Berkeley Talks: The future of psychedelic science

[Music: “Silver Lanyard” by Blue Dot Sessions]

Intro: This is Berkeley Talks, a Berkeley News podcast from the Office of Communications and Public Affairs that features lectures and conversations at UC Berkeley. You can follow Berkeley Talks wherever you listen to your podcasts. New episodes come out every other Friday. Also, we have another podcast, Berkeley Voices, that shares stories of people at UC Berkeley and the work that they do on and off campus.

[Music fades out]

Imran Khan: Hello, everyone, and welcome to this special event from the UC Berkeley Center for the Science of Psychedelics. Looking at what else? The future of psychedelic science. My name is Imran Khan, and I’m the executive director of the BCSP. Our role is to explore the potential of psychedelics through research and through education. And today’s event brings together both elements of that mission.

If you’re tuning in today and you follow our work, chances are you’re probably one of the people who already knows about the tremendous potential of psychedelics and the powerful effects that they can have. However, despite a resurgence of interest in psychedelics in science, in medicine and in society, we still know remarkably little about them. For instance, how and why did psychedelic substances first evolve? What effects do they have in human brain and in the mind? And what’s the mechanism behind their potential therapeutic role?

Thanks to the generous support of our donors, scientists at UC Berkeley are now exploring all of those questions and more, and it’s our absolute pleasure to bring a discussion with some of them here today. Over the next hour, you’re going to hear from a number of researchers, including Professor Daniela Kaufer. Daniela is a faculty member in integrated biology and neuroscience at UC Berkeley, and she’s associate dean of biological sciences. Daniela seeks to determine the neural base of human mental health problems, including post-traumatic stress disorder, depression, and looks for new ways to treat and prevent them.

We’ll also have Professor Michael Silver. Michael is professor in the School of Optometry at the Helen Wills Neuroscience Institute at UC Berkeley. I’m delighted to say he’s also my boss, as he’s the faculty director of the BCSP. Research in Michael’s Lab focuses on the brain mechanisms of visual perception, attention, and learning and also now includes the study of the effects of psychedelics.

Our final speaker will be Professor Noah Whiteman. Noah is professor in the departments of integrative biology and molecular and cell biology here at Berkeley. Work in his lab focuses on the intricate evolution in relationships between plants, fungi, and animals, and seeks to answer how and why psychedelics came to be.

But I’m excited to say that first we will have Gül Dölen. Gül is a world-renowned neuroscientist who leads efforts to understand the molecular mechanisms through which the brain engages with psychedelics and to understand how and why they have healing potential. She recently joined UC Berkeley just a few months ago and holds the Renee and U.S. Marine Lance Corporal Bob Parsons Endowed Chair in psychology, psychedelics, and neuroscience. She’s also a senior science advisor to the BCSP.

Gül, you work on a biological concept called critical periods in the brain. Could you kick us off by explaining what a critical period is?

Gül Dölen: Of course. Thank you, Imran. Yeah, I have been studying critical periods for about 20, 25 years, but they were actually originally described in 1935 to describe a behavior that was seen in snow geese. And this behavior is called imprinting behavior. And basically, what it is is that within 48 hours of hatching, geese will bond, form a lifelong attachment to whatever is moving around in their environment.

And typically that would be their mother, but if it’s not their mother and instead it’s a kooky scientist, then they will form that long-lasting attachment either to the scientist or to a flying airplane nearby. But then, after that window of time, that 48 hours passes, they no longer are sensitive to their environment in that way, and they’re no longer able to form those long-lasting memories for that attachment behavior. And so the person who described that was Konrad Lorenz, he was an ethologist, and he called that window of time a critical period.

And since that time, we’ve discovered literally dozens of other critical periods, critical periods for things like language, which will be familiar to anybody who’s tried to learn another language as an adult, it’s very difficult. You always have an accent, and that’s because the critical period for language learning in humans closes around 5 or 6 years old, a little bit later depending on some other factors.

There are also critical periods for organizing the visual system, which maybe Michael will tell us a little bit more about. There are critical periods for sensory systems. There are critical periods for motor systems, and my lab has really discovered another new novel critical period in mice for social interactions. And so this is the critical period that we think describes the reason why children are so much more susceptible to peer pressure than adults are, especially during their teenage years. Why the culture that you grow up in, you’re most familiar with, but if you try and go to another country, the rules of the other social cultures will be unfamiliar to you and difficult to learn as an adult.

And so that is basically an overview of what a critical period is. And neuroscientists have been really interested in critical periods almost since their discovery and trying to figure out ways to reopen them because we’ve had this insight that our inability to address most diseases of the brains while they’re still open is the reason why we’re so crummy at treating diseases of the brain, including psychiatric diseases, but also neurological diseases. So for almost this amount of time that we’ve known about critical periods, there’s been this sort of hunt for understanding the mechanisms. There’s literally something like 7,000 papers and three Nobel Prizes studying how critical periods close, why they close, and trying to discover novel ways to reopen them for therapeutic benefit.

Imran Khan: Thanks so much, Gül, and thanks for giving so many examples of very relatable critical periods we’ve all experienced as well. I’ve heard you say that the psychedelic trip or the psychedelic experience might be the subjective experience of what it actually feels like to have a critical period reopened. What makes you think that, and why could that be important?

Gül Dölen: Yeah, so when we first started working on critical periods, we were focused on the one that we had discovered, the social critical period, and we tried to reopen it using a psychedelic that has known pro-social properties. So MDMA is the quintessential pro-social psychedelic, and it’s sort of different from other psychedelics in that regard.

And when we reopened this social critical period with the pro-social psychedelic, we thought that’s it. That’s what this is about. But later on, we did another experiment, and then we looked at all of the psychedelics that we could get our hands on, a variety of psychedelics. And what we discovered is that whether or not they have this acute pro-social property, they are able to open this critical period.

