their cancer because we don't know the answer to that and we thought that that would be misleading if that were implied within the trial. But you're absolutely right. There are fascinating interactions between depression and immune function. And so that is a story that remains to be determined.

However, we had a number of volunteers whose disease progression continued, and certainly, this is not a cure for cancer. Whether some people had significant benefits or not, we just can't say. But to get back to the whole question about psilocybin and depression, that's another area that we're interested in. A group from the UK published this summer uncontrolled pilot study in, I think, it was 15 volunteers with treatment-resistant depression in which they gave psilocybin. And they showed large effects and sustained effects out to at least a couple of months. And so we actually now have a proposal in front of the FDA as we speak and are going to launch a trial next year to look at treatment resistant depression as a target.

And so in addition to this depression anxiety syndrome associated with life-threatening illness, we think that that's a interesting target and it remains to be seen what happens.

Rhonda: Yeah, that's fantastic. Really fantastic. I may have come across, I think I may have seen that study in the media or something like that because it sounds very familiar. And as you mentioned, psilocybin is a serotonergic agonist. So it activates, as far as I know, the 5-HT2A receptors and maybe others as well which obviously, serotonin is a pharmacological target of many different antidepressants. It seems to be very different because what you're talking about, from what I understand at least, is that you're talking about a single dose in some cases which that's not the case with anything that I've seen out there that's classically used to treat depression: SSRIs, etc. But it would be very interesting to see what, if any, long-term effects on the 5-HT2A receptors, and I know probably that maybe somewhere, someone's doing that research, but it seems to be hard to get funding. And whether or not that there's some sort of long-term effects on those receptors remediating this, or also something else, and you may have seen this work. Is there a group in France doing...maybe it's the UK.

Roland: No, in Switzerland, there's...

Rhonda: Switzerland. Okay. I think it was somewhere abroad, but it was in animals, it was in mice. And they showed that administering psilocybin, I don't remember the dose, increased neurogenesis in the dentate gyrus region of the brain, and also caused fear extinction. And this was really interesting because I had read another study that was not on psilocybin, but it was on how growing new brain cells on how neurogenesis was helping treat PTSD because of this like new mechanism that was coming out where when you grow a new neuron, when you grow new neurons, actually, you have to break a connection between an old neuron to form a new connection.

And so for some reason, there seem to be some sort of selective breaking of the traumatic type of connections. So that would be very interesting to see, if possibly, because neurogenesis is a long-term effect. If you're able to grow new brain cells, that could be a possible...I mean, I'm sure we could sit here and speculate a million different things, I like doing that kind of stuff, but at least, it's something that would be very interesting to see if the effects on neurogenesis may be somehow...

Roland: So there's some work going on right now, and I think it's unpublished from Barcelona, that is examining classic hallucinogens and neurogenesis. And I think we're going to hear shortly that there's a very interesting signal there. So that's a very interesting area to look at. In terms of mechanisms of action of these effects, psilocybin and the classic hallucinogens do bind serotonin 2A and 2C. The effects are bleed from antagonism studies to be mediated primarily through 2A, but it's very likely and I think our current hypotheses would suggest that the major effects that we see are downstream and probably are glutamate-mediated which links this whole thing about psilocybin and depression into this unfolding story about ketamine and depression. So ketamine...

Rhonda: You've done some research on that as well, right?

Roland: Well, we've done a little work with ketamine. We haven't looked at that with depression, but there may be a glutamate modulation of this system and ketamine, as I'm sure you know, has been shown to actually have very significant antidepressant effects and treatment-resistant depressed patients, at least a subtype of them. Those effects are immediate. They're pretty profound but they're very short-lived. And so it's become a real target of interest for the pharmaceutical industry to investigate this as a mechanism of antidepressant action. And it could be that we're going to have a convergence of some kind of mechanistic thing in common with the classic hallucinogens.

Rhonda: Do people experience mystical experiences on ketamine?

