Peter Weir: Hello everyone. This is Peter Weir, and I'm with Ben Lewis, and this is Communivation. Today's topic is the use of psychedelics in mental health. Welcome, Ben.

Benjamin Lewis: Great to be here, Peter. Thanks for having me.

How did you become interested in this topic?

BL: I'm an Assistant Professor of Adult Psychiatry at the Huntsman Mental Health Institute, and I've been there for nearly 10 years now as a faculty member. Most of my clinical work is really doing adult inpatient psychiatric care, so kind of a broad range of mental health conditions. Part of my job involves working with medical students and psychiatry residents with a sort of a training component of it. I think as it's probably common for most people working in mental health and working in psychiatry, it's hard to not feel impressed by the limits of the current tools that we have and just huge amount of human suffering that we see that we certainly do our best with, but nonetheless have very clear limits. And there is a toll to that that accrues, I think, over time, or has accrued for me. And I think that's one significant motivation for me in terms of being interested and invested in an emerging field that holds a lot of promise, for psychiatry.

BL: I think there's just a lot of other interesting theoretical and conceptual and philosophical issues related to this emerging science too that I find just fascinating and fun to think about and hopefully we will talk a little bit about here. That's a sort of a broad overview.

PW: I think one of the things that really piqued my interest as a primary care physician and taking care of a lot of people with mental health issues is the lack of options for patients. And it's not unusual to have a patient, let's say that has depression, that has tried, let's say several SSRIs and some of the other options that are out there, and has problems or side effects or just doesn't quite get a lot of effectiveness with the medicines, and it sort of feels like the tools run out rather quickly. And so, the idea and the possibility that there could be something else out there is intriguing.

BL: Exactly, say for instance depression, up to 30% of people don't really respond to currently available treatments and have treatment resistance. There has not been a lot of innovation and drug development in the last several decades. I think a lot of possibility for new and emerging treatments, and this is a set of treatments that had significant precedent in the past in terms of psychiatric care, and I think we'll get into that a little bit, but certainly a long quiescent period where this was really off the table as a set of treatment options and really over the last five to 10 years re-emerging with some exciting new studies and some new indications. It’s a really interesting time to be part of the field.

Episode disclaimer

BL: In talking about psychedelics and psychedelic medicines, it's important to identify what we're talking about and what we're not talking about. And as I understand our conversation today, it's really focused on medical and psychiatric indications and using these compounds and medicines within a controlled clinical setting. So that reduces certain inherent risks with these medications and chemicals. And I think it's important to talk through what are the current risks, right? What are those risks and what do they look like, and how to mitigate those risks? I think for our focus today, talking about emerging research and maybe some of the future directions for how this might be therapeutically useful in terms of treating certain mental health conditions.

PW: Okay, perfect, and I'll even be more blunt. What we're not doing is telling you to go out and recreationally take psychedelics with your buddies when you are looking for a fun time. That's not the purpose of this podcast. This is focused on the use of psychedelics in mental health. And we're doing an exploration of the data that's out there, and also, Ben's expertise on the topic.

BL: That's right, thanks.

What's a psychedelic and what's not a psychedelic?

BL: That's a great question. And that term, psychedelic, I believe was coined by Humphry Osmond back in the mid-1950s, and that was during the correspondence with Aldous Huxley. Psychedelic means, really, the literal translation is mind manifesting. So, kind of identifying the phenomenon that these compounds reveal certain elements to cognition and emotional processing and conscious experience that might not otherwise be present in the sort of normal waking life. The term is very general, psychedelic, and that gets used widely. When we think about that in terms of our focus on psychedelic-assisted therapies and sort of emerging clinical science, generally, that's referring to just a class of what are called classic psychedelics.

BL: These are typically seen to be psilocybin or the active ingredient in magic mushrooms, LSD, the synthesized psychedelic initially formulated by Albert Hoffman, mescaline and DMT or dimethyltryptamine. Those are what we refer to as classic psychedelics. You've also probably heard terms like hallucinogen, which is used in medical literature. In the past, back in the 1950s and 1960s, when these compounds were first being studied, the term psychotomimetic was in play. So really getting at the idea that these seem to at some level mimic or reproduce symptoms, characteristics of psychosis, which is not entirely accurate, but those are also terms that you probably see. I think there are certain reasons why the term hallucinogen is probably not ideal in that... Well, it's certainly possible within certain dose ranges, people have a range of perceptual disturbances, they're not typically compounds that produce frank hallucinations.

BL: Psychedelic is a term probably most used now and commonly used within medical literature. You know, another word that comes up with this class of compounds is entheogen, which really is a term that translates to manifesting the divine within. So, getting at the idea that this group of compounds, both used historically through many thousands of years in certain cases, can reproduce experiences that we typically think of as spiritual in nature. So that term entheogen kind of refers to that aspect of these compounds.

And what often gets confused as a psychedelic?