So LSD, nobody’s doing a 30-person cuddle-puddle on LSD or Ibogaine. And nevertheless, both of those drugs, ketamine also, are able to reopen this critical period. And so what that suggested to us was that this social component of it was a little bit of a red herring, and that the thing that brought together all of the psychedelics was their shared ability to reopen this critical period. And because there were also parallels between the duration of the trip and the duration of the open state of the critical period that the psychedelics induced, it sort of suggested behaviorally phenomenologically that the shared property of altered state of consciousness induced by psychedelics is just what it feels like to reopen this critical period.

Imran Khan: Really fascinating. And I know we’re going to talk to Daniela in a moment about other animal studies involving psychedelics. But before I do, I can’t resist. You talked about MDMA, and you’re also famous for administering MDMA to octopuses and understanding what happens when you do that. Could you tell us a bit about what happens when you give MDMA to octopuses and what that reveals?

Gül Dölen: Yeah, so when we did that study, we were really jumping off of an old idea in neuroscience put forth by JZ Young, that if you want to understand how to build complex behaviors from synapse circuits and molecules, really rather than just focusing on always doing comparisons to nearby species, you should look for species that are maximally different and yet capable of this behavioral complexity that we’re so familiar with in humans. And so by doing that, he argued that you could avoid making logical errors about what’s necessary and sufficient that we’re really just accidents of evolutionary history.

And so we took that approach with the octopus because octopuses are capable of really complex behaviors, and yet our last common ancestor was over 650 million years ago. And so what we were surprised and delighted to find is that MDMA, even though it’s a totally synthetic compound, I’m sure Noah has some thoughts about this, was able to interact with the serotonin transporter in the octopus brain and produce basically the same type of behavioral response, a pro-social response in an animal that doesn’t have any of the brain regions we had previously implicated in the function of psychedelics in mammals.

And so this sort of radically shifted my way of thinking about psychedelics in the brain away from circuit-level or an anatomical-level explanation to really trying to understand what are the commonalities between our brains and an octopus brain that could account for this similarity in the behavioral response. So, namely, molecules.

Imran Khan: Yeah, that’s really fascinating, and I hope we’ll get time in the Q&A to delve into that a little bit further. But now I’m going to move on to Daniela Kaufer. Daniela, we were talking about how your lab works to understand how stress impacts the brain, including in disorders like PTSD. Could you start by defining for us what stress is? And also, I’m curious, I feel like often we talk about stress as a negative, harmful thing, but clearly it wouldn’t exist if there wasn’t something valuable about it. How do you think about that?

Daniela Kaufer: Yeah, thanks, Imran. My favorite topic, except for psychedelics, is to talk about stress. And I’ll say, like Gül said, I started studying stress about 30 years ago, and then it was surprising that stress has a biological basis to it. Now, I think it’s not any more surprising to anybody.

So we know that it’s a natural response to a threatening situation that happens in our environment. It involves a very complex network of biological reactions in the brain and in the body. There are areas in the brain and circuits in the brain that are being activated. And then there’s a series of hormones that are released. We probably recognize most of the names, adrenaline, noradrenaline, cortisol, even oxytocin, the pro-social hormone that Gül talked about some of the things that might do. Even that is actually triggered by stress, and it leads to a very wide range of physiological responses and orchestrated response.

Actually, every cell in our body has the receptor for one or more of the stress hormones. So our whole body responds to that. And indeed, prolonged or traumatic stress is mostly what we think about when we think about stress is bad for us, and that could be harmful, it could have long-lasting effects. It could even lead to post-traumatic stress disorder, but it’s also a vital response.

And without that response, the organism does not survive. So it’s a very crucial response, and it’s a response that helps us live through an experience. But more than that, actually some stress, and on some people, there’s a very big inter-individual variability in the responses to stress. So stress that is not a very severe stress will help us towards stresses that come later on, it’ll actually boost our behavior, it’ll boost our cognition, and will let us do better with stresses that come later on.

My lab studies all sorts of mechanisms, molecular and cellular mechanisms that are involved in that. We have found multiple things that are involved in that. And the main one is that non-neuronal cells. So we usually think about the neurons, and we have found non-neuronal cells, glia, that are involved in the responses both for the beneficial effects of stress and the lasting, less beneficial effects of stress.

Imran Khan: Could you explain to the audience the difference between a glial cell and a neuronal cell?

Daniela Kaufer: Yeah. Neurons are the cells that connect to one another by electrical connection. And a lot of times when we say brain and when we study brain, we study the neurons and neuroscience, and the world of neuroscience has been very neurocentric, so we focused a lot about the neurons. Really, there are no more than half of the cells in the brain, maybe even less than that. There’s other cells, and those other cells are supporting the effects of neurons.

For many years, they were thought about the cleaning up crew, the support cells, but now we know that they’re the ones that drive a lot of function in regular brain function, in diseases, and our new and exciting world of resilience that we are studying, we have a new center for the study, Neuro AI study of resilience shows us that glia actually drive those things. They drive trajectories towards resilience or vulnerability.

Imran Khan: Thank you. And we were talking about how you’ve started looking at the mechanisms of how psychedelics might alleviate some of the stress-related disorders you were talking about. Are you starting to have a theory of how psychedelics are doing that? It’s very much been in the news, and how might we test some of those theories?

Daniela Kaufer: Yeah, so we started looking at animal models, and we’re looking at acute effects so far of the psychedelics, focusing on those molecules Gül mentioned, serotonin and the serotonin receptors that we know that psychedelics bind to. Those same receptors are expressed not just in the neurons but in the other cells as well, in the glia. And we know that the glia is very important for the stress responses. We know from clinical trials and for anecdotal reports that PTSD could be helped by psychedelics.

