Dr. Tanya Sippy is an Assistant Professor in the Department of Psychiatry and the Department of Neuroscience and Physiology at NYU Langone. She’s also Principal Investigator at the Sippy Lab and Associate Director of the Psychedelic Medicine Research Training Program. Her research explores the neural mechanisms that underlie how sensory stimuli become associated with goal-directed behavior.
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More information: https://www.sippylab.com/
Visit our website for more insights on psychiatry.
Podcast producer: Jon Earle
Dr. Tanya Sippy is an Assistant Professor in the Department of Psychiatry and the Department of Neuroscience and Physiology at NYU Langone. She’s also Principal Investigator at the Sippy Lab and Associate Director of the Psychedelic Medicine Research Training Program. Her research explores the neural mechanisms that underlie how sensory stimuli become associated with goal-directed behavior.
Topics:
More information: https://www.sippylab.com/
Visit our website for more insights on psychiatry.
Podcast producer: Jon Earle
NOTE: Transcripts of our episodes are made available as soon as possible. They may contain errors.
DR. THEA GALLAGHER: Welcome to NYU Langone Insights on Psychiatry, a clinician's guide to the latest psychiatric research. I'm Dr. Thea Gallagher. Each episode, I interview a leading psychiatric researcher about how their work translates into clinical practice. Today, I'm speaking with Dr. Tanya Sippy. Dr. Sippy is an assistant professor in the departments of psychiatry and neuroscience/physiology here at NYU. She's also the principal investigator at the Sippy Lab and associate director of the Psychedelic Medicine Research Training Program. In our conversation, we talk about how the brain links sensation to action, the complex role of dopamine, and the hype versus reality of psychedelics. Well, thank you so much for being with us today, Dr. Sippy.
DR. TANYA SIPPY: Thanks for having me.
DR. THEA GALLAGHER: So, we're just gonna talk a little bit broad and then we'll get more specific as the episode goes on, but can you tell us a little bit about your current research?
DR. TANYA SIPPY: Sure. Uh, we actually have three research projects in my lab, uh, two of which are funded by the NIH and the third's a bit of a wild card, but I'm sure will be funded by the NIH soon [laughs]. Um, so in the first project, we study the process in the brain that actually links sensation to action. And so when I say sensation, I mean things in the environment. So an example that my postdoc gave yesterday actually in our group meeting talk was that when she moved to New York, uh, she realized that she needed to actually navigate the streets, um, in a very different way than she had before. So wasn't good enough just to look at the crosswalk sign, she also had to pay attention to the honking taxis and the people coming at her from all directions to safely navigate across the street. And that's the, uh, central process that we're interested in because, um, I really agree with, uh, Daniel Wolpert, who actually is a computational neuroscientist who I got see speak, um, last week, and he really thinks the brain is, is to create movement.
DR. THEA GALLAGHER: Hmm.
DR. TANYA SIPPY: I think it's probably broader than that, but I think movement is an essential component. So I also think that linking that movement to things in our environment is a fundamental process. It's very important, and it underlies a lot of neuropsychiatric disease. Um, and so to study that, we looked at a region of the brain called the basal ganglia. It's very well conserved from rodents all the way to humans, and we study it in rodents. And the input nucleus of the basal ganglia is this area called the striatum. It's actually gigantic in mice, very, very, big in humans as well, um, but bigger in mice, uh, proportionally speaking. And it actually gets a lot of inputs from sensory areas all throughout the brain, and those inputs actually aren't very well studied. And so we know that the basal ganglia is important for motor output because, uh, lesions in the basal ganglia, so Huntington's disease and Parkinson's disease-
DR. THEA GALLAGHER: Hmm.
DR. TANYA SIPPY: ... people are, are movement disorders. Um, but we don't understand how sensory input influences that process, so that's one project in the lab. And I have two more I could talk about.
DR. THEA GALLAGHER: And can you just tell us a little bit about how you study these things?
DR. TANYA SIPPY: Yeah. So, uh, my lab uses a variety of, um, really cutting-edge approaches, I think. I spent a long time learning these approaches across, uh, different laboratories across the world, including Los Angeles, New York, and Switzerland. And, um, basically, the main, uh, technique that we use is called electrophysiology. Electrophysiology is used in, uh, many, uh, labs around the world. It's used in humans, uh, nonhuman primates, rodents, basically any organism you can think of, any model organism. Um, but we take a rather unique approach to this in that, um, rather than recording from the outside of cells, um, and kinda looking at how... their firing patterns, which you can do in a way that's extracellular, we actually record from these neurons intracellularly while the mouse is awake and doing, um, behavior.