BL: I think that that term is used pretty broadly currently. For instance, the term psychedelic-assisted psychotherapy is used for ketamine-assisted therapy as well, and that's a whole other topic. And ketamine certainly has certain qualities that are very similar, very psychedelic in nature. The term psychedelic gets applied to MDMA-assisted psychotherapy as well. It gets applied in certain context to cannabis. So, I don't necessarily see those being applied in error, I think it's probably more a function of that term being general, but you know all these compounds occur on a continuum of risk, right? Which represents different pharmacology. I think it is important to define terms, and when you're talking about psychedelics, talk specifically, is this grouping into the classic psychedelics or are we talking more broadly? There's a whole range of compounds, Salvia divinorum, which is a very distinct chemical and distinct mechanism of action and categorized as a psychedelic, but very different than, say, the Serotonergic psychedelics, which we'll be talking about today.

PW: That's going to be our focus, is those serotonergic psychedelics, specifically, and what we're really going to be focusing on is psilocybin, which we're going to talk about in a sec and LSD, and are there any others that you'd mention?

BL: Yeah, so the classic psychedelics are psilocybin, LSD, DMT, and mescaline.

The historical evolution of psychedelics

PW: I was a kid of the 1970s and '80s, and growing up, it was just made abundantly clear to me that if you take a psychedelic like LSD, that you will go psychotic, and you'll go to the top of a building and jump off saying that you can fly. And it really instilled fear, I think I wasn't the only person in the country that saw these compounds, these molecules as a scary thing. I'm sure nearly every listener would recall that these drugs, medicines, however we want to refer to them were used commonly in the 1960s, and then there was this big stigma against them that has lasted for decades, so do you want to just talk about that, that sort of historical evolution that psychedelics have taken?

BL: I think that's a really interesting history, just the history of these compounds in the United States. There are certainly risks, predominantly psychological risks to talk about as it relates to psychedelics. The physiologic or medical risks have certainly been over-played in the media and came directly out of the 1960s, and how this emerging field kind of interfaced with the counter-cultural movements we're seeing at that point in time and the Vietnam War and the Nixon administration, and the whole sense that there was this cultural backlash against a lot of US military presence. I think there were a lot of factors in that reaction, right? But the net effect was that these compounds had been showing very significant promise within hundreds of studies in psychiatry at that point in time, keeping in mind that standards of current research were very different at that point, right? And so, sometimes hard to interpret, but nonetheless, hundreds of very promising studies, all of that was really shut down in, I believe it was 1967, that these were put on Schedule 1 during the Nixon administration.

BL: I think there's also an interesting story from that period as to the Harvard psychedelic group with Timothy Leary and Richard Alpert, or then Ram Dass, and I think that that became pretty loose at the seams as far as how that research was conducted, and I think that that didn't help the cause certainly. And you know, resulted in those two losing their academic positions, but also, I don't think was a great face on this research, but basically from the late '60s on, this was completely quiescent, and I think a lot of the narratives around psychedelics had over-represented and over-dramatized risks involved.

BL: It has only been more recently, and I think we can probably think of that as sort of the mid '90s that people started investigating these compounds again, and very tentatively, the set of studies around that time was done by Rick Strauss from the University of New Mexico and really just involved giving DMT intravenously to normal controls, just normal people and monitoring physiologic variables, monitoring heart rate and blood pressure and seeing, can we give this safely, what are the adverse effects, what are the medical risks? From that point on, we've seen kind of a real expansion of interest in research and have entered what people are now describing as the renaissance of psychedelic medicine. From small academic medical centers like Johns Hopkins and NYU and other very prestigious places.

Are there any risks of psychedelics?

PW: You said something really interesting, and I wonder if it caught listeners' ears, from a physiologic risk standpoint, what are the risks of psychedelics or are there any?

BL: I think really important there to define terms, cause I think the risks are heterogeneous, depending on what you're identifying, and they occur on a continuum. So, when we're talking about Serotonergic psychedelics like psilocybin or the active ingredient and magic mushrooms or DMT or LSD, that is distinct from, say, what we would talk about with MDMA or even something like Ibogaine, which is derived from the Iboga tree in Western Africa. And distinct as well from something like ketamine. And thinking about the Serotonergic or classic psychedelics like psilocybin or LSD, those physiologic risks are very minimal. So, there can certainly be short-term changes in variables like heart rate and blood pressure.

BL: There are good reasons to exclude people with cardiac conditions from these studies or people who would be at risk from having elevations in their blood pressure. There are transient effects, like people can develop nausea and headache, tremulousness or tremors. There have been no recorded overdose deaths related to classic psychedelics. You know, interestingly there have been case reports of people having extravagant overdoses inadvertently on LSD, right?

PW: Right.

BL: Mistaking this for some other substance and taking doses thousands of times above what a normal so-called recreational dose would be, and doesn't necessarily seem like a great idea, but there were no long-term medical effects from those.

PW: That came out of the other end. Right.

BL: And again, it's important to, at the same token, recognize risks that are potentially more psychological in nature, and I think we'll get into that too.

What do we think psychedelics actually do and how do they help a broad array of mental health problems?