And so we decided to look at mechanisms, understand mechanisms in normal brain, and understand mechanisms in the interaction with stress. And when we did that, we realized that psychedelics actually directly activate those non-neuronal cells called oligodendrocytes. They increase calcium in them, calcium influx, they increase synchronization of those cells with one another and change myelin production. So myelin plasticity goes up, and that seems to be important for some of the effects of psychedelics. So that’s a novel way of thinking about what psychedelics might do in the brain, a different route.

Imran Khan: Fascinating. And we were talking earlier that you might be thinking about some dream experiments you’d love to do in terms of psychedelic science. Could you tell us a bit more about that?

Daniela Kaufer: Yep. So, yeah, dream experiment. This comes from something that happened in the world that I did not think to ask ever. On Oct. 7, there was a party in Israel, during the party where a lot of people actually had been consuming psychedelics, and on a psychedelic state, they were exposed to a terror attack. About a couple of thousands of people were there, many, many dead, many hundreds of dead, and many did survive the effect.

And it brought to mind something that I’ve been thinking about psychedelics from the point of view of how do we help PTSD, I’ve never thought about exposure of trauma during a psychedelic state. And so that became both an immediate need for the survivors and not understanding how to treat them because we don’t know about that state. We just don’t know what might happen to the brain. And also, a really interesting understanding that can come from that of the human mind of observing the brain’s plasticity in a very extreme state, very, very extreme state when both of those things happen together. So that’s an experiment that we’re now running on animals.

Imran Khan: Yeah, thanks, Daniela. And obviously, a different side of the stress equation when it comes to psychedelics, and all of our thoughts are with everyone who continues to suffer from the after effects of that attack. Michael, I wonder if I could come to you next. You work on the how our brains construct our visual experience of the world around us. I wonder if you could tell us a bit about how that works. We all know that light enters our eyes. What happens after that?

Michael Silver: Thank you. It’s actually very counterintuitive what happens after that. Our everyday experience is that we just very directly perceive the world around us, but this is actually an illusion that’s created by our brain. And on the one hand, the information that enters our brains through the retina is quite impoverished.

For example, there’s about one million cells that project from the retina to the rest of the brain. So if we were a digital camera, that would be perception should be about one megapixel resolution. And obviously, we experience the world at a much higher resolution than that.

So this heightened resolution of our visual experience, it doesn’t come from our eyes. It’s rather constructed by our brains in a way that is informed by our prior experiences or the visual experiences that we’ve had. On the other hand, if we consider visual information not at the level of pixels but rather as objects and features in the visual world, this kind of information entering our brain is impossibly vast.

There’s no way for us to process it all in detail. And so we’ve evolved ways for our visual system to highlight certain objects and features in the visual world for specialized, preferred processing. And this highlighting process is affected by what part of the visual environment is most relevant and important to us at any given time. And so that, in turn, is also informed by our prior visual experiences about how we come to learn what’s important.

So all these observations together have led to a theory of brain function where the brain generates visual experiences through a process of inference, which means that it internally generates models of the world around us, and it continually updates these models by comparing them to incoming sensory information. And the brain’s internal models are shaped by the visual experiences we’ve had throughout our lives that have taught us about regularly occurring patterns in the visual world. So in the context of the brain’s internal models, these previous visual experiences are referred to as priors.

Imran Khan: Thanks, Michael. And you were talking about how there’s a real felt sense that our eye works like a camera, and it’s an illusion, but it’s a really compelling illusion. It really feels like we’re perceiving the world as it is, rather than that being something that’s constructed in our brains. Could you tell us a bit about how you’re using psychedelics to better understand that process of how the brain is constructing our experience from moment to moment?

Michael Silver: Of course, yes. Robin Carhart-Harris, who’s currently at UCSF and is affiliated with the BCSP, together with Karl Friston, created a theory called the REBUS Theory. And this theory aims to explain the effects of psychedelics in the context of the brain generating these internal models of the world around us and also internal models of ourselves.

So REBUS is an acronym for relaxed beliefs under psychedelics. And the theory postulates that psychedelics reduce the influence of priors on how the brain generates our conscious experiences. So in our studies in the BCSP, we’ll be testing the REBUS theory in the visual system in the brain, which we understand quite well compared to many other brain regions and brain systems.

And our study will involve administering psilocybin to healthy human subjects to measure its effects on visual perception, while at the same time measuring processing of visual information in the brain with functional magnetic resonance imaging, or FMRI. And this study will use visual stimuli that can be perceptually interpreted in two different ways.

One of these interpretations is informed by visual priors, and another is more like a raw sensory interpretation of the world. And in this case of the stimulus. So with less influence of priors. And if the REBUS theory is correct, then we’ll observe a shift in the brain’s processing after administering psilocybin. And also a shift in conscious experience, both of them shifting towards the raw sensory interpretation. So something like opening the doors of perception.

Imran Khan: People are going to be in an FMRI machine, some will be under the influence of psilocybin, and you’ll be trying to understand how that psilocybin changes the way in which their brain takes input from the eyes and constructs the world they’re actually experiencing.

Michael Silver: Correct.

Imran Khan: So if that turns out to be true, that is the way that psilocybin is working, it’s changing the influence of our brain’s priors. What are the implications of that for the therapeutic role of psychedelics?

Michael Silver: So a big part of the reason that the REBUS theory has been so influential is its implications for understanding better how psychedelic-assisted therapy might work in the brain. So we’ve all heard about really exciting and inspiring results from clinical trials of psychedelic-assisted therapy for PTSD, depression, substance use disorders, etc.