Roland: Well, that's a good and debated question. So interestingly, of course, ketamine is a dissociative anesthetic, but phenomenologically, it's sometimes considered to be a psychedelic. Its mechanism is entirely different. Its pharmacology is going to be different, but they do have these kind of common downstream effects on the glutamate system. And some people describe the experience of going under ketamine anesthesia to have some psychedelic-like qualities. Whether or not those subjective effects are necessary for the antidepressant effects is unclear.

And one of the puzzling things too about psilocybin and its effects is, of course, these are brain-mediated effects, and that's why, in some ways, as a neuroscientist, it's embarrassing to say that these effects appear highly correlated with and possibly mediated by this mystical type experience. I mean, it just sounds on the surface of it to be an anti-scientific statement. But if you think of it as just a correlation with the underlying neuroscience, it makes sense, but there's something...there's a lot that we don't know about the nature of those experiences. There's a little bit known about the immediate effects of psilocybin. Certainly, we know that psilocybin binds serotonin 2A. We know different areas of brains that are activated and deactivated. We know something about the default mode network.

Rhonda: I wanted to ask you about that. It's very interesting.

Roland: Yeah. And so work from the UK and additional work now is showing that at least acutely, psilocybin appears to decrease activity within the default mode network.

Rhonda: So from my understanding, because I don't know much about this and this is all from neuroimaging studies you're talking about which I'm sourced in. The default mode network, is that something that's active like when you're ruminating on something, like when you're thinking about something that you...? So rumination which is associated with depression, and ruminating on the future or the past or...

Roland: Exactly.

Rhonda: That's it, right?

Roland: Yeah, that's it. And so activity in the default mode network is actually increased in depression, and here, a couple of the hubs are prefrontal cortex and posterior cingulate. And the connectivity and activity in those regions are decreased. Now, the interesting thing about the default mode network is it is associated with rumination. It's sometimes thought to be responsible for what's called self-referential processing as...

Rhonda: What's that?

Roland: Ideas that relate to a sense of self, and that's kind of what rumination is. Woe is me...yeah. So that's increased in depression, and interestingly, activity in the default mode network is decreased in long-term meditators.

Rhonda: Oh, that's interesting.

Roland: Yes, yeah. And that fits, if you think about it, with this whole story about goals of meditation being to bring you into the present moment, to drop the ego, to surrender a sense of self, if you will. So the curious thing now is that psilocybin looks very much like meditation in that regard. So that decreases in the default mode network, and that kind of fits with this story we can tell in terms of the phenomenology that one thing that people are encouraged to do when they have this experience is surrender a sense of egoic holding. That is kind of get out of the way of the experience and just be present in the present moment, and that's the thing that I...one of the qualities of that experience where you get out of past and future and your present and you're present in a way that it untangles you from this hell sense of self and constraining.

But these, of course, are all kind of words we don't have their descriptive ways of putting a framework around psychological processes, but they fall short of kind of the empirical hard science that we would like to have. So it's kind of frustrating. We're dealing a lot in metaphor at this point in terms of descriptive framework for how these experiences might affect people.

Rhonda: Well, I mean, at least you know you've got a measurable effect. It's been repeated. You've done randomized controlled trials. You've measured the same effect. So you start there and then start to try to tease apart like the mechanisms and understand how this is happening which is always infinitely more difficult. But the meditation thing affecting...because the meditation thing affecting the default mode network, why it's also so interesting is also because the mystical experiences that people claim to experience also with some forms of meditation. And so, again, which links back to the psilocybin as well. Have there been neuroimaging studies?

So with the psilocybin, what I read with the default mode network from papers you sent me was that blood flow is reduced to that part of the brain and that's how it reduces activity. So with meditation, do you know if that's something similar where it's like you're reducing blood flow to that region of the brain?

Roland: Well, it's more than just blood flow. So connectivity among the hubs of...there's something very interesting going on with respect to brain activity above and beyond blood flow, but blood flow is often considered a marker for level of activity, but the connectivity is an important...and there're also different imaging methodologies that have been used including pretty sophisticated EEG approaches that all seem to hone in on a similar kind of conclusion. So it appears to be a fairly robust conclusion, but it's...and it has face validity. And so it's really attractive, but I guess the thing that I really want to underscore is how primitive our understanding is of the nature of conscious experience.

