Adam Gazzaley, M.D., Ph.D., is a neuroscientist, neurologist, inventor, author, photographer, entrepreneur, and investor. Most notably, he’s the founder and executive director of Neuroscape as well as the David Dolby Distinguished Professor of Neurology, Physiology, and Psychiatry at the University of California, San Francisco. In this episode of the Third Wave podcast, Adam talks with Paul F. Austin about the new Neuroscape psychedelics division at UCSF, how studying individual biomarkers can give us novel insights into personalized psychedelic experiences, how different psychedelic dosages can work synchronistically with sensory stimuli, and how Neuroscape is using videogames to train attention.
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0:00:00.0 Paul Austin: Like if we could create this richly immersive, multi-sensory experience with everything in the same intention setting, rich nature, visuals and sounds of nature and comforting music and smells of pine trees, we might have... We're actually interested in that have therapeutic outcome just on that alone, and then set up really nicely, especially someone that's very uncomfortable and nervous about a psychedelic to bring in a mini dose coupled with that once they've gotten familiar and comfortable with the environment that we're establishing for them, and then I'm a scientist, I would like this driven by data when the data tells us that someone's ready to advance to a higher dose or a different compound, then we proceed along that trajectory, and I actually don't think it's just the type of approach that would diminish side effects and potentially negative consequences, which I do, but I also think that the efficacy could be greater because sometimes people are just not prepared to take away all the learnings and growth from a very high dose when they're just holding on to the edge of their chair.
0:01:07.8 PA: Welcome to the Third Wave Podcast. I'm your host, Paul Austin, here to bring you cutting-edge interviews with leading scientists, entrepreneurs and medical professionals who are exploring how we can integrate psychedelics in an intentional and responsible way for both healing and transformation. It is my honor and privilege to bring you these episodes as you get deeper and deeper into why these medicines are so critical to the future of humanity. So let's go and let's see what we can explore and learn together in this incredibly important time.
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0:04:49.7 PA: Hey listeners, welcome back to Third Wave Podcast. I'm your host, Paul Austin, here with another special guest, Adam Gazzaley who is a neuroscientist, neurologist, inventor, author, photographer, entrepreneur, and investor, Adam is also most notably the founder and executive director of Neuroscape and the David Dolby Distinguished Professor of Neurology, Physiology, and Psychiatry at the University of California, San Francisco. In addition to that, he is the co-founder and chief science advisor of Akili Interactive JAZZ Venture Partners and sensing. He is a member of the Board of Trustees and Science Council of the California Academy of Sciences and has authored over 150 scientific articles and delivered over 700 talks. Adam, welcome to the podcast.
0:05:36.1 Dr. Adam Gazzaley: Thanks, thanks, Paul, thanks for having me here.
0:05:39.1 PA: Absolutely, I'm excited to dive into you today, particularly at the intersection of psychedelics, neuroscience, and technology, psychedelics are one of those age-old tools that we've had for thousands and thousands of years, and neuroscience and technology is much more modern to explore the synthesis between those two, would be exciting for today. So the first question that I wanna open up with is just to set the frame for our listeners in terms of how this relates and your work relates to psychedelics, I'd love if you could just open up by telling us a little bit about the Neuroscape Psychedelics Division at UCSF, and what's sort of the origin story behind its existence?
0:06:18.2 DG: Sure, I'll back up. So I'm a professor at the university and I have several other ventures outside academics, which we can discuss later, but at UCSF, I am the executive director of a center called Neuroscape, it sounds like it's a company or something, but it's not, it's a non-profit research center at UCSF, and it used to be my laboratory it just got really large and we evolved it into a research center, and our focus at Neuroscape is to... The high-level focus is to develop innovative approaches to improving cognition, cognition broadly defined, our main cognitive focus tends to be attention abilities, but we now have research on memory, perception, decision-making, empathy, compassion, and so it's... And even stress and mood regulation. So fairly broad, we have lots of different approaches to enhancing cognition, but the one that we're most focused on that we're most known for is the use of technology, and we do that largely through interactive experiences. I've come to think of this as experiential medicine, broadly defined, it doesn't have to be for clinical conditions, although we're using the word medicine, improving cognition in anyone independent of what baseline you're starting at.
0:07:38.4 DG: And our interactive experience is often presented through video games with other approaches like non-invasive brain stimulation, and so that's a little background about Neuroscape. And we can dive more into what we've done with video games and virtual reality, but to answer your question, I just wanted to set that framework of what Neuroscape is because, over the last couple of years, I've been very active in trying to develop and now successfully launch a Psychedelics Division. When people think about Neuroscape, they don't think about psychedelics or even molecular interventions at all, or well known for using technology, but what happened... And so that the origin story is, several years ago, I was reading Michael Poland's book How to Change Your Mind like many other people, the gateway drug into this field, and for me as well, and it was a mind changer. No pun intended, it really... It really flipped my entire perspective on psychedelics, not that I had a negative one, I just did not think about it, in the same way, I think about the work that we're doing at Neuroscape as an experiential treatment.
0:08:47.2 DG: And it was that book that really opened my mind to the reality that although the changes induced by psychedelics are initiated by a molecule, clearly you adjust something, the outcomes, whether they're good or bad, or good or transformative, are really influenced by the experience and realizing that the experience was the driver of the outcomes and how meaningful and sustainable they were made me appreciate that this is a perfect area for Neuroscape to be involved in because we've become experts in experiential design as tools to improve cognition, everything from the rich comprehensive recording of physiology and neural activity during experiences to shaping and guiding experiences through visual and auditory, tactile stimulation, as well as feedback loops and rewards and challenges. And so the idea that I had was, could we couple all of the work that we've been doing at Neuroscape with psychedelic research, and that was the beginning of that idea, I read the literature extensively 'because I was pretty unfamiliar with it, and came across Robin Carhart-Harris work with his research, his empirical work as well as his conceptual work, talking about how the neural mechanisms by which the effects of psychedelics are delivered.