But we really, at the moment, have very little understanding of the brain mechanisms of psychedelic-assisted therapy. And the disorders that have been effectively treated, they seem to have in common these negative feedback loops in which patients develop a conception of themselves and narratives about themselves that are linked to their disorder in an unhealthy way.

So for example, someone with depression comes to believe that I’m a depressed person, I’ll never be able to achieve my goals in life and having those beliefs and the consequences of them worsen the depression. And so within this REBUS framework, those kinds of beliefs are a type of prior, a preconception, that, in this case, affects how the brain constructs one’s experience of themselves, including self-identity.

So for people suffering from PTSD, depression, and so forth, those kinds of priors are maladaptive, and reducing the influence of those priors with psychedelics together with the appropriate therapeutic environment could enable people to construct different and healthier priors about themselves.

So it’s a really exciting theory, currently very difficult to test in the human brain because we have so little understanding of how the brain creates constructs such as self-narrative and self-identity. In comparison, our understanding of the visual system is much more advanced.

And so our initial studies at the BCSP, were taking the conceptual heart of the REBUS theory and then using the visual system as a testbed for the basic predictions of the theory at the level of neural mechanisms. And then, through our research, we hope to gain basic understanding of the actions of psychedelics in the visual system, which then can be extended to other parts of the brain.

Imran Khan: Michael, you talked about some examples of priors that people might have in the context of mental health. Could you give an example of what a visual prior might be? How might that not work in the visual cortex?

Michael Silver: So visual priors in general are implicit and unconscious. We’re not even aware that we have them. So they’re priors about, for example, interpreting the patterns of shadows and objects in a scene, taking into account the type of illumination or where the illumination is coming from.

So the famous dress illusion, where the same dress in the photograph could be seen as blue and black or gold and white, that really comes down to people’s unconscious assumptions about whether the light in that photograph is coming from within the store or through the store window from the outside. And once you make that assumption, then the ambiguity that’s intrinsic in the image disappears, and you have one very stable perceptual interpretation.

And when you’re having that interpretation, there’s no room for the other interpretation. That prior is dominant at that given moment. We also have priors that are very simple, such as an object that’s moving will continue moving in that same direction, or objects that are in a certain location are likely to stay in that location. So these are all very regular and reliable patterns in the world that the brain can take advantage of to reduce computational resources. So it doesn’t have to re-derive the visual scene over and over again.

Imran Khan: And building on that, Michael, people often report that under the influence of psychedelics, they experience visual distortions, changes in how they experience the world. How does the model you’ve just outlined, including the influence of visual priors, explain why those visual distortions under psychedelics might happen?

Michael Silver: At first glance, it doesn’t. So from people who’ve had psychedelic experiences or studied them, the REBUS theory seems very counterintuitive. Psychedelics distort our visual experiences, they cause hallucinations. How would hallucinations be a result of a reduced influence of priors in the brain? It seems like it’s enhanced internal processing and really visual processing that’s causing a misperception of the world.

I think the explanation arises from this fact that we get so little information from our eyes compared to the richness of our visual experience. Our brain fills in the gaps and uses priors to make its best guess about what’s in the world around us.

So in our everyday life, we unconsciously are making these assumptions about the visual world to construct these experiences. So we have visual priors, for example, that trees don’t have faces. Faces are for people and other animals. So even if the individual features in a tree resemble the eyes, nose, and mouth of a face, we see it as part of the tree and the pattern of bark.

And because our prior is telling us, well, that’s what that pattern is, it’s much more likely to be bark on a tree than a tree having a face. But with psychedelics that are reducing the influence of these priors, maybe we now will be more likely to entertain the possibility that there is a face in the tree. And seeing faces in plants and inanimate objects is a classic visual effect of psychedelics.

So you can think about that as a manifestation of the reduction of the influence of that particular prior. So in that sense, psychedelics reducing the influence of the brain’s priors, it allows us to broaden the range of possible perceptual interpretations that we have. And so, that can lead to visual distortions and even hallucinations.

And broadly speaking, this fits really well with known effects of psychedelics enhancing creativity or enhancing cognitive flexibility. It also, I think, fits very nicely with the idea that psychedelic-assisted therapy is broadening people’s narratives about themselves that they consider, and that enables them to heal in a way that allows more healthy priors to be established.

And so the work of the BCSP, we hope that we can establish a neurobiological-based framework for studying the effects of psychedelics in the human brain, and then to use this framework to ultimately better understand how psychedelic-assisted therapy works, and that eventually will lead to development of more effective and precise therapies for treating mental health disorders.

Imran Khan: Thanks for explaining that, Michael, and also for really showing clearly how we see with our brains, not necessarily just with our eyes. Noah, I’m going to come to you now. You study evolution, and many people ask why is it the case that psychedelics evolve, but I wondered if we could start by talking about other substances. There are many psychoactive drugs that humans use, nicotine, caffeine, cannabis, that are synthesized by plants and fungi. Why do those chemicals occur in nature?

Noah Whiteman: Yes. Thanks so much for having me here and for asking that question, which is my favorite question. And I have this image here of a book I just wrote that covers some of these topics, in case people are interested. And I thought I would attempt to answer your question in part by showing you some illustrations from the book.

And the first one shows us a visage that includes nicotine, which is, of course, a nicotinic acetylcholine receptor target. And this is produced by plants and the tobacco lineage, along with other members of that family. And we have to think from the plant’s perspective as to why it would make this from an adaptive value. It’s certainly not making it for our benefit. And it evolved, the ability to make a drug like nicotine evolved tens of millions of years before humans were around. And so we can’t understand the origin of nicotine from our perspective.

We have to look at it from the plant’s perspective. And it turns out that nicotine is a potent natural insecticide. So the tobacco plants evolve to make it because it benefits them in the presence of enemies like caterpillars. Now, there are some caterpillars that have evolved the ability to sequester, to take on nicotine and use it as a weapon, like this tobacco hornworm that can secrete it through its spiracles and sort of prevent things like that wolf spider from predating it.