Um, and in that way we can actually look at not only the firing of, of the neurons, which is kind of the tip of the iceberg, we can look at all of the activity, which we called sub-threshold activity, that leads to that firing. And that lets us look at really important cellular properties, um, that no one else can access really.
DR. THEA GALLAGHER: And what is the big question that you're hoping maybe to answer or the small question that you're hoping to answer with this project particularly?
DR. TANYA SIPPY: So we really wanna understand how learning changes sensory representation. Um, and we wanna understand how that happens in a normal model and then we wanna understand how that process goes awry, for example, let's say in addiction, um, where often what addiction is, uh, well, it's very complicated, but one thing that really leads to relapse is that you have an overrepresentation of things in the environment.
DR. THEA GALLAGHER: Hmm.
DR. TANYA SIPPY: So let's say, you know, you walk into a bar and you see people there. And you see the glasses, and you hear the cheers and you smell the alcohol. Those are all things that might lead somebody, even if they don't want to drink, to drink. Same thing, you can imagine, for smoking or really any drug. Um, and so, uh, we'd like to understand first how this happens in a normal setting and then understand how it goes awry in these different conditions.
DR. THEA GALLAGHER: And can you tell us a little bit about the two other projects?
DR. TANYA SIPPY: Yeah. So the second project, uh, also NIH funded, uh, is one [laughs], um, basically where we're really trying to find out what is the function of dopamine. Um, and I know that sounds like an age-old question-
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: ... because it is, indeed, an age-old question. Uh, we've known about dopamine for a hundred years, so better part, better part of a century, maybe not quite a hundred years. Um, and it was really Arvid Carlsson in 1957 who, um, really described that dopamine is not a precursor to other neuromodulators. It, itself, is a neuromodulator. Um, and that's when we really realized that, you know, dopamine is doing something, um, aside from being a precursor. And it really, um, was also Peter Milner with James Olds, and this was in 1953, um, they really started to do these self-stimulation experiments in rodents, um, where they realized that, um, if you, if the rodents were able to self-stimulate their brain, so where the dopaminergic cell bodies were, that they would do anything for this cell stimulation.
DR. THEA GALLAGHER: Hmm.
DR. TANYA SIPPY: So would press a lever many, many times. And so this was a pleasurable phenomenon. So then, um, you know, I think we knew as a field, I mean I wasn't alive then-
DR. THEA GALLAGHER: [laughs]
DR. TANYA SIPPY: ... but I think the field knew at that time that dopamine might have something to do with reward.
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: Um, in 1996, uh, Wolfram Schultz and his colleagues, um, they actually showed in nonhuman primates that dopamine neurons, when you record from them, do something very interesting. Um, and that is that, um, if you pair dopamine, uh, with an unexpected reward, or if you pair, um, a cue, a sensory cue with an unexpected reward, um, what you'll see is an increase in dopaminergic firing. We call that a phasic firing because it happens briefly, so you see a brief increase in the firing of the neurons and then it goes back down. Um, and you'll see that at the time of the reward if the reward is unexpected. So let's say, you know, the, the animal or the human hasn't learned that the sensory cue predicts the reward, you'll see the dopamine at the time of the reward.
Um, if you then pair with the sensory cue over enough trials and the animal learns that you, uh, that they're gonna get a reward after the sensory cue, dopamine neurons do something very interesting in that they fire at the time of the sensory cue and they no longer fire at the time of the reward.
DR. THEA GALLAGHER: Hmm.
DR. TANYA SIPPY: So when they know the reward is coming, dopamine neurons fire, right? And then the last thing that, that they showed in this landmark paper is that if you then omit the reward, so you have the sensory stimulus and, you know, you're expecting to get a reward but it's omitted, the dopamine neurons will actually pause their firing, so see a dip in their firing. So this was very interesting and it led to this idea, um, called, um, reward prediction error and also, like, a huge, uh, concept in the field called reinforcement learning. Um, and this is based on the idea that what dopamine is doing is signaling this reward prediction error. So it's not so much that it signals reward, it signals the difference between an actual reward and expected reward.