PW: The so-called "bad trip" — we'll get into in a bit. But what I'd like to do is, get into the evidence and the studies about psychedelics, the promise, but before we do that, I'd like to just dive into a short conversation about, what do we think psychedelics actually do? What is the mechanism of the action on the brain, and why would it help a broad array of mental health problems like depression and anxiety and post-traumatic stress disorder and anxiety related to end of life, how does all this work? How do you tie all that together?

BL: That's a great question, and in many ways kind of the million dollar question, and I think kind of a question that's really in the process of being investigated and answered. I don't think we're there as far as a full answer to that question, but let me take a stab and maybe let me start with, what do psychedelics do, from a standpoint of alterations and subjective experience, or conscious experience, and then look at maybe what's happening in the brain and why those might be related and why they might be therapeutic for certain types of conditions? Contained in your question is also that, yes, important observation that it's interesting that there are a range of sort of disparate indications, right? It's interesting that this might be useful for, say, tobacco use disorder, and major depressive disorder and OCD or eating disorders, right? And what's going on with that? I think that's an important question.

BL: As far as what are psychedelics doing, phenomenologically or as far as the types of experiences people have, I think that certainly there can be a range of very significant global changes in conscious experience. The way people perceive their body in relation to the external world, the way that people are perceiving time and the way they're moving through time. People's emotional experiences can be very altered and changed and intensified. People's cognitions are dramatically changed and perhaps having very unusual or out-of-the box or uncharacteristic types of thoughts and sensations and maybe changes in the way those can bleed together and what we think of as synesthesia. There are significant changes in mood that occur with these compounds. Interestingly people will reliably certainly within specific dose ranges, describe experiences that are maybe better or better thought of as visionary in nature or spiritual type experiences.

BL: One really interesting thing about these compounds is their ability to reliably occasion these mystical experiences where people maybe feel at one with their surroundings or that the boundaries between themselves and the world have dissolved in some fashion, or that they have kind of lost a sense of self that's distinct from the rest of the world. There can be this feeling of overwhelming connectedness that is maybe hard to capture in language after the fact. And there's a sense that something very profound and in many ways sacred about that experience that people will reliably describe after using these compounds. And I think that there are just many questions about that, but I think one thing that's important about focusing on that initially is that it's very interesting with these studies so far that at some level, the intensity of those so-called mystical experiences does seem to track the degree of therapeutic change.

BL: So those people, whether that study is looking at major depressive disorder or tobacco use or alcohol use disorder, one reliable measure of who gets well, what is the magnitude of their therapeutic change is really, did they have a full mystical experience? And people will reliably track back to aspects of the experience as kind of a fulcrum for their own personal change, so there is something about it that seems deeply meaningful, deeply significant. In fact, in one of the earlier studies out of Johns Hopkins, a vast majority of participants in the study rated the experience with psilocybin, and we can talk a little more about dosing, I suppose in a little bit, but rated that experience as the most significant and meaningful experience of their life. And of those that it wasn't the first, you know, the vast majority identified it is among the top five most meaningful experiences, which is just a very strange and interesting thing about ingesting a drug and a compound.

BL: I think that that's what people can see phenomenologically with psychedelics, and it does seem like there is a relationship between the experiential aspects of psychedelics and what ends up happening both neurobiologically and therapeutically down the road for them. I know I'm talking a lot about that one question here. Kind of the next phase of that question, what's happening in the brain basically with psychedelics and why would that be helpful? There are several lenses to look at that question with, right? The classic psychedelics that we're talking about here, psilocybin, LSD, similar compounds, they all act as agonists or they stimulate serotonin, a sub-class of serotonin receptors in the brain, namely the serotonin 2A receptors. And most people have heard of serotonin in the brain as a monoamine, a chemical in the brain that is important for a broad range of things, so implicated in cognition, certainly implicated in mood regulation, so kind of the basis of our standard antidepressant treatments which alter serotonergic functioning.

BL: Serotonin seems broadly related to emotional processing in the brain, and those receptors are widely distributed in the brain. Serotonin 2A receptors are more densely expressed within certain hubs in the brain that we see as potentially related to some of the explanations for what psychedelics might be doing and namely, hubs associated with the default mode network. I can talk a little bit more about that. Before I get to that, there are also lower-level explanations for what psychedelics might be doing in the brain that are more related to neuroplasticity or this notion of Synaptogenesis. So, your brain being this widely distributed network of neurons all talking and cross-talking to each other, and there are direct effects, acutely actually, but also measurable longitudinally or downstream from a single psychedelic administration on Synaptogenesis. So, basically the growth of new dendrites in the brain, so you can see that with other factors in the brain too like BDNF or Brain Derived Neurotrophic Factor.

BL: But it does seem like this class of compounds has direct effect at the level of just neuronal connections, and there might be something there related to why we see therapeutic effects. For instance, we see similar explanations used for effects of ketamine or even downstream effects of antidepressants in the hippocampus as far as neurogenesis and kind of growing a healthier brain in a sense.