And so the book that I wrote looks at the ultimate origins of these chemicals that are found in nature, and we have to think, from the perspective of natural psychedelics, think about that too with them. Why would a mushroom, why would a toad, why would a vine, a tropical vine, make a chemical like that?

Imran Khan: And so you are saying, Noah, that from the plant or the animals’ perspective, they’re creating that chemical for their own defense and their own benefits. How could it be the case of those if they evolved to be harmful, they ended up being beneficial or perhaps even pleasurable to humans?

Noah Whiteman: One thing to think about is that we’re animals, too. And even though we are special in many ways, we share nervous systems with things like flies. There’s probably one origin of the nervous system in animals. And so the way that those neurons operate, the way that the brain operates in many ways is similar across all of these species.

So, for example, another example would be caffeine. That is a great natural insecticide that acts on the adenosine receptors of everything from insects to humans. And so humans have tapped into that to use these things as tools, but that is not why they evolved. And we should always remember that I think when we’re thinking about these things.

But the pharmacopeia, the modern pharmacopeia, maybe half of all chemicals we use as drugs arose as natural products and plants, fungi, microbes, and animals. But they did not make those things for our benefit, right? We’re tapping into them secondarily, and one example are tannins that are produced by oak trees in response to a little wasp that makes a gall. And this iron oak ink, that was the main way that people wrote documents, including the constitution, Declaration of Independence, the iron oak gall ink was used to make those documents, and those tannins evolved to protect the oak plant from attack. So that’s another example.

Imran Khan: Fascinating. So I wonder if we could start to apply this to psychedelics. As obviously many of the audience will know that psilocybin, for instance, comes from fungi, mescaline is found in cacti, DMT is found in a range of different plants and animals. How do those substances fit into the theory you’ve just talked about?

Noah Whiteman: Well, I think actually this is a big unanswered question and something that my lab and others are interested in. And you can see where my line of inquiry will go in that things like, in this case, psilocin, which looks a lot like serotonin, the neurotransmitter, is produced by mushrooms in the genus psilocybe as well as many other genera, actually, or have the capacity to produce this.

And you’ll note in this drawing that Julie Johnson made, she also included a pleasing fungus beetle, the little ladybird-like beetle on the top and a fungus gnat that’s flying around and sort of on the bottom of that mushroom. And so one hypothesis is that the mushrooms are producing these tryptamine alkaloids as a way of manipulating animal behavior. And often the sort of idea is that these are also defenses, chemical defenses. And so to start thinking about that, it turns out something very interesting happens when a psilocybin-producing mushroom is wounded either physically, say you took a little pin and ran it down the side of the mushroom, the mushroom would start turning blue.

And this is just showing another beautiful, pleasing fungus beetle eating a different kind of mushroom that also turns blue. And there’s this so-called bluing reaction. This is showing a mushroom cut in half, a psilocybin-producing mushroom cut in half. And what you can see is the blue reaction that is occurring there. And for many years, it was speculated that the psilocybin and its derivatives were actually causing the bluing reaction.

But recently, scientists in Germany discovered that the mushroom produces enzymes that immediately transform the psilocybin into the active form psilocin with the phosphatase. And then there’s a lacase that oxidizes that psilocin and turns it into a set of linked psilocin oligomers that actually form a blue color, have a blue chromophore, much like indigo, and actually much like the tannin I showed you before. And the hypothesis is that as soon as an insect would start chewing on the mushroom, instead of getting a dose of psilocin, it would immediately get a dose of this blue compound in its gut, which probably acts as a toxin.

And so the idea is that the psilocin is perhaps not the actual evolutionary sort of product of this arms race between fungi and animals. It’s one of the beginning steps of a cascade that eventually results in a toxin. And so many toxins work like this, from cyanide to mustard oils.

And so it’s not surprising to me if this would be the case that it just happens be sort of a consequence, not a cause, that the psilocybin is something that is active in our brains that if you were from taking it from the mushroom’s perspective, it would tell you that, well, no, this is part of a chain of things that is required to make actually a defensive chemical. And I think this is surprising to a lot of people and something that we need to test. And so I can talk more about that too, if you’re interested.

Imran Khan: Yeah, please. How would you go about testing a theory like that? So the theory is that from the mushroom’s point of view, it’s trying to defend against beetles, where are the members of the animal kingdom?

Noah Whiteman: And this next slide is sort of taking it from a broader perspective because we know that plants in this case, Phalaris aquatica, which is, Phalaris is a genus of grasses that are actually growing in many people’s backyards, hedgerows, fields around the world. And these plants produce DMT and 5-MeO-DMT as well as other tryptamine alkaloids that are very much like psilocybin and are found in things like ayahuasca, and Sonoran toad venom, and things like that.

And what’s interesting about this is that when sheep graze on pastures that contain these plants, they end up getting something called the Phalaris staggers, where they kind of stagger around, they’re lethargic, they have seizures, and some die from eating these plants. And for many years, people tried to figure out what the cause of the mechanism was. And it’s still a little controversial, but it seems that the tryptamine alkaloids that are produced by these plants in pretty high quantities, including some of the DMT and 5-MeO-DMT chemicals, may be causing this in very large doses, directly or indirectly.

And so the mechanics of this are still a little unclear. The same phenomena has been observed in kangaroos that are also feeding on Phalaris grasses in Australia. So to get at this, whether and how these things are toxic or not, we propose to use the fruit fly, the Drosophila fruit fly, which is the venerable genetic model animal that has had the entire brain mapped. So every neuron, the connections between neurons are known. This is the first sort of complex animal where this has been sorted, and we can feed these flies particular amounts of chemicals, and that is kind of the way that we would do this. And then try to understand both what happens to their brain but also to their body. Are these things toxic, and how?