I know we have this thing called the hard problem of consciousness, and that's, why are we conscious? What is it and is it explicable? Is it reducible in the extreme? That hypothesis questions whether it's even reducible to neuro-physiological process. As a neuroscientist, we go in with the assumption that's got to be true because otherwise, we couldn't do our job when we come in in the morning, but that's an open question for some people. But the point is, in fact, that it's open, is that the complexity of consciousness is so daunting that we're nowhere near beginning to scratch the surface.

I mean, there are going to be emergent network properties. The complexities of this are just overwhelming. So I don't expect that we're going to have any answers soon to very colored and complex experiences such as the mystical experience that appears to be reorganizational at some level about the way people think and hold and perceive themselves in the world that has to have neural correlates, but where to look for those neural correlates is anyone's guess. So we're a long ways from explaining these phenomena, but I would say as a scientist, that makes this really, really interesting.

So, we have these phenomena of the biology of...or the replicability of these reorganizational experiences that we know occur in humans spontaneously or naturally, these mystical-type experiences. And sometimes they're called epiphanies. Very often in the religious literature, they're considered conversion experiences or openings, but since time immemorial, we have descriptions of people going through such experiences and radically changing how they hold themselves in the world, and some of their underlying beliefs about the world. Those are often linked with religious and theological systems, but they needn't be.

But we know that this is part of the human condition. It's occurred so erratically and so unpredictably that it hasn't been amenable to science up to now. And so here, we have a model if you will and that's the psilocybin given under these conditions in which we can quite reliably produce these effects in most people that we study. And so that opens up the prospect of doing prospective scientific investigation of these reorganizational experiences that we're gifted with through our evolutionary biology, the purpose of which we don't understand, and there's a huge...and it relates kind of to this core sense of existential awareness. I mean, it's part and parcel to the question about, what are we doing here? What's what happens when we die? What's the meaning of life? Those are the deepest questions that I know of, and now we have a model system that can at least produce some of that phenomenology and we can investigate it. And so, as a scientist, it's just really exciting.

Rhonda: Really exciting. When you keep saying these reorganizational experiences, in my limited neuroscience, what keeps coming to my mind is neuroplasticity and the ability to change the connections in your brain which happen...well, as we age, that becomes worse and worse, we're unable to do that, but is that something that's also affected by psilocybin? Do we know if that part of the neuroplasticity is all effective?

Roland: I mean, it has to be, right?

Rhonda: Yeah, it has to be.

Roland: By definition. So yeah, they're going to be complex neuroplastic changes and...

Rhonda: How do you measure that? Can you measure that in people? I know you can measure them in rats, probably, but...

Roland: I don't know. It's a question of where to look.

Rhonda: Where to look.

Roland: Where the locus of those changes are going to occur. And so if you go into the phenomenology of it, people describe this altered sense of self and this touchstone experience and they have now seen and experienced the interconnectedness of all things. And so they hold themselves differently in the world, and that affects their belief systems. And that's the way they describe it, but that's just their description. And so what we don't know is surely, there must be corresponding changes that are occurring and neuroplastic changes.

Rhonda: There has to be, yeah. And this has to also relate to some of your other research that you've done on like addiction, like smoking cessation, right?

Roland: Mm-hmm.

Rhonda: I mean, to be able to like change the way you see yourself and change your personality in a way, I guess, I don't know if that's even accurate, but it's not common. It's not something that commonly happens at least after, I don't know, adolescence or early 20s or something. I don't know what the actual age is, but...

Roland: Yeah. Well, that phenomena is showing us, after these mystical-type experiences, they are enduring changes in the personality dimension of openness. And so that's just reflecting some kind of dispositional characteristic that would correlate with people. If you ask them how they've been changed, they'd say, "I'm more open. I'm free." And so there is a change in what's considered core personality or these dispositional characteristics. And personality theorists would tell you that doesn't happen. Those personality characteristics are locked in kind of from mid-20s. And if anything, openness decreases then across the lifetime. And here you see an increase in openness. So something interesting is happening there.