Micro-dosing versus a full dose

PW: Yeah, that is fascinating, and I had no idea the depth of where people's understanding is with the psychedelics, so interesting information. So, one of the things that you said early on the phenomenological part of these molecules is that the degree of a mystical experience people have, it corresponds to the therapeutic impact the patient receives. And I want to just jump into something that I thought we might talk about later, but maybe now is a good time, which is this idea of micro-dosing versus like the full dose.

PW: It sounds like what you're saying is, and it might be hard for, especially for a patient that's peering over the abyss thinking like, I'm about to go on this trip. But it sounds to me what you're saying is the data would suggest that kind of going into that full-blown dose and getting a truly strong mystical experience is the most likely indicator of success versus all this discussion, which you hear a lot about, especially this one author that's really popularized James Fadiman, the idea of micro-dosing. Could you maybe go into a little bit of that?

BL: You know, in some of the background to that question, that is I think related to the concept of micro-dosing, is this historical distinction in the field between say, a psychedelic model of therapy versus what's called a psycholytic model, and this distinction went back even to the 1950s and 1960s, when people were really starting to look at this in a therapeutic sense. And yeah, absolutely, the psychedelic variant there is high dose, somebody has a full-on experience and you're not doing a whole heck of a lot of therapy during that time, right? People are in their own space, typically listening to music, eye shades, having a robust internal experience and then subsequently unpacking that kind of integration session after the fact, but not a lot of active engagement during the session. The psycholytic model for psychedelic-assisted therapy is lower doses and kind of based on the idea of loosening somebody up to better engage with their therapeutic process, so their defenses might be lowered.

BL: Certain emotional content might be more readily accessible, certain difficult issues might be better able to surface, right? And so, there's a more active kind of engaged process with it. I think there's just so many questions right now, like, what are the optimal ways of doing this? And I don't think we really have answers to most of those questions and yes, the current best study model that we're seeing now with recent studies is that psychedelic model of a high dose, maybe just one session, or maybe one or two sessions, and then having that wrapped into preparatory work and then subsequent integration work. And that's an important theme too, not just the experience itself, but what do you do with it? And I think that's a big emphasis with that form of psychedelic-assisted therapy. Your question is really related to micro-dosing, and that's a very hot topic right now.

BL: And you mentioned James Fadiman, who has studied this mainly in terms of subjective reports that he's gathered from people doing a range of different kinds of self-blinded home experiments with micro-dosing, classic psychedelics. I think it's very early to say much about micro-dosing, and on the one hand, it wouldn't be radically surprising if a potent serotonergic agent had some sort of signal for mood and anxiety or those sorts of things, cause that's kind of the model of current psychiatry, right? On the other hand, I think it's very hard to know what kind of conclusions to draw from people self-blinding and self-reporting, and there have not been robust studies that would kind of help us understand what would the role be for micro-dosing? To define that term, micro-dosing, it's really taking sub-perceptual doses of a psychedelic. So, typically less than a 10th of what you might consider to be a standard dose.

BL: The goal is not so much to alter immediate conscious experience, but to take this at a certain interval to treat underlying conditions. James Fadiman's work, I think, is interesting and intriguing and there does seem to be a potential signal there for depressive symptoms, for attention, ADHD symptoms, potentially. His data does suggest that there can be a corresponding increase in anxiety, so I don't quite know what to make of that, but it seems like there might be certain conditions for which that would not be a good idea. All that being said, I think it's too early to say anything of significance about micro-dosing, but I think it's certainly taken on popular imagination and interest.

PW: Okay, so before we dip into more about the research, there is something that just I found interesting, which is this idea of psychedelic-assisted therapy, and the idea that people are taking, let's say, a dose of psilocybin, sitting in a comfortable or laying in a comfortable position with eye shades on and listening to music versus I think the way a lot of us having again, grown up in previous eras have thought about how people take psychedelics where they're walking around parks and looking at water and looking at trees and standing there looking dumb founded. Would that be a typical protocol that studies would use, is that very typical?

BL: Yeah, yeah, that's a good question. And you're right, it's a different model than say, going to a Grateful Dead show or how most people conceive of psychedelic use. And interesting to note that those studies are over-represented with people with prior psychedelic experience, maybe unsurprisingly, right? And there are clear distinctions as to the types of experiences that even very experienced users have within study settings compared to prior associations. But yeah, you're exactly right. Within these study scenarios, both historically and currently, the model, if we're talking about psilocybin-assisted psychotherapy is very much internally directed, so it is typically two-on-ones, so two therapists per study participant, and there is emphasis in different circles of having both a male and female therapist present for the entire duration, typically an eight-hour session. And again, very internally directed, so people have eye shades on for a majority of that session, a music track that's typically played over headphones. People might be emerging from the experience and talking briefly, but the emphasis is mainly supportive and moving internally and book ended by very intense preparatory sessions before the session, and then integration sessions afterwards.

What does the data show and where are the shortcomings in the studies?

PW: That's a great explanation and some clarity about how those things are done. So let's jump into a little bit more about what does the data show. We won't go into too much depth on this, but can you give us just a broad maybe state of affairs in terms of where the studies are and what the data shows, and where there are shortcomings in the studies.