Imran Khan: Very cool. Thank you so much for outlining that, Noah, and raises so many more questions about our relationship with these substances and the organisms that produce them. So thank you.

We’re going to be going to a Q&A shortly. I know there’s already been questions filtering in from the audience, but I also know that the panel members, they’ve got such diverse research interests, but they definitely overlap with each other, and some of them might want to ask questions of each other, too. Michael, I wonder if I could come to you first.

Michael Silver: Yes, I have a question for Gül about the octopus research. Just a stunning result that creatures different from each other as octopuses and humans have this fundamentally similar response in terms of social behavior after MDMA and that they socialize more with each other and come closer to each other.

And I’m curious about this because species seem to vary so much about how much they innately socialize, with some animals pair bonding for life and others in big groups, and others solitary. And I think the octopuses that you were studying were quite solitary in general, and probably they evolved to have that solitary life that was advantageous to them.

So I’m curious how you think about this in terms of evolution that why would an animal that has evolved to be solitary have this hidden mechanism for becoming more social with MDMA?

Gül Dölen: Yeah, thanks, Michael. Actually, that is very much one of the motivating problems that we were trying to address. Octopuses are asocial, as you mentioned, there’s only one known species that has sociality, and actually, its sociality is similar to human sociality in that it has both the pair bonding and the group sociality, which are sort of unique in that one species.

The rest of them, including octopus bimaculoides, which is the California two-spot octopus that we did the MDMA study in are asocial, aggressively asocial. They’ll kill each other if you put them in the same tank without anything else. But even that aggressively asocial species will suspend asociality during mating, so at least bimaculoides. So we think that that means that it has neural circuits available for sociality, and for whatever reason, that behavior is suppressed outside of the reproductive window. Now, it could be the other way around, but we also suspect it’s that way because octopuses, compared to all other cephalopods, are the only group that is mostly asocial.

So other cephalopods, like squids, and nautilus, and cuttlefish, they’re all mostly social. And so it suggests that there’s something about the transition to the benthic lifestyle and maybe something about territoriality that is driving or influencing this adaptive asocial lifestyle, especially because the one social species that we know of, the larger Pacific striped octopus, doesn’t live in the intertidal and as much of a benthic lifestyle and is instead in the deeper open ocean. So these are all testable hypotheses. That’s kind of how we started on this.

But honestly, now that we’ve had this about psychedelics and octopuses and the insight about critical periods, we’re really more interested in trying to understand, use octopuses to understand big questions like why do critical periods exist? Why do they close? Why are there mechanisms available for reopening them? And we think the octopus has a number of advantages to let us ask those sort of higher-order questions because we don’t know if they have a critical period. We don’t know if they have the same mechanisms that encode them if they do, but we do know that they do have the ability to sense MDMA at the very least. So it’s a really amazing tool that we can use to ask these higher-order questions.

Michael Silver: Very cool. Thank you.

Imran Khan: Daniela, you were talking about the research that you wanted to do and hoping to do regarding the experiences of people who were having a psychedelic experience when they suffered severe stress and trauma in the terror attacks in Israel. A number of people in the comments have asked to know more about that research and how they can find out more. Could you say a bit about the direction of that research and where people might be able to go?

Daniela Kaufer: Yeah. So clearly, it’s not published yet. We are doing animal work on that. I know that there are groups in Israel that are working with the survivors and collecting human data. I saw that somebody asked if that actually could be beneficial as well, being exposed to trauma while in the psychedelic state. And when we started the experiment, it was open. It could have been anything. You usually start and you have a hypothesis. It’s going to go this way or that way. My hypothesis was it could go either way. It could be that exposure to trauma on psychedelics is actually beneficial for the stress response and for the survivability and even for PTSD trajectories after that.

And it could be that it actually worsens that because of this heightened plasticity of both situations. And interestingly, the answer seems to be both in the individuals that survived it and in our animals, both. There are animals, and there are people who say they actually fared much better, and they were able to run faster and go through the situation in a heightened state that helped them survive, and that they’re doing better afterwards. And we see that in some of the animals. And then we see individuals who actually have very severe stress response and PTSD-like symptoms, and we see that in the animals.

Imran Khan: Gül, thank you. I’m sorry, Daniela. Thank you for sharing that. Gül, there’s a question which I think is squarely for you. Someone asked, after taking a psychedelic, for instance, MDMA, does the critical period drop off right away or does it stay open for a while? How does that vary between different psychedelics? And perhaps if you could also talk about the implications of that for the therapeutic value of psychedelics, that’d be really great.

Gül Dölen: Sure. Yeah. So one of the big insights that we had by trying to understand how psychedelics are working in a therapeutic context from our studies of critical periods is that the critical period reopening that we see across psychedelics lasts for a long time, but that it’s completely variable and proportional to the duration of the psychedelic trip duration, right? So if you have a psychedelic that produces a very short trip like ketamine the the critical period, which lasts about 30 minutes to two hours, the critical period open state is also sort of short, 48 hours by four days, it’s already coming down.

Whereas the very long-acting psychedelics, so things like Ibogaine, where the trip lasts 36 to 72 hours, then the critical period seems to stay open for at least four weeks, maybe longer. We didn’t really test further out than four weeks. And so that proportionality between the duration of the trip and the duration of the open state of the critical period tells us that, first of all, it suggests it’s more evidence to support this notion that what it feels like to reopen critical periods is just what it feels like to be in that altered state of consciousness.

But also, it really sheds light on maybe some missed opportunities and also some things that we need to be careful about in the design of clinical trials, right?