And then in terms of kind of the radical reorganization that occurs, there are these other potential therapeutic applications, and so one of them is the addictions. And so we've done a pilot study in cigarette smokers, 15 smokers. We embedded the psilocybin manipulation in the context of a cognitive behavior therapy for smoking cessation. And remarkably, we had 80% abstinence rates at 6 months which in the smoking world is just completely unheard of.

Rhonda: Completely, yeah.

Roland: The varenicline which is probably our best treatment for smoking, 20% to 30%, now that's an...what we don't have is a controlled group for that trial so we're running a controlled trial now. We're doing neuroimaging pre and post. We're working with Elliot Stein at the National Institute on Drug Abuse who's done very sophisticated work at looking at brain centers responsible for addiction to and an abstinence from cigarette smoking. So we're kind of probing into that. But the point here is that these kinds of reorganizational experiences, it may be possible to embed them within different treatment contexts for different disorders like the psychosocial distress of cancer patients, and in this case, for addictions. There's work going on at NYU in alcoholism. There's some work going on at University of Alabama on cocaine dependence.

And so I think this is potentially promising, but we don't want to get ahead of the data. But my guess would be that there is something about the nature of these reorganizational experiences, the opportunity for plasticity and change that can be embedded within intention and context that could have a variety of positive therapeutic applications.

Rhonda: Right. And possibly even things like PTSD, OCD.

Roland: PTSD, OCD, eating disorders, other types of...

Rhonda: What about just...I mean, you're talking about in the context of someone who's diagnosed with terminally ill cancer and they're facing death soon. But we're all kind of facing death at some point, and there is a background underlying fear. I experience. I have a fear of death. I'm sure I'm not the only human being on this planet that experiences that. So it seems as though this...there may even be even broader potential therapeutic implications, but...

Roland: But certainly beyond cancer. I mean, the cancer patients, of course, are...I mean, it's clear and we can all empathize with someone who has a life-threatening cancer diagnosis and maybe reasonably young and is looking at the potential endgame of their life. And we can all empathize with that, but we're all terminal. We're all going to die of something. And so ultimately, this kind of intervention may be relevant for end-of-life care generally, and again, it's probing that existential dimension of meaning that is so potentially important.

But for our immediate therapeutic target, it's cancer and it's this depression and anxiety associated with cancer. Wherein the groups that I'm working with are in very early stages of communicating with FDA about undertaking a phase three clinical trial which would be the necessary next step, and if efficacy were demonstrated, then there's the potential for approvability of psilocybin as a medication.

Rhonda: Wow. That was going to be my next question.

Roland: And were to be approved, we would see it approved under very constrained conditions. Perhaps the drug would be held by a central pharmacy. It would be dispensed to clinics that offer this kind of therapy with clinicians who know how to deliver this therapy because it is this interaction of context and pharmacology. This is not just an effective of psilocybin. And in fact, there are risks associated with just taking psilocybin that we really shouldn't minimize. Those are some of the risks that resulted in the deep cultural misunderstanding of these compounds and ultimately the removal of them from clinical research for decades, but we just, actually very recently, completed and published a large survey study of people who...this was about 2000 people, and we asked them, have you ever had a bad trip after taking psilocybin mushrooms? And then we asked them to describe their very worst experience with psilocybin mushrooms.

So we don't have any denominator to know what the frequency of this sort of thing is, but the results of that are sobering. So if you ask these people what were the consequences of their worst experience, we have about 10% who say that they may have put themselves or others at risk of physical harm during the experience. And there's some percentage of people who say that they have enduring psychological problems for which they are seeking out psychological or psychiatric help with a year after the experience.

So it suggests that there can be immediate dangers and we know that, to exposure to psilocybin. People can put themselves at risk. And most often, that occurs in fear or anxiety responses, but under conditions where people take the compound and they don't know what they're doing, they don't know what dose they're getting, they're not supported, and then people can end up dying. And so there's that risk. And then there's the potential risk of vulnerable populations, people who may already have pre-existing vulnerabilities to psychotic disorder or to...they might have personality disorders or some other mood...pre-existing disposition toward mood disorders that may make them unusually sensitive to potential negative effects of psilocybin.