0:10:20.0 DG: And what really caught me... Caught my attention were the papers he published on context and also on experience and music and its role. I went out to the UK to give a talk at Oxford and meet Robin and his group, and it became clear that he would be an excellent, outstanding Director of this new division, and it was really a very, very powerful meeting of our perspectives and our backgrounds, which although they overlap in neuro-imaging was really quite distinct, and so over the last year, the big covid project I had was helping bring Robin across the world over to San Francisco at UCSF, and that has now successfully happened, he is here in the Bay Area and is a distinguished professor at UCSF and is the director of the Psychedelics Division at Neuroscape, to help accomplish that goal of really taking psychedelic treatments to the next level in terms of a deeper, richer understanding of the experiential aspects, sometimes called extra-pharmacological effects, so that we can deliver more personalized and precisely targeted treatments. That's the main goal.
0:11:40.0 PA: Let's dive further into that before I do wanna back out at some point and talk a little bit more about neuro-racer and the video game element, and we'll have some time to weave that in, but just to go a little bit deeper into Neuroscape and UCSF, there's a quote that I actually got from Tim Ferriss about the PR release when Neuroscape came out with the $6.4 million in funding, and it was that Neuroscape and UCSF are perfectly poised to address fundamental questions about psychedelic therapies that have been largely untouched by research to date, and I believe this new effort represents the dream team, which I would agree with, for exploring this extremely promising and complex train, and so I'd love just for us to go a little bit deeper into that in terms of what fundamental questions are you and Robin addressing as it relates to psychedelic therapies that have yet to be explored within the current research that's been published?
0:12:32.6 DG: Great, that is my favorite topic to talk about, so I'm glad we're gonna spend some time there. When I started diving into the psychedelic research literature, I found that there were two dominant research domains, one is what I think of as the very basic science, what happens in a dish or an animal model in terms of receptor binding and pro-plasticity effects and the inflammatory effects, just really getting under the hood and looking at a mechanism at a molecular level. And then the other research domain is the big, important clinical trials, as we know, there were just several... The MAPS trial for MDMA treatment for PTSD and the work that Robin's done on Psilocybin as a depression treatment. And so you have the very basic science and you have these really advanced clinical trials that are even now positioning for FDA approval, what was noticeably missing to me was the entire middle of the field, what's often known as the translation, how do you move the insights from the basic science into the clinical trial, so that they're more precisely targeted, decreasing side effects, increasing efficacy, all those outcomes, and almost feels sort of developing linearly, where you do a lot of basic science work, you start understanding how to translate and then eventually get into the clinical domain.
0:14:00.9 DG: But I would... I could only speculate that because psychedelics have just evolved so unusually as a field with 50 years of suppression of global research, when you look at the literature... Or at least when I looked at the literature, I saw a very unusual pattern of research findings from the basics and then the clinical is not the entire way that you use to optimize and personalize and Target, and understanding all the individual differences, all of that was essentially missing. And so that's the fundamental area of innovation and research that Robin and I were both really excited about, and the way to understand that is by focusing our research designs, our experimental methodology on what is known in the field is set and setting. So this is the other irony about it, not just that you have a field that's missing the middle, that's missing the translation, but everyone... I mean, everyone I've ever talked to, whether it is on the ground therapist or a shaman from South America, or a researcher from Johns Hopkins, everyone believes that set and setting context experience of using all these words relatively interchangeably is critical for the outcomes.
0:15:16.9 DG: But if you try to find the research studies, prospectively designed research randomized trials that manipulate aspects of set and setting to determine how it influences outcome, there's almost nothing out there, almost nothing at all. And so it's a very interesting sort of disparity between what everyone believes and what actually exists scientifically, normally they're not disparate, the things that are missing scientifically, no one really believes. Here, we're starting with the foundation that through thousands of years of treatment that practitioners and the diverse array of practitioners, as I sort of alluded to, all have discovered through their own practice that these elements are critical, and so it's founded in true real-life experiential practice. But the research studies that are really important to understand the details and to allow us to really be able to determine which individuals might benefit from which treatments with which experiential aspects, and to be able to do so predictive-ly so that we could start from the beginning as opposed to the end of one experiment on every person to figure out what works best for them, all of this is just not... It's just non-existent in the research domain.
0:16:45.2 DG: So that's it in a nutshell, really understanding the translational details of how we go from our basic science understanding all the way through clinical application. That is a lifetime of work. There's no way that Robin and I will live long enough to see all of the experiments that we could list on a whiteboard right now, there's just so much that needs to be done there, so that's the area that we're gonna focus on.
0:17:12.0 PA: I love it, and there are a few things to sort of dive in deeper there, what is Stanislav Grof's notion of psychedelics as non-specific amplifiers, right, which speaks to the importance of the contact, the set and setting in which it's done and how for each individual... The stories that they're coming in with are going to be completely and totally unique, so that sort of set and setting needs to be unique for that situation, and this has been one of my gripes with the current clinical research as you mentioned, which is that it's really rooted in more of what I would call an industrial framework, as much as the FDA Clinical Trials are rooted in industrial framework, which is everyone gets the same amount, everyone has to go through the exact same setting, and although that was useful, let's say in the 50s and 60s, what we're learning now, through the technology that we have available to us, for example, I'm wearing an oura ring, I can get blood work done, there's many other things that are available, I can start to better understand how psychedelics impact me on a personal level, and there's really only one other study that I know about, and that's MDMA as it relates to epigenetics that Dr. Joe Tafur and Dave Rabin are doing with MDMA for the phase three trials.
0:18:19.2 PA: And what you are focused on is more from what I understand that it's coming at it from a neuro-scientific perspective, and I'd love just to drill down a little bit more than in terms of what metrics would you be measuring as it relates to neuroscience in other words, the set, and setting, the context, the medicine, what are you looking for, number-wise or quantitatively in terms of how that's impacting someone's EEG or someone's alpha, theta or whatever it is.
0:18:47.9 DG: Yeah, it's a great question. So I view the research that we're planning on doing and what we're writing, and we've been working for over a year now, writing research proposals and setting up all of the machinery to do this type of research, it takes a long time, there's a long list of acronyms of agencies that need to approve it. We need a big heavy 5000-pound safe to be able to store these compounds in a safe way, and then the proposals and the funding, so right now we're doing all the work, but what is it... The advantage of doing that work before you actually begin the research is that you really think deeply about the study design, the outcome measures, and all of the details that sometimes don't get the appropriate amount of attention up front, and it should, and so that's the good part about being slowed down by this process.