BL: Maybe I'll start with the caveats, actually. I think that some of the limitations of these studies that are remarkably positive and remarkably encouraging, include the fact that they're very difficult to control, so most people in the room, the participant and everyone else tend to know who got the active drug and who got the placebo. So, it's very hard to control, with a placebo. These studies are all small studies.

PW: How many people are we talking about?

BL: For instance, the two, probably strongest randomized control trials to date, from 2016, one was at Johns Hopkins, and both were for end-of-life anxiety and depression associated with a cancer diagnosis, or this idea of existential distress. And both NYU and Johns Hopkins came out with strong studies in 2016. I think Johns Hopkins was about 50 people, and NYU was about 30, if I'm remembering correctly. And both of those studies, looking at existential distress and remarkably positive within... Acutely, so remarkably positive at reducing scores on the scales we use for depression and anxiety, acutely and interestingly, even after a single session sustained at six months, NYU had recently put out a follow-up from three years, that showed remarkable sustained response, given just a single session. So, there's something very, very interesting about that. But yeah, small numbers.

PW: Another curious question. What are they using for placebo? How do you get people that take something that is a placebo, to think this could be a psychedelic? [chuckle]

BL: There have been a range of things used. The Johns Hopkins study I just mentioned did this crossover design. So they had a very like an ultra-low dose psilocybin, I believe, something like one or two milligrams versus a full, essentially 25 or 30 milligram dose, in the active group and then they just crossed over their participants in the second half of the study. Other studies have looked at more active placebos like Niacin, which causes a flushing reaction, so people will have physiologic changes. There have been studies looking at stimulants as a placebo, so something like Methylphenidate, where people might have alterations and conscious experience, not typically psychedelic experiences. People have used Dextromethorphan as a comparison, which is kind of an interesting placebo in certain ways

PW: Yeah, we've heard about kids taking Robitussin with Dextromethorphan to get some kind of altered mental state.

BL: That's right.

PW: And I do not speak from experience, in case any of you are wondering.

BL: Important caveats or disclaimers rather. I think that that's a real challenge with this field is, how to design studies that have placebo control.

Where else is the data being collected and in what other disease states?

PW: To summarize then, just the bit that you said, we've got some small studies, but they've attempted to control them, 30 to 50 participants, and with that existential crisis that people have, there's been some good data to show some significant improvement, and also it sounds like it's not just a one to two-day thing, this is six months and even, it sounds like they went as far as looking at a three years. Where else is there some data and in what other disease states?

BL: If you currently look at what's listed with the FDA as current trials underway, there are over 60 currently. So, people are looking at this across the board. There's a study right now, at Johns Hopkins, looking at Anorexia nervosa, a range of substance use disorders, OCD, major depressive disorder we've talked about. Another interesting study that I think is worth mentioning also comes out of Johns Hopkins and was run by Matt Johnson, looking at tobacco use disorder, and I think that was 2014. Again, pretty small. I think it was 15 participants, and these were hardcore smokers. So, on average, smoking a pack a day. These were people that had tried a range of our traditional smoking cessation interventions without success, and they did two or three higher dose psilocybin-assisted therapy sessions in conjunction with a curriculum for smoking cessation, and then they tracked these people with biological measures of nicotine in their blood, over time. And again, very, very strong results, 80% at six months abstinence.

PW: 80% is better than anything in the market. It blows away, it sounds like anything that's available. I know of CHANTIX, I think that's a brand name, but that medicine is what, 30%-ish.

BL: My understanding is, yeah, if you can get to 30% kind of buttressing with all of our motivational tools and nicotine replacement plus minus things like Varenicline or CHANTIX, 30% is really the upper limit of what we could possibly see. So really encouraging, for a disorder that causes a huge amount of morbidity and mortality, that we're typically not that great at treating, and that overlaps with a ton of other social challenges and financial challenges, and psychiatric challenges, too. So again, small study, but very encouraging.

Have you had experience or are you looking to gain experience doing clinical trials here at the University of Utah?

BL: We have two trials currently under way. It's taken a long time for us to get there. It's almost three years to get to the point we are now. The first trial is a small pilot study at the Huntsman Cancer Institute, looking at group administration of psilocybin for cancer patients with existential distress.

PW: Group administration is very interesting.

BL: Yeah, so exactly, I think that's the potentially innovative aspect of that study. It's very small. We're mainly looking at the question of, "Does this work? Can we do it? Is this feasible? Is it safe?"

PW: And are people interacting with each other? Is that the design? It's not like eye shades.

BL: And to be clear, we've only just started recruiting for it, so we haven't run our first cohort yet. So, it'll be interesting to see how that goes. We're hoping, basically next month, to run our first cohort.

PW: But with the design, will there be interaction between participants?

BL: Yeah, I think our protocol is basically to have a group of six, and the space that we have, again, when you design these things, you're dealing with what kind of space you can even get. And then how do you use that in a way that would be reasonable, safe and the space we have is like an infusion center in Huntsman, and it has these separate bays, where people are normally getting a chemotherapeutic agent or some sort of medication. And so, it has a little bit of a private, cordoned-off area for each person, but it's a big room, a big group room. So, I think it'll be interesting to see how that goes. We will have a communal music track, rather than headphones, the ratio of therapists to patients we'll be using is one to one. So, we'll have one therapist to one study subject, which is reducing the overall ratio.