So we really need to footnote all this work and make sure that the take-home message is, "Great, everybody should take psilocybin mushrooms." No, there are going to be some people who are going to truly be hurt and we need to do everything we can to protect people, particularly young and vulnerable people.

Rhonda: Yeah. So it sounds like both the context of we're taking this drug and also potential genetic interactions, people that are predisposed to other brain dysfunctional disorders, those are the two major...what seems to be, at least what we know now, things that predispose people having a negative effect. When you're selecting your sample population, so how do...you said you spend eight hours with the person. Is that like part of the selection process or how do you figure out the...?

Roland: Well, let's see. So just in terms of screening people into our protocol, we do extensive medical screening and then history screening. And so people are screened out if they have any even second degree relative with history of psychotic disorder or bipolar disorder. So we're conservative in that regard, but we're concerned with that as a vulnerability. In terms of whether people had difficult experiences, we can't protect against that. So even under our conditions where many people have these greatly valued experiences of transcendence, some of those same people may have experiences that would...our classic bad trips that are experiences that are among the most challenging and difficult of their lives.

The difference in this context is that we can support people through those experiences, and sometimes, those experiences can be a very short duration. Sometimes they can open into experiences of great insight or transcendence. And for some people, the very fact that they've had components of that difficult experience makes their overall experience more meaningful, but we have about 30% of our volunteers who will describe, at least for some duration of time, experiences of significant fear or anxiety come up. So we have not learned how to eliminate those. We don't even know whether they should be eliminated because we don't understand the processes that are underlying the nature of these experiences that seem to be so important.

And furthermore, I can say that our ability to predict who is going to have a difficult experience or not is almost zero. I mean, so in spite of the fact we get to know these volunteers really well, and at this point, we have treated over 260 people with psilocybin, we have experience of over 570 sessions with psilocybin. So we have a lot of experience. But if we ask the clinicians that are closest to the volunteers to rate the probability of difficult experiences, their ability to predict that is almost none at all. So we don't really understand.

Rhonda: What about dose? Does dose play a role?

Roland: Dose plays an important role. We know these effects are dose-dependent.

Rhonda: All the effects including so like the mystical experiences?

Roland: Yeah. So we've gone up to...our highest dose is 30 milligrams per 70 kilograms which is a...

Rhonda: A bodyweight?

Roland: Yeah. High dose of psilocybin. And the phenomenology of the types of things that'll occur with psilocybin or as you might imagine, dose-related, we've gone down to doses of 5 milligrams and I suspect that there are threshold effects lower than that. And the probability of mystical-type experiences and challenging experiences also increase as a function of dose. What's kind of interesting is that the probability of the very difficult experiences increase pretty significantly between 20 and 30 milligrams per 70 kilogram. So if we dose people at about 20 milligrams for 70 kilogram, we're much less likely to have the very challenging experiences. And with the cancer study, for instance, the dose that we used most often in that was 22 milligrams per 70 kilogram. So we were holding it back from our full-on dose.

Rhonda: Yeah. I would imagine that having a really stressful experience like being diagnosed with cancer, but also the stress that you're experiencing, obviously, that's what you're partially trying to treat, but would also maybe shape the experience you're going to have in a way.

Roland: Well, that was one of our questions going into that study. In spite of the fact that there was previous data suggesting efficacy, I was concerned frankly that this is a vulnerable population. I mean, they're depressed. They're anxious. They're facing the big existential question. And I was concerned that perhaps some of these deep experiences of the existential emptiness and fullness might end up potentially traumatizing some at least subset of those people. Maybe they would come out worse for it, and I was concerned about that.

Happily, the answer is that we have no indication that happened. In the 51 volunteers we treated, and the 29 that were treated at NYU, we have no indication that people were harmed by these experiences, but that was a concern initially and it led us to want to give a somewhat lower dose, and that dose, as it turns out, worked just fine.

Rhonda: And for your placebo, you actually gave a really low dose.