0:19:39.0 DG: And I see that we have these two big giant like Twin Towers, from my perspective, the one is what we've been talking about, are the elements of the setting that we get to guide, how do we change what you see, hear, smell, feel, how do we... Either record or help guide intentions at the beginning and processing, as we all know, there are aspects of the environment and the setting that occur before the research, before the treatment, if it's a clinical treatment during and then after, so this... All of those aspects, and we could talk more about that, but to answer your question, so that's one piece of it, and we're setting up digital scent delivery systems, we're working on that part and in parallel working on the other part, which is what you referred to, which is what are we recording? How do we know that what we're doing and what we're changing is having an impact and what that impact is, and how are we quantifying it? And we're doing that through several different approaches, so the main one that we've been... This is the interesting intersection of what we already do at Neuroscape and psychedelic research, and that we have for many years been using a wide array of physiological recording devices to understand what we now refer to as state, the real time state of an individual.
0:21:11.1 DG: Now, we're not going to be able to actually see or interpret the content of someone's thoughts unless they tell us, but what I do believe is accessible to modern-day technology, neuroscience, machine learning approaches, signal processing advances is a real-time representation of state, such as the level of arousal, the attention, the stress, the mood, maybe even some reflection of awareness, and to accomplish that, we will record data from many different recording devices. So over the years, I've become very sort of depressed with what I see in neuroscience, and I think it's true for many fields of some of the smartest human, most successful research is just sticking to an instrument, a single methodology. There's nothing wrong with that, but from my perspective, we will never, ever understand anything as complex as the human brain, unless we look at it from many, many different perspectives, and so we call this approach multi-modal Bio-sensing. We actually have a whole research program at Neuroscape devoted to it, MMBS is our internal term for it, and multi-modal Bio-sensing is supported or it's sort of framed on the hypothesis that we need to record as much information as possible that are giving us all different pieces of the larger picture, of what someone's state is in the moment.
0:22:46.2 DG: And so over the last year, we set up what we call the dream system, and it's all set up and we're already doing research with it right now, minus the psychedelics, we're just still waiting for some of the approval processes, but we can already start looking at very inaccessible states like meditation or what's happening when you're playing a video game, maybe even soon, looking at sleep, and the things that are in our system are high-density EEG, recordings of peripheral physiology. So autonomic recordings like galvanic skin response also known as electrodermal activity, heart rate and heart rate variability, respiration recordings, we can look at eye movements, pupillometry, facial expression, other EMG recordings of posturing and musculature, we could do voice recordings, so we do it all, we record all of that information, we even have other approaches looking at heart rate, not just heart rate but contractility of the heart to give very sensitive measures of autonomic activity.
0:23:49.8 DG: And the goal is to record all of this data, and then to use machine learning approaches to and pattern classification to understand What is the most meaningful data and to integrate that into more sort of reduced composite so that we could make decisions bit about that data, and then the other big challenge is to do all of that in real time, so most research done all around the world, including in Neuroscape, is you record all this data from someone, and then you analyze that after the fact, and then you combine it for many different people, and you wind up getting a result, that's what most of our papers are.
0:24:31.3 DG: We need to move beyond that. We need to think about multi-modal Bio-sensing in real time, so that we can understand these states while they are occurring, and then use that data in a closed loop system to guide how we change the environment to lead to better outcomes. That's the eventual goal, and that's gonna be a long-term goal, so that's a little bit of insights into what we record, and the last thing I wanna say is what I just described to you, we call our EEG system, and it's the most user-friendly, 'cause you could sit in a room, it doesn't take that long to put the headset on and to hook up all the other components that I mentioned, we also have a multi-modal bio-sensing that sits inside the MRI scanner, and so that couples it with functional MRI. So for a lot of our studies, our plans are, it'll be a two-visit one in FMRI as the main neural recording modality and the other with the EEG, but both of them coupled with the full array of other bio-sensors, and that gives us both a deep dive into the neuro-anatomical networks with FMRI 'cause of the higher spatial resolution, and with EEG, which loses the spatial resolution, but gains the temporal resolution, that means you can look very specifically at the timing of events in the brain, bringing them together gives us a really, really complete view of what someone is experiencing during the treatment.
0:25:57.5 PA: Wow. First of all, that's my initial reaction, that is incredible in terms of all of the things that you're setting up for that. The closest that I've heard to that is actually from a colleague of Robin's, Mendel Kaelen.
0:26:12.5 DG: Mm-hmm. Yeah, I sure do.
0:26:13.2 PA: Who you may be familiar and dealt with too with wave-paths, and I remember we met a couple of years ago in the Netherlands, and we're still close friends, but in that initial meeting, he had showed me some of the technology that he was attempting to design to sort of... Like you said, on the go, almost like navigating the client into... If they're going into a sad space that's becoming darker and darker, to bring them out of that with music, that would be much more sort of uplifting, and so music obviously is one of those elements, the amount of medicine that one takes is also one of those elements, and that's something that I wanted to go a little bit deeper into, most of the clinical research that's been done so far on psychedelics, let's say at Johns Hopkins with psilocybin or even imperial with psilocybin, even with MAPS and MDMA tends to be at these high doses.
0:27:01.1 DG: Mm-hmm.
0:27:01.4 PA: So the core bedrock of the research of Johns Hopkins has been psilocybin and the mystical experience, and then how that translates into efficacy for depression, addiction, alcoholism, etcetera, etcetera.
0:27:12.8 DG: Mm-hmm.
0:27:13.5 PA: And one of those other elements that you were talking about in terms of the missing gap from my perspective, is also these sort of lower doses, I wouldn't even go to say so far as microdosing, I think that's even very low, but let's say mini dosing, museum dosing, anywhere from 50 to 100 micrograms of LSD or anywhere from a half gram to a gram and a half of psilocybin, however that equates from a synthetic perspective, and I'm just curious to hear your thoughts and perspectives on when we start to combine psychedelics with other tools and modalities, breathwork, neurofeedback, the two have a synergistic effect, one amplifies the other, and I'm just curious to hear from an experimental research perspective, how are you looking at dose level for psychedelics specifically, and are you looking at these very, very high doses, are you looking at medium doses as it combines, what's the approach and perspective that you're taking as it relates to dose level?