So if it’s true that the therapeutic effects are in part because we’re returning to this state of susceptibility, and vulnerability, and ability to learn from our environment similar to childhood, then if we just focus on the day of the trip and don’t instead also focus our therapeutic efforts on those weeks after where the critical period is presumably still open, then we’re missing the opportunity to really integrate those insights that happen during the trip into the rest of the network of memories that are supporting those learned behaviors. And so that’s the missed opportunity.

And then the caution is that we don’t want to be opening up these critical periods and then, for example, returning people to a traumatic environment or exposing them to potentially bad actors like Charles Manson.

So we want to very careful about the way that we take care of patients after they’ve been in this open state of the critical period. And I think there’s a lot of anecdotal evidence to suggest that indeed patients are in a sort of prolonged vulnerable state, and that the same way that we protect patients, say, after a heart attack, where we say, okay, your muscle tissue is going to be very fragile for several weeks afterwards, you really need bed rest and you need to take care. We need to be applying that same sort of rationale in the context of reopening these critical periods and returning people to this vulnerable, suggestible, childlike state.

Imran Khan: Thank you, Gül. And I do want to take the opportunity to say, you’ve mentioned the risks and the potential harms of psychedelics, that the BCSP does have a public education mission, as well as trying to explore the potential benefits and opportunities relating to psychedelics research. We also want to make sure that the public at large know about the risks and the harms and how to reduce this potential risks and harms, particularly as more people come into contact with psychedelics. And if you want to know more about risk and harm reduction, please do visit our website at psychedelics.berkeley.edu.

Michael, I wonder if I could come to you next with another audience question. Someone made the comment that they’re fascinated by the way the brain constructs or predicts our visual experience. When her mother was declining due to dementia, her eyesight also suffered, and she was unable to see new brands or new items in the grocery store that she’d not previously purchased, but she was still able to see familiar brand items. I know that’s kind of a bit beyond what we’re talking about today in terms of psychedelics, but would you like to talk about that in terms of how you think about that as a side to studying the visual cortex?

Michael Silver: Absolutely. Yeah. This is, I think, priors being observed in the context of diminished sensory information. And so this person was probably seeing familiar items that were more consistent with priors and less able to see new items that were, in some ways, not represented by priors. And so, I think it fits very well. And just in general, that’s the value of priors is that it enables us to efficiently perceive familiar and predictable kinds of situations.

And then there are cases in which it goes wrong. And so most visual illusions come down to the brain having a prior that it is sort of stubbornly imposing an interpretation of a visual image that’s been designed in order to produce this illusory perception. And so it’s kind of the exception that proves the rule. Most times, priors are very helpful for visual perception, but visual illusions reveal the mechanisms. And so I think it’s not an illusion per se, but it’s an example of that where the ones that are most familiar and most reinforced by the priors are dominating conscious experience.

Imran Khan: That’s really helpful. Thank you, Michael. Noah, we’ve got a question for you. Someone wants to check. Is it generally the case that across psychedelic plants that most of the compounds that have psychedelic effects are just consequences of what’s under selection in an arms race in the plant or the animal kingdom?

Noah Whiteman: Yeah, I would say that’s the general null hypothesis that these things all evolve long before people were around. And for example, plants also use serotonin as a very important signaling molecule in many of their tissues. And for example, if you feed fruit flies serotonin, what happens to them? Well, they eat less, they move less. This would generally be a good thing from the plant’s perspective, right? Because the enemies would be sort of dissuaded from eating is the general idea.

But I do think that these are still hypotheses that need to be tested, and the way to do that is to knock these pathways out or put them in organisms that normally don’t make them, over express them, like for example, in plants that normally don’t make them, and see what happens to the plant. Does it get eaten even less? Does it get eaten more? But yes, I think in general, the idea for the person who is watching is that these are serving some adaptive function for the organisms that are making them.

One big hint, as I said with the Sonoran Desert toads, with those big parotid glands behind their eyes, many toads that are in people’s backyards, if you grab that toad, it will secrete toxins out of the parotid gland. And very often, they contain cardiac glycoside heart poisons that are very bitter, but they’re also very emetic. So the organism would vomit if they came into contact with them. And those are the same kinds of chemicals that are in monarch butterflies that they get from milkweed plants, and they’re using them, the monarchs, as defenses against birds. So monarchs are toxic. They contain about as much cardiac glycosides as a pill of digoxin would that would be used to treat congestive heart failure.

So we look at the Sonoran Desert toad, which has tryptamine alkaloids in its parotid glands, including 5-MeO-DMT. That is not there for our benefit. Those are probably there to keep enemies at bay. And just exactly how they work in those animals that would encounter them is an open question and a very important one, I think, that gives us a lens to look at these things not as gift from the gods but instead as natural products that evolve without us involved in the equation. So, yeah.

Imran Khan: Noah, I’ve heard some people speculate that maybe it is humans that are targets of some of these compounds, that maybe psilocybin is the way that mushrooms influence humans to facilitate the growing of more mushrooms. What would you make of that theory?

Noah Whiteman: Yeah, I think that’s true for a potato, just as it is for a psilocybin-producing mushroom, that humans, our plants, our animals, our fungi, we like to think of them as ours, right? And when the domestication process starts going on, then definitely there’s more of a co-evolutionary dynamic where each is dependent on the other for those particular lineages that we’re bringing into the fold. But these things, Sonoran Desert toads, they would be just fine without people. The wild psilocybin-producing mushrooms would be just fine without people. We may be enhancing some of their fitness, but I think that part of it it’s not like its corn, right? It’s not like it’s a pig. It’s not like it’s some kind of domesticated organism per se.