PW: And it sounds like you're thinking about sort of scalability issues.

BL: That's right. Yeah.

PW: Interesting.

BL: Yeah, exactly. I think that that is another challenge here is that it's very resource-intensive, at least initially, in terms of time and therapist's time. So, we'll see. That's one of them. The other one we're doing is a study looking at augmenting a mindfulness curriculum with two ketamine-assisted psychotherapy sessions for patients with opioid use disorder, that we're doing with Eric Garland in the department of social work. So yeah, we have a couple of studies under way, that's been very fun, very exciting. It's been a huge learning process for me and a really a new thing for me. But yeah, just a lot of fun and I'm really excited about it.

Safety and risks: Are psychedelics addictive?

PW: Yeah, that's excellent, I love it. Okay, so what we'll do is, we'll segue here, to a little bit about safety and risks. One of the things that when you talked about the mechanism of action for psychedelics is, you didn't mention the neurotransmitter, dopamine. And I'm sure everyone listening knows that dopamine has a strong association with addiction. Are psychedelics addictive?

BL: There is no evidence that classic psychedelics have abuse potential in the same way that we think of other addictive drugs, like for instance, cocaine or nicotine or alcohol. And yeah, you're right, it's thought to be in large part cause they're not hacking our dopaminergic system in the same way. It does turn out that LSD at higher doses, has some dopaminergic effects, as I understand it, but there's really no associated withdrawal phenomenon that people get, after using psychedelics. People develop tolerance very, very rapidly, to these compounds. So even after a single high dose session, it's difficult to re-dose within any quick window of time, and they're not typically reinforcing. So, for instance, euphoria is not typically a standardly reported feature of psychedelics. If you give rats the option of pushing a lever and getting LSD, they don't tend to push the lever again. They push it once and they're done.

PW: One dose is enough. [chuckle]

BL: So, thought to be a very low risk of addiction potential.

Potential psychological harm: “A bad trip”

PW: Okay. And that kind of brings us to this question of the "Bad trip," the psychological harm potentially, that these molecules can cause. Now, I've read a tiny bit, and what I do know is that, in the psychedelic assistant model that we talked about earlier, and the ones that we described in the clinical trials, it sounds to me like the risk is really reduced, whereas if you've talked to people that use these in a more recreational manner, it's not uncommon to hear someone say they felt like they were losing their grip with reality, and it causes extreme anxiety and panic. Let's go into that a little bit more, and then maybe if you could introduce the concepts of set and setting as well.

BL: To return to your former question too, again, it is important there to distinguish classic psychedelics from, say, MDMA or ketamine which do have higher abuse potential, and we see that. So, yes, important distinction there. But yes, the concept of psychological harm and psychological risk, and this notion of the bad trip, I think... And you're right. In the context of current research, these risks are quite mitigated. So there don't seem to be clear indications of psychological harm, downstream. It's worth noting that there are some very unique factors of that environment. And you talked about those terms, set and setting, and those are fairly general terms.

BL: The idea of set, gets at the set of intentions that somebody has, going into one of these treatments, sort of the orientation they have, what they're hoping to get out of it. And that ends up driving a huge fraction of the experience. Within these trials, the set for individuals is largely therapeutic. There's a set of things that they want to work on, that aren't working well for them, or the symptoms they're having are very difficult. There's a very therapeutic intention surrounding it. Setting really refers to the environment, the container for that experience. And again, in these clinical trials, it's very closely monitored and thoughtfully organized, and there's a ton of preparation leading up to it. And you have support throughout the whole thing, if things are going off the rails, as it were, or people are having difficult experiences. And those aspects, set and setting, can be just highly variable in recreational settings. And people might find themselves in chaotic environments or without support or in context of poly-drug use. And so, there's so many other variables that can really set things askew.

BL: The other thing to note with these research studies is that they're really rigorous about screening participants. And there are certainly people for whom the risks of taking psychedelics probably largely outweigh the benefits. And so, the people that are really rigorously screened out of existing studies are people with pre-disposition for psychosis, so they've either had a psychotic disorder in the past or had experiences of psychosis. They screen out people with first degree relatives with a psychotic disorder and second-degree relatives with psychotic disorders. So that's a big one. They screen out people with Type 1 Bipolar Disorder, they screen out people with certain variants of personality disorders, screen out active substance use disorders, people with active substance use disorders. So, you're looking at a select group of people, and you would expect a lot more heterogeneity and risk without that kind of caution about who's receiving the medicine.

PW: Are those theoretical risks? So like somebody with a psychotic disorder in the background, say our first degree relative, are there known cases where this is sort of set off, it's tripped into a psychotic episode, or is that more of a theoretical risk?