0:28:06.7 DG: Yeah, great question. I'll answer it in several ways, so first, when we're talking about... I just wanna comment, and I know Mendel, we're even looking to collaborate together, as you mentioned, his focus is on music, but we are also very interested in visual stimulation, especially nature, visual views of clouds and forest, it doesn't have to... I'm not talking about watching a movie, but just seeing nature is very powerful and olfactory system, again, something that has been completely ignored, not just in psychedelic research but in treatments in prospectively design research studies across the board, but we know that the olfactory system is intimately connected with our emotional systems and memory, and so it's very easy to hypothesize very strong effects of introducing the sense.
0:29:00.0 PA: It's the strongest I think even in terms of...
0:29:00.8 DG: Very powerful.
0:29:01.0 PA: What smell it can bring up from a new perspective.
0:29:02.4 DG: Yeah. Very powerful. And so combining a scent, visual, sound, nature sounds and music, and even tactile stimulation like wind and low frequency vibration is very, very interesting to us, so I just wanted to put that in perspective that there's a lot that can be done on what we call and people in the field called multi-sensory integration, how do you bring in multiple different inputs that are synchronized in time to create these powerful unity effects that really transport you? And the reason I wanted to start my answer to your question with that is because you can imagine that with such a powerful sensory-induced experience, you may not need as high doses to help create these synergistic effects, or the other way of thinking about it is that you may... And this is a hypothesis that we have and we're very interested in...
0:30:02.5 DG: We're curious of how you can change the sensory stimulation in the environment, even on a high dose treatment across time, so as many of your listeners probably appreciate, there's sort of an on-ramp where even before you take the compound, we're setting the mood and the environment and bringing in these nature stimuli might help to relax and to open up one's capacity to receive all of the quite complex stimuli that are gonna be occurring both internally and the ones that we're gonna be delivering, and then you can imagine during the peak of a high dose, this can be stripped down even to silence and darkness, like a current, and then it could be sort of brought on again as you descend on an off-ramp, and data hopefully can guide when the stimuli are richer and when they're more impoverished. And we think that this could create a beautiful flow to help not just support maximal outcomes, but even for safety and comfort, perspectives of people that have never done... Experienced a treatment like this, to be able to give them comfort as they move through this... What could be a six, 12 hour journey depending on the compound.
0:31:25.5 DG: So we are very interested in the high dose work that has been done, but re-imagining it through this dynamic approach to contextual guidance, and that is something that really hasn't been done in the research lab, but I do wanna say is really important to say... I always assume that people... And maybe people listening to this already know, but in the real world, this is what happens, this already is occurring. So even going back thousands of years, this is sort of the essence of what it means to be a Shaman in the Shamanic guided experience, and that the aspects of music and rhythm and dance and touch and smells are being dynamically adjusted throughout the treatment. It just hasn't occurred in the research domain, especially with this much physiological recording, so I believe that we could reframe how we think about the high dose experience by really appreciating the time course of the effects and then appropriately delivering sensory stimuli when it could have the most positive impact. So that's one answer. So the other is, maybe you don't even need that high of a dose if you have all of these other aspects that can help guide and create a framework for people still to do a lot of the internal work.
0:32:49.9 DG: We're not telling them what to think, we're just sort of creating almost like a palette that they can paint upon, which is essentially what I think that the music does right now, but we even have more levers from the visual and olfactory and the tactile. So maybe a mini dose is all that we need when coupled with these type of environmental stimuli, that is unknown, talk about a big giant research field that is unexplored is really looking at the interaction between dosing and this type of physiologically guided closed loop sensory environmental guidance, this is completely uncharted territory. And I personally believe that a smaller dose will have a very, very powerful effect, maybe even more powerful than we currently get with the high doses and even a better safety profile, because it'll just be less jarring, especially to the uninitiated and people who are really reluctant to have their perception so deviated, so that's at least my thinking, and again, this could change over time for a person that maybe the many doses are more appropriate starting and then over time, higher doses.
0:34:06.5 PA: That's the point that I was gonna dive into. I was reading this book, The Archaic Revival, which is a collection of Terence McKenna essays and talks from the '80s... '70s, '80s and '90s, and it was I think a talk that he was giving in the '80s, it was him and Ralph Metzner, who... I'm sure you know of Ralph, 'cause that's the distinguished chair that you've...
0:34:27.4 DG: Exactly, yes.
0:34:28.0 PA: Set up for Robin.
0:34:29.9 DG: That's the chair... That Robin's chair is named after. Yep.
0:34:33.0 PA: And so Terence and Ralph are talking about this, this is in the '80s, with psychedelics coming back and sort of the evolution of humanity, can everyone handle these high doses of psychedelics? And Terence's response was essentially... 'Cause Ralph was asking him this question and Terence's response was essentially, I really only believe that maybe 5% to 10% of people can handle the chaos and sort of the total shifts and changes that actually come from these very, very ego-dissolving 5-MeO-DMT or psilocybin experiences and at the rest of folks, these lower dose levels may be more appropriate, and this is often something that I think about from a metaphorical perspective, is... I often compare it to when we learn how to swim as children, we don't just often sort of get on the diving board and jump in the deep end and start doing flips and turns, we usually start in the shallow end and we have our swimmies on and we have an instructor there, and we first learn how to navigate the water in that way before we go deeper and deeper into the depth of consciousness, and it feels like a lot of the multi-sensory things that you're setting up are the sort of swimmies, so to say, so you can start at these lower doses, you can calibrate the experience based on a safety profile as need be, and that way, there's a lesser chance of having, let's say, a traumatizing experience, because we know that can happen with psychedelics.
0:35:56.1 DG: Yeah, I agree 100% with you. I've even been thinking about the first sessions, not even having any psychedelics at all. If we could create this richly immersive multi-sensory experience with everything the same, intention setting, rich nature, visuals and sounds of nature, and comforting music and smells of pine trees, we might have... We're actually interested in that, have a therapeutic outcome, just to that alone, and then set up really nicely, especially someone that's very uncomfortable and nervous about a psychedelic to bring in a mini dose coupled with that once they've gotten familiar and comfortable with the environment that we're establishing for them, and then... I'm a scientist, I would like this driven by data, when the data tells us that someone's ready to advance to a higher dose or a different compound, then we proceed along that trajectory, and I actually don't think it's just the type of approach that would diminish side effects and potentially negative consequences, which I do, but I also think that the efficacy could be greater because sometimes people are just not prepared to take away all the learnings and growth from a very high dose when they're just holding on to the edge of their chair and being like, What is going on right now? And so the outcomes may be greater as well by baby stepping into it and learning how to navigate such an unfamiliar internal domain that they've had no access to before this.