DR. THEA GALLAGHER: Hmm.
DR. TANYA SIPPY: And that's basically how we learn from, from rewards in the environment.
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: So that story goes on. So do- [laughs] dopamine is not actually, we don't know what it's doing yet. So we think, you know, it's for reward prediction error. That was, again, I told you, and this is 1996, so you might say, okay, the book is closed.
DR. THEA GALLAGHER: Right.
DR. TANYA SIPPY: Why are you still studying dopamine? Well, the thing is, um, just because, you know, dopamine, you know, correlates with these RPEs, and you can do many other, you know, causal experiments, it doesn't mean that we know how this process is actually working in the brain. So we don't actually know what dopamine is doing to the downstream neurons, which happen to be in the striatum, which is the nucleus I told you about before that we study in my lab. We don't actually know what it does to those neurons to allow for humans or animals, for that matter, to learn. And so that's what this second project is about.
DR. THEA GALLAGHER: And so if we did know more about that, how would that maybe move, move, like, the research forward?
DR. TANYA SIPPY: So it would move the research forward I think in a number of ways. So I think if we could understand what are the downstream effects of dopamine, we could start to understand, for example, in addiction-
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: ... what are the neurons that are actually responsible that are leading to the use and how can we then, um, modulate their activity, um, not by just targeting dopamine, but more specifically, targeting the neurons that are responsible for mediating the behaviors that, that dopamine is, is enabling?
DR. THEA GALLAGHER: Maybe.
DR. TANYA SIPPY: So that's, that's one way, but many, many other ways as well.
DR. THEA GALLAGHER: Mm-hmm. Yeah. It sounds like you're saying dopamine isn't in a vacuum. There are a lot of other things it's connecting to that we're trying to understand because maybe you can impact parts of the cycle or parts of the pattern.
DR. TANYA SIPPY: Exactly. I mean, dopamine, again, and it, and it might even be this red herring, you know? It's so many studies are focused on dopamine.
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: And you get to the end of the study and it's like, oh yes, dopamine correlates with this, or yes, dopamine does this. But it has to be... Our brain is not just dopamine. If it was, I wouldn't be speaking to you right now.
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: That's some elements, but you know, there's so much more. And I think that's what we really need to understand.
DR. THEA GALLAGHER: I think you said there was a third project you wanted to discuss?
DR. TANYA SIPPY: Yeah. So this project, um, directly stems from my work as a psychiatrist. So, uh, when I was an intern here at, um, NYU, um, it was, it was a very difficult transition to make for many reasons. I went from, you know, being in a Swiss lab to being in Bellevue Hospital, and those are quite different environments. Um, and one of the things that I was doing, um, quite a bit was, um, dealing with very, very, very sick patients. Um, and actually, uh, something that I was really reckoning with, um, quite a bit was how difficult it is to give patients the news that their life is going to end. And, um, that was something that took a huge emotional toll on me-
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: ... um, and really made me question whether or not, you know, I wanted to actually finish residency because it was so, you know, emotionally burdensome, and I wasn't sure if I was the person who should be in that role. So I came back, um, from work, you know, one day and, and, you know, my husband knew that this was a very, uh, difficult time for me. And, uh, you know, he asked me if I had read this article in The New Yorker, and I said, "No, of course not, I don't have time really right now to be reading The New Yorker."
DR. THEA GALLAGHER: [laughs]
DR. TANYA SIPPY: And he told me about, um, a, a doctor, uh, named Stephen Ross who, um, had spent a great deal of time actually getting a clinical trial off the ground at NYU where he was looking to treat patients with terminal diagnoses with psilocybin to help them with their anxiety. And, um, I thought that this was just a beautiful demonstration of how pharmacology could make a huge difference in someone's life at a time where they really, really need it, um, and in a way that is super meaningful. So luckily for me, Steve, uh, was, was... or Dr. Ross [laughs] was working on my floor, um, when I was on 20 West doing a psychiatry, uh, rotation. And, uh, you know, he, he's very open and, um, I knocked on his door and just started chatting with him about this work and how I could possibly be involved. And we started, uh, psychedelic, uh, research interest group for residents.