So I would say locally, maybe yes, there’s some enhancement of the number of individuals, but in other cases, in the case of the Sonoran Desert Toad, for example, it could be a problem. I mean, these things are very limited in their distribution. If people are seeking them out for using them and the 5-MeO-DMT in them, that can be a problem from a conservation perspective too. So you could make the opposite argument, actually. I think a better way to think about it is that we are tapping into these things like we are to many of the other natural products that we need now in order to sort of live our lives how we imagine that we should be living them, which is healthy, longer, etc.

Imran Khan: Yeah. Thanks, Noah. Michael, there’s kind of a meta question for research, which I’m going to throw your way. Someone wanted to know how the submissions to the UC Berkeley Human Research Protection Program dealt with the research protocols that are coming forward, and in terms of whether people in those bits of university and research bureaucracy understand the risks and benefits of psychedelics research. Talk a bit about what it takes to get a human-subject psychedelic research study up and running and what you’ve learned through that process.

Michael Silver: So this kind of work is highly regulated, this kind of work meaning work with controlled substances in human subjects, as it should be. There are real risks, and those risks need to be justified by the potential benefits either to the participants in some of these patient studies or to the expansion of scientific knowledge that has benefits for people in general.

So all of these studies are subject to FDA approval, and so they go through the same review process that any clinical trial for a new drug that would, for example, be introduced by a drug company would undergo. Every university has an institutional review board that reviews all human subjects protocols. And I think that’s what the question is about here. The state of California actually has a separate review panel for experimental protocols that involve controlled substances. So all of these agencies need to review the protocol in detail for safety, confidentiality, any concerns about what the patients will undergo in terms of the experimental procedures.

And so our experience with the Berkeley Institutional Review Board has been very positive. They clearly took it very seriously. This work has not been done in our campus before, and so they brought in outside physicians to review the protocol.

But I’ll say also that we are building upon a lot of work that came before us in developing clinical research protocols for work with psychedelics and, most obviously, at UCSF. So a number of members of our study team have joined appointments within the BCSP, but also at UCSF. And so they have a lot of experience doing work, specifically the MDMA for MDMA-assisted therapy for PTSD and also psilocybin research. So their expertise has been invaluable for us to be able to develop our protocol and our infrastructure here so that we can conduct this research in a rigorous and safe way.

Imran Khan: Thanks, Michael. We are almost out of time. I think there’s time for one last question, which I’m going to throw towards Gül. Gül, someone wanted to know that there’s a focus in some of the literature when it comes to psychedelics on neuroplasticity, but drugs of abuse, also known to induce neuroplasticity. Could you just define briefly what neuroplasticity is and why psychedelics are different when it comes to potentially being able to provide therapeutic outcomes?

Gül Dölen: Yeah, so the word plasticity just gets thrown around a lot. It was actually first coined over 100 years ago to define changes that were happening at the molecular level that weren’t necessarily visible. Neuroscientists who study synaptic plasticity really focus on response properties typically recorded from electrophysiological whole cell patch clamping type of recordings. Again, neuron-specific responses.

And as we have sort of correlated those synaptic responses to other changes that happen at the same time, there has been a broadening of the use of this term to include changes to the shape of the neurons, changes to the physiological responses of other cells in the vicinity, like glia, bigger changes at the level of oscillations and blood flow. And clinicians go all the way too far and basically use plasticity to refer to anything that changes over time, which I think when you broaden the definition of a word too much, it sort of loses meaning.

When I talk about plasticity, I try and reign some of that in by specifically focusing on subsets of plasticity. So I define metaplasticity, and I define hyperplasticity. And the reason I’m so focused on differentiating those two things is that I think that this general sense that we have that more plasticity is good, is misleading. And just like in cancer, not all growth is good growth. Sometimes it’s cancer.

Similarly, with plasticity, sometimes too much plasticity is what is thought to be responsible for some of the addictive properties of drugs of abuse, as is mentioned. Others have also noted that there’s too much plasticity in cancer. Others have noticed that some forms of intellectual disability and autism reflect too much plasticity.

And so for those types of too much plasticity, we talk about hyperplasticity, whereas what psychedelics really seem to be doing is not hyperplasticity, but instead restoring the ability of the brain to induce plasticity. So this metaplasticity literally means the plasticity of plasticity and reflects the recognition or the understanding that as the brain matures, in your young brains, plasticity is easy to induce, probably because of subthreshold receptor responses, but as the brain matures, it gets harder and harder to induce plasticity. And that metaplastic downregulation is one of the mechanisms that’s thought to be involved in closing of critical periods.

Imran Khan: Fantastic. Thank you so much, Gül. Sadly, we are at time. I’m sorry we couldn’t get to all of your questions, particularly some of the questions about direct clinical or therapeutic roles of psychedelics. We’re not able to supply clinical advice, but I hope you can find more information at the BCSP website at psychedelics.berkeley.edu.

I just want to say a final thank you to our speakers, Professors Noah Whiteman, Daniela Kaufer, Michael Silver, and Gül Dölen. I also want to say a big thank you to the BCSP’s donors and supporters. Everything that BCSP does is supported by philanthropy. So if you’d like to join them and support the future of psychedelic science education, there’ll be a link displayed right after I finish talking.

For those of you who are joining the private family and friends donor and supporters event right after this, you’ll have been sent a separate link. And if you’re interested in joining that group in the future, please get in touch with the BCSP, and we’d be delighted to talk to you more about what we’re doing. But thank you once again for your attention. Thank you for your questions, and hope you work with us in the future and follow the future of psychedelic science and education. Thank you.

[Music: “Silver Lanyard” by Blue Dot Sessions]

Outro: You’ve been listening to Berkeley Talks, a Berkeley News podcast from the Office of Communications and Public Affairs that features lectures and conversations at UC Berkeley. Follow us wherever you listen to your podcasts. You can find all of our podcast episodes, with transcripts and photos, on Berkeley News at news.berkeley.edu/podcasts.

[Music fades out]