0:37:28.7 PA: Yeah, we refer to it as sort of like the skill of psychedelic use, in other words, how can you onboard more people into that skill? Someone's just learning how to do Jujitsu, you don't throw them in the ring with a black belt, typically you take it easy to start with.
0:37:42.5 DG:ubtedly. And the other aspect that I wanna mention here, 'cause I think it's very relevant, is we've been doing work at Neuroscape on different meditation mindfulness practices, and often delivered digitally, 'cause that's our way of creating high accessibility and also systematic delivery so that we can do randomized control trials but it's not meant to say that it's any different than real world meditation and mindfulness practice is just how it's delivered, but what we've really come to appreciate, and many people have appreciated this long before I have, is that the act of learning how to control your attention and your thinking through all sorts of different meditation and mindfulness practices should have a very valuable role in what we're discussing now, so here you are entering this altered state where your thoughts are much more fluid, your perception is now being shifted on how you both view external events and stimuli, as well as internal events and stimuli, and if you don't have the skills in terms of recognizing information and focusing your attention and moving it thoughtfully with intention and making decisions, then you may just be lost and it may be fun, or maybe not fun, but it may not be transformative as we hope it would be.
0:39:13.8 PA: And so that's really the... That even comes into the role of intention setting within a psychedelic experience, a lot of it is... I think Grof said that psychedelics are like a microscope in terms of how they can help to focus attention on a trauma or on a vision or whatever, it might be, what I'm hearing from you is you can use then these multimodal tools to help train the ability to really focus consciousness.
0:39:38.2 DG: Exactly. And I tend to think of it as intention and attention, so intention is setting your goals and knowing what you want to accomplish, and that's really important, and that takes practice and guidance as well. Some people are like, I don't know what my intentions are. I wanna be less sad, but is that enough of an intention and so you could have the best intention setting, but still not have the attentional skills to focus on the stimuli and the decisions that allow you to reach the best outcome, so both intention setting, as well as attentional deployment, can both be refined through technological approaches, that's what we already do at Neuroscape, and then couple that with everything we're discussing from multi-modal Bio-sensing and closed-loop systems and sensory contextual guidance with the psychedelics. That's what I say is the future. That's how you really get that personalized and precisely delivered treatments that we just don't have right now, but I believe that that is the future of psychedelic treatment.
0:40:41.4 PA: Beautiful. Well, one thing that we haven't yet doven into is sort of your personal story, not necessarily specific to psychedelics, but just more broadly speaking, you started to get into the psychedelic world, it sounds like a few years ago, with Michael Poland's book and starting to Neuroscape psychedelics division but you have a long illustrious career before psychedelics, and so I'm just wondering if you could bring our listeners a little bit into that, what inspired you to both get an MD and a PhD, how did that lead to neuro-racer, which is a video game that helped with attention, and then eventually, I think it was endeavor Rx, which was the first video game approved by the FDA for therapeutic use, which when I read that, my mind was kind of blown, it did know that was even possible. So I'd love it if you could just bring our listeners a little deeper into your origin story, 'cause I think there's a way that this is all tied together with where we're at now.
0:41:36.6 DG: Yeah. I'd be happy too. So I grew up in New York, and I didn't really come from an academic background. I was the first in my family to actually go to college, but my parents were very educationally-focused, so... I don't wanna overstate that. I always knew I was gonna go to college growing up, even though we didn't really have those role models, but what I wanted to do as I moved through high school and then college is to bring together both science and medicine, I was always fascinated with science and really inspired by people like Carl Sagan and watching cosmos and thinking about the space was like many other scientists were sort of my gateway drug and eventually into biology, but Astronomy was my original love, and I realized that over time, focusing the microscope inside as opposed to the telescope outside was more rewarding to me and the human component, and after having done the research for so many years as an undergraduate, I realized that research alone wasn't what I wanted to do, I wanted it connected with the human experience, and this was from volunteering at hospitals and so I wound up going to Mount Sinai in New York for an MD-PhD program called the MSP program.
0:42:57.8 DG: My PhD is in neuroscience, and my medical training is in neurology, so I'm a neurologist. I went to residency at Pen and did all the clinical work to be able to treat patients. My clinical focus was Alzheimer's disease, aging, diseases of aging is actually my clinical focus. I don't see patients right now anymore because all the things we're talking about are a full-time commitment, but I did see... Those are the patients that I did focus on. And I moved to California in 2002 to go to Berkeley and to move my Research Methodology from microscopy to the approaches of human cognitive neuroscience, functional MRI, EEG, non-invasive brain stimulation like TMS. And I started my faculty position at UCSF in 2005, and also the director of the new functional brain imaging center here. So it's been 16 years now, I've been at UCSF, and for the first six years or so, things were going great, my work was advancing and my focus was on understanding how a better understanding of neural networks can allow us to hopefully understand and then even improve things like attention, and my research was on distraction and multitasking, and aging.
0:44:19.8 DG: I actually wrote a book on this topic called The Distracted Mind: Ancient Brains in a High-Tech World, and it's sort of like my last chapter, this book of my research, really understanding what changes in the brain, as we get older, that lead to our susceptibility to distraction, and then my research realized that it wasn't just getting older, all our brains are very acceptable to distraction, this is sort of a well-known story now, but it wasn't at the time, and so now we're in 2008, 2009, I just got really frustrated with my research. I was doing well from a pure academic point of view, I was getting all my grants and my papers were published in high tier peer-reviewed journals.
0:45:00.3 DG: From every perspective, I was successful, but I felt like I was failing because although we were advancing our understanding of the brain and its vulnerabilities, it wasn't what I really wanted to do from the beginning. It's not why I got an MD and a PhD. I wanted to help people, and as intellectually satisfying as it was to study the brain in the way that I was doing in my lab at the time, it wasn't leading to any outcomes that were making a noticeable difference in people's lives, and so that was like a transition zone for me, 2009, where I started thinking about how can we use our insights from neuroscience and the methodology that we've been using in our lab to help attention as opposed to just understand why attention is so fragile and upon thinking on what to do, I sort of had this epiphany at the time that the molecular approach wasn't bearing fruit, we have all these drugs that we give for attention deficits and other types of memory impairment like in Alzheimer's disease, and they were modestly well, they help some people but not everyone, they have side effects, and I was inspired by the work on plasticity that our brain is capable of modifying itself at every level, structure, chemistry, function, and thinking about how we can create experiences that drive plasticity.