Roland: We did. And one of the dilemmas in doing research with any psychoactive drug but in particular the hallucinogens is that these doses, of course, are discriminable. People, they produce marked changes in consciousness and conscious experience. And so then the question becomes, so how do you run a double-blind study under these conditions? And the issue that relates to that is that we know that these experiences can be driven or very much affected by expectation, but the set and the setting under which people take the drug.

So if they have strong expectations, that can also drive the experience. And so we've been very interested in trying to unpack to what extent these experiences are simply expectancy effects versus reflective of real pharmacology. And the answer to that is both. These kinds of effects are driven in part by expectancy, but expectancy does not account for the full effects, and we've run different controls in different studies. Our first study, we actually gave a pretty high dose of methylphenidate or Ritalin as a control substance, and these were people who had never had a hallucinogen before. And furthermore, they were told that they could get 11 different kinds of psychoactive compounds. So they didn't even know what signal that they were looking for or what constituted an experience of a classic psychedelic...

Rhonda: So you were trying to like eliminate the placebo response in a way?

Roland: Yes. What we were trying to do was throw in controls that would maximize expectancy and produce some confusion. And what happens under those conditions as well as conditions under which we run something like a low dose condition is some people will have full-on mystical experiences. So if you get the set and setting conditions right, and we should expect this. I mean, that's what happens in meditation. When you set your intentionality and you're told, "Go for it, this is going to be great." So you have people having transformative experiences. The percentage of people that have those experiences is tiny relative to when you give psilocybin.

We've actually had people in our long-term meditators study in which they're...now, these are people who are deeply familiar with different states of consciousness brought on by meditation. They know a lot about the workings of their mind, and we think they're actually unique in being able to navigate these experiences because they have spent so much time examining the nature of mind. But in that study, we have a real placebo versus active psilocybin dose. And we've had a couple volunteers who have come out of that experience, of course, they're meditating during this experience, have come out absolutely convinced that they got psilocybin, and so convinced that they convinced us that they must have been. Of course, were blinded, that they must have gotten psilocybin because they had these experiences unlike anything they had ever had.

And then it was not until two months later when we break the blind and we say, "You know what? You didn't get psilocybin. You need to come back in because this is a study that if they didn't get it, they come back in." So the power of suggestion is really large, really salient, but it does not account for the extent of the changes that occur with psilocybin. And for those people who thought they had gotten psilocybin previously, when they finally did get psilocybin and then they're asked, "Okay, was that like the other one?" And they go, "Well, no. No, that was something else. This is..." But we lack the vocabulary to even describe what the nature of these changes are.

Rhonda: So what were you looking at in that study? What was...?

Roland: Well, the study in long-term meditators is something that's...it's near and dear to my heart because I'm a long-term meditator now.

Rhonda: Define a long-term meditator.

Roland: Well, these are people by and large that have a daily meditation practice for, very often, decades, and have done a number of prolonged silent meditation retreats. So these are people who have spend a lot of time...

Rhonda: Vipassana or something, that it's called? Something like that?

Roland: Exactly. A lot of it is mindfulness. We have overrepresentation from Buddhist traditions and vipassana could be one of those traditions. And so during that study, people come into our session room. We have them do series of meditations throughout the day. And when they get psilocybin, so we're very interested in how the phenomenology of those experiences change. We're comparing it to placebo. We're looking at pre and post neuroimaging to see...looking for brain changes, and preliminarily, we're seeing day-after changes which is exciting and gets to this whole issue of neuroplasticity. And we also have a condition in which we actually administer psilocybin to people in the scanner. So we're looking at meditation when people are on, in this case, a pretty low dose of psilocybin.

And our interest there in meditation is that we think of meditation as kind of the tried-and-true path for exploration of the nature of mind. I mean, that's really what it is, is that this is methodology that's been developed over thousands of years to turn the attention inward and watch one's own mental processes and become familiar with the way mind works, how it's constructed, and then through that process, very often, people...I hesitate to say gain control, but in effect, they can change the repertoire with which the brain is activated. They can watch thoughts come up. They can release thoughts in a way that someone who's unpracticed with meditation is much less likely to be able to do so.