BL: No, there's definitely cases of that. And even with my work, doing inpatient psychiatry, we see that not uncommonly, that this can precipitate or catalyze an episode of psychosis. And sometimes, it's not entirely clear what's going on with that. Is this somebody who has a vulnerability to this anyway, and this has somehow been accelerated or reared its head through psychedelic use? We see something similar with cannabis actually, that that can seemingly precipitate psychosis for people that have a vulnerability. So that certainly seems to happen. It hasn't happened within study settings, I think in large part, because of these factors, controlling set and setting, really screening participants. You talked about this notion of the bad trip, and that... I think most people in this field reframe that terminology, as a challenging trip. And that's certainly not to say that there might not be things that are clearly harmful, that people have experiences that, all things considered, it was just presenting risk and harm to them.

BL: But the notion of the challenging trip, I think, gets at this notion that, man, even among people that have really positive downstream effects from engaging in these studies, it is potentially a very, very challenging, very, very difficult, very not fun kind of thing that they might be experiencing, at least at times during that session. And there's not a correspondence. So actually having a very, very, "challenging experience," can actually foster really significant personal and therapeutic change. And so, it's not necessarily a, "bad thing." But I think, in large part, again there are risks here that are psychiatric and psychological. These experiences, even apart from mounting a psychotic episode, where you need to go to the ER or receive medication or end up in a psychiatric hospital, even apart from that, these can be very destabilizing experiences, if there's not thoughtfulness and sensitivity about how and when this is being used and... Or if somebody is not prepared for this and doesn't quite know what they're getting into. And there can be huge psychological effects from that, that can be harmful for a person.

Psychedelics within the therapeutic model

PW: Very interesting. I like the replacement of the word, "challenge," instead of, "bad trip." Just wondering, the thought of how that therapist is helping somebody. So, I'm imagining somebody sitting on a couch with their eye shades on, listening to music and saying, "I'm freaking out, I feel like I'm going to die, I feel like I'm losing my sense of reality." And then what does the therapist say? 

BL: I think there's a lot there in that question too, right? And most of the mechanisms of therapeutic engagement are fairly general, but I don't think that necessarily means that they're simple. Cause I think there's many difficult aspects within how psychedelic therapy happens, depending on what's showing up for a person in those sessions, right?  The phrase I thought of when you were describing that event was somebody really struggling, or having a negative experience, or overwhelmed, frightened, stuck or trapped, feeling some sense of no escape. People might feel like they're losing their mind, they might feel huge paranoia, or they might feel like this is never going to end, there's no exit.

BL: And phenomenologically, that might be really compelling within that moment. Typically, within the therapeutic model, the idea is that it's not so much the content that's coming up that's hard, it's the struggle with it. So, it's the moving away or the attempt to move away from whatever's arising that might... That really is causing all the problems there. The instruction, the implicit and explicit direction in those contexts, is to move into it. You go towards it. Whatever's happening, you go directly into it. All is welcome. So that phrase, "All is welcome." It's coming up for you, you don't know if you can do it, move into it, all is welcome, even this. There's a lot of things that I think are interesting about that idea, and kind of resonate with a whole range of other ideas.

PW: It sounds like a good philosophy for life. I think a lot of times when things happen to us, it causes a lot of fear, and the typical human reaction, which I'm definitely one of them, is avoidance and to get away. And sometimes the best thing you can do is to confront and deal with it.

PW: Any other ethical issues that you want to just note or discuss?

BL: I think ethical issues at stake in psychedelic therapy right now, I think a big one relates to two big ones that immediately come to mind relate to diversity. And so, if we look at current studies, they're very homogenous in terms of steady population, and there are some good reasons to see limitations in that domain. I think access is a big concern here as well, particularly given the huge burden of mental health conditions, among many underserved populations, with a style of therapy and intervention that might be hard to see how it fits into current insurance models and how to scale it. I think access will be a big issue. How do we make this readily available and safe and accessible to a wide range of people?

MDMA and the future direction of psychedelics

PW: Okay, let's segue to our last segment here, which is future directions. MDMA made a bit of a splash, at least for my eyes, in Nature, the journal Nature, this year in 2021. Tell us about MDMA, and not related to MDMA, but Oregon is moving like they typically do in a very progressive manner, and give us a little bit of information too, about where they are as it relates to the legalization of psilocybin. So, thoughts there.

BL: Again, very rapidly changing landscape here. Where we're at right now, you mentioned MDMA, and you referenced the recent Nature paper publishing their first phase three results, looking at MDMA-assisted therapy for PTSD, and that's the main indication right now for looking at MDMA, and the main avenue for FDA approval for MDMA, with the timeline looking to be around 2023, although I don't know how that's going to play out exactly. And I think that's a really exciting thing again for a disorder that we're very limited in terms of how we can treat it, and a disorder that carries a huge burden in terms of individual and societal cost. And so those results... And we haven't talked a lot about MDMA here, but again, very, very, very promising and very exciting to have this new treatment option on the horizon. Again, very intensive in terms of administration. The protocol that MAPS uses for MDMA involves the MDMA sessions and three integration sessions between each of those sessions, and it's two therapists present for each study participant. And so, I think a lot of the success there hinges on really making a compelling argument about longitudinal cost savings.