0:46:18.1 DG: Now, experience-dependent plasticity is one of the cornerstones of modern-day neuroscience, it's not a controversial topic, it's more controversial and complicated in how you deliver that experience optimally and what it does, but the fact that our brain modifies itself in response to experience is the basis of all of learning, if that didn't happen there'd be no education system and no therapy, it is completely grounded in some of the best work over the last 50 years, but what hasn't happened is that we haven't really translated, going back to the term early in our conversation, our understanding about plasticity in neuroscience into therapeutic approaches to help people, we've done so molecularly, that's the whole basis of all modern neuro-medicine is bringing the advances from the basic science of different neurotransmitter systems into our current drug tools, but we haven't done it for neuroplasticity.
0:47:14.5 DG: And so when thinking about how do you deliver an experience in such a way that it is personalized and adaptive and accessible to people, I started thinking about video games 'cause they're fun, they're immersive they're... You could deliver them on phones and tablets that get into people's lives very easily. And I came up with an idea basically built upon that inspiration that I just described of building a video game to improve attention abilities and really guided it based upon our work at Neuroscape on what types of mechanics and interactions would lead to network activation in the brain that would have the potential to lead to multiple benefits if you engaged in.
0:47:58.1 DG: And so I designed a game that I called NeuroRacer, and I reached out to friends of mine in the video game industry, at LucasArts is the company, unfortunately no longer with us, and I was able to bring down some of the best brains from the video game industries, from programmers to engineers and artists, and created NeuroRacer, which we then ran through multiple research trials and eventually published the results years later in 2013 in Nature, which is as good as it gets for a scientist... It was the cover of Nature in 2013, September 2013. And what we showed was that playing this video game for one month, 12 hours was able to improve the ability of older adults to pay attention to very different tasks, not the game itself only, which we tested before and after, as well as some aspects of their memory. Now, we also recorded brain activity during gameplay to show what the neuro mechanism of that change was, essentially it was strengthening of the networks between the prefrontal cortex and the rest of the brain, and that was an incredibly exciting moment in my life and many people's lives, there were dozens of people involved in that research, and it became the beginning of Neuroscape.
0:49:12.6 DG: Our center is really built on that foundation of the closed-loop, closed-loop, meaning that the elements of your experience, the challenge, and the rewards are driven by your own data, that's what happens in our games, and it's everything that I just described to you what Neuroscape does. And it's consistent with all the work that we'll be doing on psychedelics, and the other thing that happened really with that publication and that first technology was the co-founding of the Akili Interactive, which was a company I'm the co-founder of, and what Akili has done over the years is built a much better video game on that premise that I already described of the NeuroRacer, of how NeuroRacer works, and now it has gone through multiple clinical trials that I've not even involved in most of them, including a phase three trial to look at the benefits of what this game became, which is Endeavor RX on attention abilities and children with ADHD, and we had positive findings, our study was done out of Duke, then it was positioned to the... This is a long 12-year story that I'm telling you in hyper-speed, but it was positioned to the FDA years ago.
0:50:20.7 DG: First time a video game was put in front of the FDA to get clinical approval as a Class II medical device to treat inattention and children with ADHD, and last year, right in the heart of COVID in 2020, it was approved by the FDA becoming the first-ever FDA-approved video game for any clinical treatment, the first digital treatment for children, the first treatment that actually targets cognition as opposed to symptomatology, and we're really proud of that, there are now hundreds of people involved in that from Akili and Neuroscape, and it really sets us on a path of what I think of the bigger picture, not that it's just a video game, video games are essentially how we deliver the medicine, but the medicine is the experience itself, and video games are a great means of delivering it, but not necessarily the only one. So I call this field experiential medicine, and now with the De Novo approval of that first video game for ADHD, we set up a new category at the FDA where we can position other treatments that have similar benefits across different cognitive domains in different clinical populations.
0:51:27.5 PA: You pioneered the first-ever video game for FDA approval to treat something, ADHD in children that have largely been treated pharmacologically with Ritalin, and Adderall and I sense there's a similar landscape that you're now pioneering with psychedelics, which is why you are doing precisely what it is that you're doing because you have this background of how do we take an experiential component that was never really approved by the FDA and bring it through and kind of what I see you stepping into with UCSF and Neuroscape psychedelics is something that just is another layer of complexity in terms of what gets to be weaved in for the benefits of the patients that they get to work with us.
0:52:13.4 DG: Exactly. Now, it makes so much sense, and it took us an hour to fully unpack that, and that's why I will never do like 10-minute interviews 'cause it's just...
0:52:23.0 PA: Yeah.
0:52:25.5 DG: It's really... It takes a bit to say, Why would someone that's been building video games as medical treatments now bring psychedelics into their research domain, and after all that we talked about, I mean, to me, it just makes so much sense. These are experiential treatments, they all have different ways of initiating the process, but the tools that you use to understand them and guide them to the best outcomes are the same, and so... Yes, and this is what brought Robin and me together, this is what we talk about pretty much every day. And it's vast, the number of things that can be done here is super exciting.
0:53:01.1 PA: And that's what makes it such an affirming mission to work on, is I feel the same way about the work that I do on psychedelics and education and training, new treats and all this, it's like... This is like a 100-year mission. It's not anything that can be likely completed, so to say in my lifetime, which makes it that much more fulfilling to work on.
0:53:22.7 DG: Undoubtedly, I love the long path from the idea of a video game as a treatment for attention deficits of all sorts, my initial focus was on aging, it was 12 years until we now have a product on the market right now, doctors are prescribing a video game right now for kids, that has started. But that was a long, long time, and it was a fun ride, frustrating, really difficult, but now I've learned that that's how I like to operate, and I see what we're gonna do in psychedelics, is also a long path, and I want us to do it really well as everyone in the field does, and the rushing this is really not a good idea, it's complicated, it's... The reason why everyone is so excited about it, is 'cause it's powerful, and with power comes the potential to do harm, and we need to really do our work, not just to avoid harm, but to reach the maximal potential that is capable, we really have to be thoughtful and go a bit slow and we're prepared to do that.