Um, and then fast-forward about four years when I started my lab, the Center for, uh, Psychedelic Medicine was established at NYU, and um, they were looking for someone to kind of help them with a training program that they had set up with the generous support of MindMed. And they asked me to do it, and one of the postdocs in the program, um, who was actually researching this as a professor, decided to come to my lab and start doing pre-clinical work to understand what the psychedelics or doing in the, in the brain. Um, so she came. Uh, her name is Sarah Mennenga. We, uh, got the appropriate licenses. That took two years [laughs].
DR. THEA GALLAGHER: Oh, yeah.
DR. TANYA SIPPY: Um, and now, um, we have research underway, um, that's really investigating whether or not, uh, rodents are an appropriate model to understand how the psychedelics are working in the brain. Um, and so that's kinda where we are, um, with that project, and I think it has great potential. Um, and I also have a graduate student named Jahel Guardado who's working on this now.
DR. THEA GALLAGHER: So again, you're kind of looking at more of the granular level trying to understand the mechanisms and trying to understand how it works?
DR. TANYA SIPPY: Absolutely. We do not know what, um, the particular serotonin receptor that the psychedelics work on is doing. It's called the serotonin 5-HT2A receptors, many other receptors as well, and we don't know if it's that receptor, other receptors, or how, um, these drugs have their therapeutic effects. And we really don't understand even in the acute scenario with what these drugs are doing acutely, how that relates to what their therapeutic effects are later. And that's something that we can very much track in a rodent because the tools for tracking rodents nowadays have exploded. I mean, you have these deep learning algorithms now that can really track rodent behavior at a level of detail we couldn't do before. So the time is really right to understand what are these drugs doing, um, and then relate that to what their long-term effects may be.
DR. THEA GALLAGHER: Going back to that time you were talking about when you were giving people this news or talking with them, I'm just curious, what was the, the hardest part? Was it, like, seeing other people struggle so much with the fear around the concept of their own death?
DR. TANYA SIPPY: When you tell someone that they are going to die, you realize that no matter who they are, they don't actually want to die.
DR. THEA GALLAGHER: Hmm.
DR. TANYA SIPPY: And I think that that realization was the hardest for me.
DR. THEA GALLAGHER: Yeah. And, and seeing, like, the realization for yourself or watching them experience that or a combination?
DR. TANYA SIPPY: Both, definitely.
DR. THEA GALLAGHER: Mm-hmm. Yeah.
DR. TANYA SIPPY: It's like, what, what do you say in that scenario and you realize, like, there is, there's no magic sentence.
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: And there's no, there's no hug or look or smile or anything you can do in that moment, but I, I strongly feel that if you can give them an experience, um, like you can potentially with, with a psychedelic that gets them out of the context of themselves-
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: ... which is really what these drugs do, and rethink about the news that they've been told in a totally different way, in a totally different brain state, you have the potential for them to come potentially, you know, to a, to an understanding and maybe an acceptance of what's gonna happen.
DR. THEA GALLAGHER: Yeah. I mean, I think all the psilocybin research is so fascinating, um, and you know, I work with patients with anxiety, severe anxiety, PTSD, and I think this concept where it sound... Like, what I'm interpreting from what a lot of people are saying is that for people to get, like, a little bit of space away, to get a little bit of perspective, um, what we try to teach people to do in mindfulness but can be so difficult, um, you know, when you have anxiety and stress. But for people to get that space where they can see their thoughts almost like a movie where they can really kind of disconnect from them or not feel so, um, you know, overwhelmed by them. I feel like that's such a fascinating part of what's happening in the research.
DR. TANYA SIPPY: Absolutely. And you know, I'm, I'm not sure that, that rodents are the best model for all of that-
DR. THEA GALLAGHER: [laughs]
DR. TANYA SIPPY: ... but I, I do think that, um, you know, they, they are models for, for many things that we, we can study that are related to that, to that process. Yeah.
DR. THEA GALLAGHER: Mm-hmm. Well, it sounds like what a lot of your research is saying is that we understand these things work, but it's really important to get a better sense of how they're working and the intricacies that exist.
DR. TANYA SIPPY: Yeah. And also, you know, establish the safety profile, the dosing, how often-
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: ... in what se- and setting. I think, you know, with, with animals, we can do this research relatively quickly. And if, if the drugs are doing similar things in the animals, then we should be able to study all of these things quite well and use what we've learned to apply them.