So it's an investigation of the nature of mine. And similarly, I've come to think of psilocybin as also a convergent methodology for investigation of the nature of mind. It's the meditation on steroids, if you will because there's such abrupt shift of the nature of consciousness that it wakes people up to the extent to which kind of their normative cognitive processes or the normative way they hold reality is just one way of holding reality. And so there can be something shockingly interesting about that.

However, psilocybin is not a substitution for meditation because it doesn't lead to any stability of the awareness state. So we would say that meditation is kind of the tried-and-true way of stabilizing the nature of awareness and coming to understand mind, and psilocybin might be the crash course in that.

Rhonda: And you say you practice meditation. Is that something that you do every day?

Roland: I do.

Rhonda: You do? How long do you meditate?

Roland: I'd rather not get into the details around meditation practice, but yeah, I've been doing it for almost 20 years.

Rhonda: Wow. I'd read a study showing that there were gene expression changes that occurred after like the first five minutes of meditation. There was like 500 different genes were changing their gene expression, which to me is very phenomenal that you can actually just...just by actually stopping the rumination and sitting there and whatever it is that you're thinking in the present moment or there's lots of different types of meditation, but that you can actually just change the way so many different genes are working, many of those in the brain, of course.

Roland: Yeah, and there're long-term consequences to meditation. And there's work suggesting effects on telomeres.

Rhonda: Yes, I was forgetting. Elizabeth Blackburn show that annotation and Elissa Epel, I think, that meditators had longer telomeres than age-matched control. Which makes sense because stress does the opposite. Stress accelerates telomere shortening. I mean, that's all not such a surprise, but just one other thing I wanted to talk to you about was I know you've done a little bit of work on Salvinorin A, and it's not something I'm so familiar with so much as the kappa-opioid pathway. A good friend of mine, Sheba Meucci [SP], had told me a little bit about the Salvinorin A pathway. He was doing some literature reading on it some years ago for whatever reason, and so how it came into my awareness. And he was telling me about how agonism of the kappa-opioid receptor had a feedback loop effect where it actually caused mu-opioid receptors which bind to beta-endorphins to become more sensitized to the endorphins.

And so I read up on this, checked the literature and references, and found that indeed the agonism of it does actually cause mu-opioid receptors to become sensitized to endorphins and I thought that was very interesting. Around the same time, I started getting into using the sauna, so heat stress. And I started to notice...so when I was in graduate school, I was very stressed out, lots of pressure, failed experiments, and exams. And so I started using the sauna a lot before I'd go into the lab and I noticed that there was a very profound effect on my brain because I started to be able to handle stress better. My anxiety was lower. I felt good, and these were lasting effects. I felt good days later.

And so I started reading about what's going on here. I started reading about heat stress, and I came across the dynorphin pathway which is an endogenous opioid that we make in our brains, sort of the counter to endorphin because it sort of makes you feel dysphoric rather than euphoric. And then I started reading about how dynorphin actually is a part of the...both endorphin and dynorphin are part of the thermoregulatory pathway. So dynorphin actually cools the body down. And when your body heats up, you increase dynorphin to cool it down. It's sort of a response mechanism.

So when you're sitting in a hot sauna or when you're working out really vigorously and you feel that sort of uncomfortable heat where you're like, "Oh, I want to stop. I feel..." I think that's probably dynorphin. So dynorphin binds to the kappa-opioid receptor which then sensitizes the mu-opioid receptors. So now, I was thinking, well, maybe some of these lasting effects from the sauna were mediated through that. Of course, that's all anecdotal. I mean, I know some of the biochemistry is out there, but I don't know if that's necessarily been shown, but that's how I became really interested in that pathway, my sort of personal story.

And then I started reading somewhere, someone sent me some article about people that were addicted to...I think it was opioid, prescription opioid. They were being treated by giving them the sauna as a detox, "detox," which I don't know if that's actually legitimate. But I started thinking about possible, maybe there's some truth to it by resetting the mu-opioid receptor pathway or something. So I just thought that was something very interesting that maybe I could send you some of the studies if you're interested in seeing some of those.