0:54:35.7 PA: Well I'm glad you brought up maximum potential, 'cause that's the next paradox or tension that I wanted to ask you about, which is you have a background as a medical doctor in neurology, a Ph.D. in neuroscience, you've gotten an FDA-approved therapeutic with Endeavor RX, you're now working on psychedelics as medicine, and yet you also have this sort of element of going beyond medicine and looking at optimization and looking at peak performance and looking at these other things, so I'm just curious, both personally and professionally, how do you see that tension in your work and maybe also speaking to how do you see that playing out with the work that you're doing at UCSF and in psychedelics.
0:55:17.9 DG: That's a great question. Akili is focused right now 100% on a clinical treatment where if they approve, we don't have any... We don't put out any other products that are not FDA approved right now, and we are a medical device company, and people are always like, Why? There's so many more people that need an attention approving treatment, especially one with no side effects than just people that have a diagnosis of ADHD and they're right, there are... And I think that is part of Akili's future and Neuroscape in general is much more interested in how we improve cognition in everyone, regardless of your baseline, even if you're a high performing person and want to squeak out an extra 3% of benefit across the domain, we should be able to give you the tools to do that. And certainly the people that are suffering debilitating conditions, obviously need those immediately, but when it comes to the brain and understanding how we approach this, we're fairly agnostic at Neuroscape to that, we just think about these neural systems as these processing units that can be optimized through the approaches we're doing, regardless of the level that you're starting at.
0:56:40.3 DG: Now we tend to think about our work in buckets like education and clinical wellness, because that is how the world has largely separated these things, and there are different regulatory agencies, there are different funders that are only interested in certain domains, there are different institutions like our education system, our hospital system... Healthcare system that focus exclusively on these buckets, but the buckets are made up, and they're often very arbitrary, and I'm not saying that people aren't suffering from real clinical conditions that might have genetic components and other aspects of it, but often the lines in cognition between where someone is healthy or not healthy are very blurry, and sometimes people move from one domain to another and back again, and our goal at Neuroscape is to pioneer new approaches to improve cognition across the board for anyone that wants that... That ability to be able to do regardless of whether they're suffering a condition that has a clinical diagnostic label or not. And a lot of the work that we do now are not on clinical populations, most of our papers, if anyone goes to Neuroscape on our website and looks at our publications over the last five years, most of them are on healthy people, often older adults, going back to my expertise in aging, which is really where I began.
0:58:11.6 DG: Even my thesis work in 1990 was on aging. So how do we improve the ability of healthy people of all ages to engage in the world is an important part of our mission, and then the translation of how do you bring that to the world in a way that is validated and appropriate when there's not a regulatory agency like the FDA, really acting as a goalie and not allowing anything through is actually a big challenge. I've seen a lot of things get marketed through non-clinical pathways with over-inflated claims, because there was perceived to be a lack of a regulatory agency that was policing them. It's actually not true. The FTC, the Federal Trade Commission will sue you if you make a claim, even if it's not clinical, as has happened with companies that have put devices out there and claimed improvements that were not validated. So, my answer is in two parts... Just to summarize, one, from a research perspective, we are completely devoted to looking and creating and validating approaches to improve cognition and remember cognition, I'm defining very broadly here in people of all ages with all different baselines, clinical and non-clinical.
0:59:34.3 DG: And then the second answer is, in terms of the real-world implementation outside of the research focus, 'cause I do both of those things, there's still a lot of complexity about how to put these things in the world, either through an FDA clinical pathway or the non-FDA sort of consumer pathway. And we're still trying to figure that out. Everyone's trying to figure that out.
1:00:01.3 PA: That's kind of what I wanted to ask you next actually was... Even a little bit of your top-of-head thoughts or initial intuitive thoughts about the developing psychedelic landscape, right? So we have, as we talked about, MAPS has MDMA in phase three clinical trials, Compass Pathways is now taking psilocybin through Phase 2B, will probably likely start phase three trials soon, and there's a bunch of other companies now that are bringing them through, some legit, some maybe not so legit. So the FDA sort of approval pathway is burgeoning, it's happening, there are hundreds of millions of dollars that are going into that pathway. Concurrently, Oregon has now legalized psilocybin therapy, California has a bill in the legislature to do something similar, Oakland, which is in the Bay Area, has decriminalized all medicines plant entheogens as well as Seattle, Detroit, Denver, etcetera, etcetera.
1:00:48.6 PA: So this sort of brings up the... Even going back to your point, clinical versus now in clinical, and one thing that you really emphasize with the research that you're doing at UCSF is the translational element of it, bridging the gap, and I'm just curious to hear kinda top I had thoughts from you about taking that one step further, how are you thinking about even the experimental research that you're setting up, and it's relevance to the way that psychedelics may potentially roll out from a legal or from a sort of youth case perspective, whether that's underground, that's a decree that's in these states that are legalizing, etcetera, etcetera.
1:01:27.8 DG: Yeah, well, I'll answer that in two ways. The first is that I feel strongly that if you take a path of commercialization that's not clinical but doesn't have FDA regulatory oversight, it's still really important that it's well-validated and that it's monitored for safety and efficacy, it's not any less important because it's not clinical, there are more people that would be impacted than the clinical population, the other population is even larger. And I feel like that has been a big mistake on many companies that have decided to go the non-clinical route, is that they think that they don't need as much research and validation and monitoring. And that is just not true. It should not be true. And so I think it's really important for any group, whether it's a company or a foundation or academic group that's developing approaches to help people that don't have clinical conditions with clinical conditions, it's really clear FDA as a whole pathway. Everyone does the same thing, it's with the non-clinical that you wind up getting a bit of a wild west mentality and it just does not serve us well, and so that is something I feel strongly about.