BL: And I think it's not hard to see how one makes that argument, and there's some data actually, some initial data that's really... I can't remember it off-hand, but just very, very supportive of the fact that, okay, you invest... I think the estimated cost to run that protocol for a given individual might be around $15,000, but if you play out that math with a burden of chronic PTSD, say, within the VA system over 30 years, those costs are astronomical. And so I think you can imagine how you can make those arguments, making that compelling to the way we currently structure healthcare, particularly in non-VA settings, I think is tricky and challenging. There's a whole lot of questions about how to make that happen in such a way that it's not just for, say, the affluent who have that available. You mentioned Oregon and Proposition 109 which legalized psilocybin-assisted therapy.

PW: So, they didn't legalize just the recreational sale of psilocybin.

BL: That's right.

PW: They legalized the therapeutic use of psilocybin under the right circumstances.

BL: That's exactly right. And all of these terms are very specific and we're in the space where there are decriminalization measures like we've seen in DC, Ann Arbor and Denver, and that's not legalization, that's distinct, right? It means it's not a pressing priority for law enforcement. And Oregon's measure, yeah, was legalization of this form of therapy. To be honest, I don't know that many details about how that will roll out, but I do know they have this three-year process to figure that out, right? So they have various medical people in that space, and people from the psychedelic-assisted therapy world and legal people. And I don't... I haven't seen any models for what that will look like, but the goal is really... This is a controlled intervention, right? This is not necessarily a medicine you would show up at the pharmacy to purchase, right?

BL: It would be a medicine that is accessible and legal within certain well-controlled and defined parameters, right? And we have some medicines that we currently have that kind of broader infrastructure around like Clozapine, or Methadone for instance, where there are these other kind of safeguards within how that gets administered and specifications for the context it can get administered. And my understanding of how that is proposed to roll out in Oregon is something along those lines, but yeah, I don't know anything more specifically about that, and it'll be interesting to watch that unfold.

How do we fit psychedelics in the context of the swelling need for mental health treatment  that we see and feel in our community?

PW: It's very interesting. The last thing I want to finish on is something that this Communivation Podcast is all about, which is innovative health care delivery and how it can impact our community. As an impatient psychiatrist, I know that you see sort of that top end of people coming in under desperate circumstances. Can you maybe just comment on, kind of from your perspective, how do we fit psychedelics in the context of the swelling need for mental health treatment, mental health therapies that we see and feel in our community? And it feels like it's almost growing like monthly. I mean during COVID, it feels very much like an exacerbation of normal circumstances. But what are your thoughts and comments about where psychedelics might fit into that community need?

BL: I think ideally, as a promising and robust set of tools, among other tools, I think not a panacea, I think not for everybody or for everything, and very likely for certain kinds of conditions and for certain people and certain sorts of disorders, I think very, very promising, and having an armamentarium that might include ketamine plus minus MDMA, plus minus down the road, psilocybin. I think there would be a lot of promise to treat a lot of things that were otherwise really not great at treating, even considering pharmacologic interventions or psychotherapeutic interventions. So, I see just a huge amount of promise here. But again, I don't think it's a set of treatments that would be for everything. And I think there would be all kinds of interesting innovative ways of using these medicines even within an inpatient setting. You could imagine having people come in for a period of time, do an inpatient unit and having an intensive set of interventions in this regard, and maybe not having downstream repeat readmissions, or... I think there would be a lot of ways of going forward here that... Yeah, it would be just really really interesting and worthwhile to explore.

PW: Thank you for that. So I want to thank you, this has been, for me, a fascinating topic, and I really feel like you're the perfect guest for this, your expertise comes through, it's quite clear. So we appreciate your interest in this topic and really appreciate you taking the time to talk through this topic and do it in a way that I feel like is really accessible for people. So thank you very much and I hope we can come back, turn around and have something else, maybe like a part two discussion down the road.

BL: Oh, that'd be great. I'd be really happy too. I thought this was a lot of fun. You've done a lot of reading obviously on this as well. Fun opportunity to talk about all of this and look forward to future conversations.

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PW: Well, I hope you enjoyed our podcast today. For me, the topic was incredibly enlightening and informative, and I hope you feel the same. I do want to underscore a disclaimer that I made at the beginning of the podcast, and that is that the purpose of today's discussion is not to condone the recreational use of psychedelics. It's not that at all. It's meant to be a conversation that focuses on the scientific study of the therapeutic use of psychedelics in mental health. We also are seeking your feedback about what topics you'd like, and about how we handle the ones that we have covered. Please check us out at www.accelerate.uofuhealth.utah.edu and search under our podcast name, Communivation. I do love feedback and I take it seriously. I also want to thank Sofia Loucao, she is the Business Medical Group fellow and has replaced the irreplaceable Isaac Holyoak. If you're listening Isaac, we miss you. Sofia has done a stellar job with the production and editing of this podcast. And lastly, my co-host, RyLee Curtis is back. Look for another podcast shortly. Thank you very much.

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