DR. THEA GALLAGHER: Yeah. It, it's interesting from my, uh, interview with Dr. Bogenschutz, he said that a lot of patients had this similar experience and, um, just kind of with what you're talking about, you know, he said that a lot of them reported it was, this experience was intense, memorable and meaningful. And I think that's just, it's gonna be so interesting to see how that all continues to, to play out, um, and it's a, it's amazing that you're doing the research too to kind of understand more of what it's exactly doing as well.
DR. TANYA SIPPY: Yeah.
DR. THEA GALLAGHER: So, personally, why is this such an exciting, um, or interesting area for you?
DR. TANYA SIPPY: Which one?
DR. THEA GALLAGHER: I guess let's go with the dopamine.
DR. TANYA SIPPY: So, uh, dopamine is, um... So I, I have also, like, a long, complicated relationship with dopamine, I would say.
DR. THEA GALLAGHER: [laughs]
DR. TANYA SIPPY: I, I think that ultimately, potentially, dopamine is a large reason... I'm not sure, maybe I was born a scientist. I have no idea. Um, neither of my parents are Nobel Prize winners, you know. You know these, like, scientists where, like, you know, their parents were Nobel Prize winners.
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: And then you're like, this was just epigenetic, like in your destiny.
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: You know, you see them, like halfway through their career and you're like, "Yeah, you're, you're also definitely getting the Nobel." I'm not in that boat, I would say. So, but, but, um, at some point in, uh, college, uh, so when I was in university, um, I knew, you know, I wanted to be a doctor. I wasn't sure, like, what element the science was gonna play. Um, I ended up getting started in, you know, in a lab where I was just doing synaptic transmission, and that was, that was fascinating, actually, area of research, um, just how two neurons communicate with one another.
Um, ultimately, when I was in graduate school, um, that wasn't actually, um, sufficient anymore. Like, I, things had become a little bit more... you know, you grow older and I realized I was doing an MD-PhD, and at some point, um, I was looking for, okay, like, what, what is really meaningful for me, you know, to study?
DR. THEA GALLAGHER: Hmm.
DR. TANYA SIPPY: And dopamine really came up as, you know, something that, that could be interesting. And the reason why is because this was just years after Wolfram Schultz's work, and I was like, "Okay, dopamine is, like, reward and pleasure in the brain, and that's what I want to study. I want to study reward and pleasure."
DR. THEA GALLAGHER: [laughs]
DR. TANYA SIPPY: So that was, like, 2007 and '08. Um, and even like my Twitter handle at the time said like, "I'm a scientist who prefers not to limit experiences which allow for the release of dopamine in my head." That's w-
DR. THEA GALLAGHER: [laughs]
DR. TANYA SIPPY: That's where I was, you know, in 2008, '09.
DR. THEA GALLAGHER: [laughs]
DR. TANYA SIPPY: Um, that stayed there actually for many years. I just removed it recently. And the reason I removed it is because, um, it is too simplistic of a view of dopamine. So I kne- I knew that I wanted to study it, um, but then, you know, as I started actually doing work in the striatum, and this was my work in Switzerland, um, in the lab of Carl Petersen, where I was actually studying the function of striatal neurons, um, during that time and then also as I transitioned to faculty here at NYU, I realized that dopamine is so much more than a reward neuromodulator.
So, um, dopamine is actually active in, in a lot of different scenarios, um, when we encounter anything that's novel. Um, certainly, for motivation and learning, I think that's been well established and we've already talked about that quite a bit. Um, but the other thing that dopamine is really, really important for is movement, and that's how these projects kind of tie together. So, um, in Parkinson's disease when you have a loss of dopaminergic function, patients cannot move.
DR. THEA GALLAGHER: Hmm.
DR. TANYA SIPPY: And so there's been a lot of work actually, um, by, you know, some people at NYU, including Nicolas Tritsch, um, but also, um, Rui Costa and Josh Dudman and many others out there, um, Anatol Kravitz, and I can go on and on, um, Anatol Kreitzer, that is, um, and Lex Kravitz. Um, but many, many people who have studied, um, the role of dopamine actually in, in other, um, in other functions and other behaviors, and one of those is just movement. Um, and so, um, what this has really brought up is that, okay, dopamine is, is, is active during reward, right? It is active during movement, and how does this neuromodulator accomplish these two functions when all the cell bodies are in the same place and projecting to, you know, different areas, but there's a lot of overlap, right? So how is it that in one context dopamine can be doing movement, and in another context dopamine is doing reward? And this is where I think the field is at.