1:02:44.3 DG: That the high-level validation, monitoring, and constant oversight is critical out of clinical as it is with clinical. If it has the power to help people have the power to hurt people, if it has the power to help people a little bit, it also has the power potentially to help people massively, and so it needs the same level of respect and validation outside of the clinical domain. So that's one thing that... And I often have this conversation completely independent of the psychedelics conversation, it's just what do you do with technology that has the power to induce changes in cognition, but you're not targeting a clinical population, do you not need any data anymore because you don't have the... They, of course, you still need the data so that people know what they're getting, and that you can make sure that it's well-targeted and doesn't have side effects. So that is something that I just wanted to state really clearly, and hopefully, that is happening more and more and I see that happening more and more.
1:03:43.6 DG: In terms of how our work will have a role in psychedelic... I'm gonna use treatments, for lack of a better term here, but both clinical and non-clinical being defined by whether or not there's a diagnostic entity associated with the condition, I think it'll be the same. Again, a lot of what we're doing at Neuroscape with psychedelics is also agnostic to the condition, so all the studies that we're planning right now, Robin and I, Jenny Mitchell, also an incredibly valuable member of our team... She led... She was the first author on the nature of Medicine paper for MDMA for PTSD treatment by MAPS. She's also a neuroscientist and has a great team. The proposals that were written up now are on healthy people.
1:04:35.4 DG: Now we might say, healthy people that are suffering a bit in terms of mood or stress, which is essentially everyone, we are in the middle of a global pandemic, but starting with people like that. A, I think it's the responsible way to start with less vulnerable populations than people that are suffering in an extreme way, and this is with the approach that we talked about, multi-motor bio-sensing, sing and stimulus manipulation. We're new territory here. So we wanna start with essentially people that are healthy, meaning that they don't have a clinical diagnosis to understand how we can predict who's gonna benefit the most, what are the underlying brain mechanisms, what are the different states, as Robin talks a lot about a struggle versus release, we need to understand our whole foundation, the library of levers that we can push and pull to help guide people better, what are all the state changes that occur? This is just in everyone, just in the human brain is really our question right now.
1:05:42.8 DG: Now, of course, there will be more selective targeting to different conditions, maybe autism or PTSD, traumatic brain injury, Alzheimer's disease, depression, but we have to back up a little bit first and understand just how the brain can be... Have a beneficial effect from psychedelics, especially when integrated with these other approaches we're talking about. So if you now fast forward 10 years with school, I like to think in decade increments. Now we're 10 years in the future, Robin's Bihar, UCSF for a decade. Our division has continued to grow, and the approaches that we've been discussing together in terms of multi-motor bio-sensing and sensory immersive deliveries and closed-loop systems are now very advanced, those tools should be applicable both in the clinical domain as treatments under medical care in a hospital, let's say, or a clinic, as well as maybe decriminalized and who knows what, where we're gonna be in a decade, people that are using compounds to help improve their functioning, even if they don't have clinical conditions. I would say that the tools we're creating should be equally applicable to all those different populations.
1:07:01.6 PA: And as a follow-up to that, are these tools that you have something that can be done without a facilitator oversight, so to say. I just think of my own neurofeedback experience, when I did neurofeedback, I had a facilitator there, they had to hook it up, they had to put it in the computer, etcetera, etcetera. How are you developing these tools in terms of the way that they're being used, I suppose?
1:07:23.8 DG: Yeah, right now, they certainly need a facilitator, and that's because we know so little as we've been talking about... So our first studies are deep, deep laboratory dives, tons of recordings where experts are required to both record and analyze, but the goal is that as we understand where we could reduce the number of electrodes instead of like the gear that we use now, we can do it through a ring or a watch, so the future is a more reduced aspect that can be operated without a lot of oversight, but our first approach is like, "Let's just go for it. Let's bring on the highest level of physiological monitoring and computing power and signal processing and all of it so that we can make more informed decisions about how we now reduce those systems to make them more accessible and usable." And so that's our approach that we're currently setting up to do in terms of delivering psychedelics coupled with the technologies we're talking about. And the role of a person is not a person, and that it's something that's still very unknown to me. I see a really valuable role of a person being there, especially in the early phases of someone that's unfamiliar with psychedelics, especially if someone's suffering and not a condition that's really debilitating to them.
1:08:55.5 DG: I view the data that will be generated by our recordings and the AI-guided advice to a facilitator that could then push and pull on these levers as a really exciting implementation, so how... My vision right now, I definitely see a person in the loop. I think it has its own therapeutic value of having someone there that's a human being that's gonna help us all of this fancy technology and these molecular compounds to guide you in an empathic way. But could there be a future where someone could reach a certain stage of safety and experience where they may be able to have sessions after the fact that is not as dependent upon a human expert? Sure, I think it's possible. I think we have to baby step into that, but it makes sense to me.
1:09:54.0 PA: Beautiful. Well, Adam, I'm mindful of time, I know you have a dentist appointment that you get to... At some point along the way, I just appreciate you dropping in for an hour plus and sharing everything that you've shared with us. The density of information that we've covered since what 90 AM this morning has been phenomenal. So I'm just very grateful for your time and your energy for joining us for the show.
1:10:20.0 DG: Thanks for having me, this is a really, really exciting area, and I applaud you for being a leader in educating people, and also so informed. It is so much fun to have this conversation 'cause we could just get real deep... Plus, "So what do you do again?" So I appreciate the time you took, and I hope that your listeners are appreciating that where... When I say we, myself and Robin and Jenny, our team at neuroscience, are excited about the future, but we'll also feel very humbled by how powerful these tools are and our ability and the necessity for us to be really careful, and I still look at this field is something that's very vulnerable. We all know what happened in the past, it could happen again, and so we want to be rigorous and careful as well as innovative and futuristic, and excited. Really trying to run right down the middle of that line is the tight walk that I do, and we all do at Neuroscape. So super excited to have shared it with you and your audience.
1:11:30.7 PA: If they wanna find out more about Neuroscape or you, any sort of places that would be great to check out?
1:11:36.3 DG: Yeah, so Neuroscape has a website, neuroscape.ucsf.edu, if you just search Neuroscape, you'll find it, and there are descriptions of all our divisions, including our psychedelics division with Robin as our director, and our publications are there and podcasts and videos and tons of resources and then I have my own website, gazzaley.com where I used to aggregate across all the different domains. I am a nature photographer as well, I have a lot of things that I bring together on that site.
1:12:08.3 PA: Beautiful. Well Adam again, thank you for joining us. It was an honor.
1:12:12.7 DG: Thanks so much for having me.
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