Roland: Yeah, yeah. I'd be interested in that. We got interested in the Salvinorin just as a model system because it does produce dissociative and it's roughly classified as short-acting hallucinogen. Excuse me. So is roughly classified as a short-acting hallucinogen, but its phenomenology is very different than the classic hallucinogens.

Rhonda: Do people get a mystical experience from that?

Roland: People generally do not get a mystical experience. They do have a profound experience of being in some kind of altered reality, sometimes with other entities present. Generally, people don't particularly enjoy the experience which would be consistent with dynorphin. It's a unique perturbation of consciousness, but it doesn't look like it has the kind of reorganizational meaning that appears to come out of the classic hallucinogens.

Rhonda: Have you ever looked at any long-term effects like...?

Roland: We have.

Rhonda: Let's just say hypothetically, if it was somehow sensitizing the mu-opioid receptor, then possibly, days or weeks later, I don't know how long those effects last, but if they maybe felt better. The next time they released beta-endorphin from hugging their loved one or whatever it is that causes a person to release endorphin, maybe they feel a little better from it than they would have.

Roland: Yeah. We haven't looked at that. The effects of Salvinorin, this was inhaled Salvinorin, are very short-lived.

Rhonda: How short?

Roland: Less than 10 minutes.

Rhonda: Oh wow.

Roland: So it's a very rapid onset and people are completely back to baseline within 20 minutes, but most of the effects have resolved much quicker than that.

Rhonda: That's kind of like the dimethyltryptamine, right?

Roland: Yes.

Rhonda: But that's a serotonergic agonist.

Roland: So dimethyltryptamine, DMT, is a very short-acting classic hallucinogen of the serotonin type, and its phenomenology is distinct from Salvinorin.

Rhonda: Is its phenomenology similar to psilocybin, though?

Roland: Well, that gets complex because it's so short-acting that it's hard to compare. And DMT is also the active ingredient in Ayahuasca which is the brew that's consumed mostly in South America, and by some of these syncretic religions. And that's when the DMT is combined with an MAO inhibitor that slows down the metabolism in gut. And so it changes the duration of action and makes it more like psilocybin, and under those cases, those effects certainly looked more like psilocybin than just smoked DMT.

But direct comparative pharmacology studies haven't been done with any of these compounds. So we have yet to tease apart the real differences and similarities.

Rhonda: And there's a lot of the indigenous populations that use some of these hallucinogens like psilocybin, I think, too, because...

Roland: Oh sure. So psilocybin has been used for hundreds of years in Mexico, and Ayahuasca DMT in the form of snuffs or as this brew have been used for as far back as documentation allows in South America. Of course, we have peyote which is mescaline which is another serotonergic 2A agonist used by the American-Indian. There's evidence of probably almost 200 species of psilocybin mushrooms and those are used...have been used around the world. So there's plenty of indigenous use of these compounds.

Interestingly, for the most part, if a culture has historical use of these compounds, it's done in a highly controlled cultural context, in general, for religious or healing purposes or for divination, but they're not used casually.

Rhonda: Okay. So I guess people are obviously using it for other cultural reasons and have been doing so for quite a long time.

Roland: Yes. And it's very, very likely that the use has been enculturated in a context in which the meaningfulness of the emergent experiences has been thought to be a value to that culture.

Rhonda: It makes sense if you're having a mystical experience that's often, and hand in hand, goes with some sort of religious. Sometimes, a lot of people in religions have mystical experiences when they're...for whatever reason, they talk to some higher power that they believe in or something. So kind of all makes sense, but this has all been super fascinating, Roland. Really, thanks a lot for talking with me and I learned a lot today. I know that you don't really have a website or anything, and if people want to find more about you, they can just google Roland Griffiths and they can find your TEDMED talk, your TEDx talk, and you do have websites out there, and I'm sure there's lots of other articles that have been written on you and interviews that they can find.

Roland: They can track me down.

Rhonda: Yeah, exactly. So I think...

Roland: Okay, pleasure talking to you.