DR. THEA GALLAGHER: Hmm.
DR. TANYA SIPPY: There's, there's actually a scientist named Vanessa Ruta at Rockefeller who, uh, does work in Drosophila, and one of her most recent papers is really just looking at this like, how can dopamine neurons actually accomplish these two, um, these two jobs? Um, so I think that's kind of like a very exciting direction and something that I'm really interested in and many neuroscientists are. And um, I think for, for now, that's kind of why I study it, because it's both involved in the first project and movement but also by itself, you know, i- I do think, you know, studying reward in the brain is also still exciting. So now it captures, you know, all of this, basically.
DR. THEA GALLAGHER: And when you're talking about, you know, movement and pleasure, do you see them as two separate functions or are, are there any crossover?
DR. TANYA SIPPY: I think there's a lot of crossover. I mean, I think in order to move, you need to be motivated-
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: ... um, at some level, and so I think, you know, a lot of people would, would say that. So I think there probably is crossover. Um, but when you actually look at the timescale of dopamine signaling, and this is something, um, you know, a lot of labs are starting to do. There's a new tool actually, um, that was, um, disseminated by a couple of labs. Actually, we use the one by Luke N. Lowe. And basically, um, this is a, um, a sensor actually, um, that you can actually put into the brain, um, and you can, you can now, um, at least in rodents, and certainly you'll be able to do this in other organisms as well, um, you can actually track the release of dopamine in real time. And this is revolutionizing the field basically, because now, um, you can actually see real time during behavior, um, fluctuations in dopamine.
And what we're realizing, and this is actually, um, more work actually by Nicolas Tritsch, who's my colleague here, um, at NYU, and his graduate student, Anya Krok, um, is that dopamine is actually fluctuating all the time.
DR. THEA GALLAGHER: Hmm.
DR. TANYA SIPPY: So not just during movement, but also in periods where, you know, the animal is just stationary, you see dopamine going, you know, up and down. Um, and you also see, you know, as many people have reported for many years, this phasic increase in dopamine during reward. So we're understanding that dopamine release is much more complex, and it might be accomplishing different things in just the timing or the way, um, that it's released onto different, onto different subpopulations.
DR. THEA GALLAGHER: And that would be pretty fascinating also with people with various mental health conditions, right, like, ADHD or bipolar, understanding, you know, what is maybe the impetus for the dopamine or, or, you know, the relationship to the mental health condition.
DR. TANYA SIPPY: Yeah. I mean, dopamine is probably involved in almost every psychiatric disorder you can think of-
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: ... um, to some extent, it's probably related. Again, not sure if it's, you know, a red herring or if it's actually involved. Um, it's really, really hard to know in psychiatric conditions, and maybe we're giving dopamine a bit too much credit. I mean, obviously, you know, dopamine is major target of many of the drugs that we use in psychiatry, interestingly, mostly for psychotic disorders, and there's where you really see the crossover, okay. So you have a patient who is psychotic. Maybe they're manic, right?
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: So maybe, you know, they have, like, too much energy. If anything, maybe their reward systems are in overdrive.
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: We give them an antipsychotic and what happens? Not only do those systems come down to baseline, which is what we want so they can be functional, but they also have terrible movement disorders. And there you see the crossover of how dopamine is really important for both of these things. Um, but it's also used, um, you know, some of the antidepressants target the dopaminergic system much less so. Of course, serotonin, um, and how serotonin and dopamine are working together, we have no... I mean, this is a field that we are embarrassingly far behind in, I would say-
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: ... um, you know, how neuromodulators are working together and especially these two, dopamine and serotonin. Uh, this is a project we're likely gonna take on in my lab, um, but I think, you know, many other labs are gonna start to become interested in and just how neuromodulators are working together. Um, and, uh, you know, norepinephrine, for example. Um, yeah, so just really understanding this problem of like, how... okay, they're released at these times, but what are they doing to downstream neurons? And how can we use that to better target therapies?
DR. THEA GALLAGHER: And do we understand anything about the serotonin-dopamine connection?
DR. TANYA SIPPY: So we're starting to.
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: So, um, again, there was a paper actually published last month in Nature in 2023 from a young, uh, scientist actually, up and coming. Her name is Zeynep Okray, um, and she comes from Scott Waddell's lab. Um, and basically, they were looking at the interaction of the dopamine and serotoninergic system, um, while, um, basically looking at, um, a, a le- a sensory learning task, basically, also on Drosophila. There's been other work as well, for sure, but this is the most recent example I can think of and a really beautiful demonstration of how the, how the two systems might be interacting.
DR. THEA GALLAGHER: Mm-hmm. But like you said, there's more to learn and it will, it'll probably inform, like you said, clinical care in the future.
DR. TANYA SIPPY: Absolutely, yeah.
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: And these tools, we really can use them very, very well in animal models. So if you really wanna track in a single brain area in real time release of dopamine and serotonin, at this point that work, it's really best to do it in, in, um, animal models.
DR. THEA GALLAGHER: When you're talking about the psilocybin, I think it's so interesting how you, your story of how you actually kind of came into being interested in that research, and it seems like it started with a very human experience, connecting with other humans. Um, and then it sounds like you find a lot of value in doing the work at the, I don't know if we say, like, the rodent level, but at the micro level. Can you tell us about how, um, how those feel connected to you?
DR. TANYA SIPPY: Yeah. I mean, I think that's kind of, you know, gonna be a lifetime of work in, you know, my own sort of personal journey and then also, you know, in my experiences. Um, and you know, it's slow, would like to speed it up. I'm not getting any younger, I would say.
DR. THEA GALLAGHER: [laughs]
DR. TANYA SIPPY: Um, but right now, um, I see, um, I, I do see these times where I, where I have these big leaps of understanding, you know, how these things are connected. Um, so, you know, the perfect example of that is when Michael Bogenschutz and Stephen Ross, you know, w- we discussed that, you know, I would be a part of the center. And then we started doing this work in my lab. That happened in the first year I started my lab, right? This was something I was thinking to myself, "I'll do this 10 years from now. I'll do this 20..."
DR. THEA GALLAGHER: Hmm.
DR. TANYA SIPPY: Once I have tenure, not worried about where money is coming from, I'll just do, you know, I'll just do this work. And you know, it happened in year one, so there was one major leap there. Um, I do have plans, um, for sure, to link these things, um, together I think even more concretely. Um, but we, we'll see how these unfold in, in the next few years. I think for now, I'd really like to get a handle, um, scientifically on what these, what these, um, compounds are doing in the brain and then take it from there.
DR. THEA GALLAGHER: Mm-hmm. And people are so excited about psilocybin, right? Like, everyone's talking about it, everyone's really excited. Um, and you talked about how it took even two years to get the license and we're learning more about the dosing. Um, what is your kind of advice or thoughts about, you know, I think clinicians are excited to be able to hopefully, you know, recommend this in the future, but I think we have to obviously be patient with this process. So yeah, what are your, what are your thoughts about kind of the pace that it's moving, the excitement [laughs]? Um, do people have to dial it back or, you know, we need more time? What are you thinking?
DR. TANYA SIPPY: I'm so happy you asked this question. Um, I think people need to dial it back for sure.
DR. THEA GALLAGHER: [laughs]
DR. TANYA SIPPY: Like, I, I think, you know, you, you do need... I mean, look at, you know, for example, diversity, equity, inclusion. Okay, this is perfect example.
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: And it's just, you know, these things are so important. They're so fundamentally important, right? You-
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: And I wanna be very, very careful with how I approach this. I absolutely am a supporter of diversity, equity, inclusion. I sit on many committees. I think it is fantastic, and you need the world to get behind, you know, certain, um, concepts and, and, you know, certain ideas, um, that are important for our society as a whole. Um, but you, you also don't want to get to a point where you're stifling people's opinions, you know, people who might, you know, have a little bit of, you know, but what about, think... what about this side of the argument, you know? And, and that's, it, I think it's important to at least hear those people out.
We are in a country where, you know, you should be able to have freedom of thought and freedom of speech, not so much that it harms other people, right? But I, I just worry that when the pendulum swings so far in one direction that maybe we are silencing people who, who might have, you know, very interesting opinions on the subject but don't necessarily agree with the vast majority. Um, and again, I, you know, like I said, I'm, I'm, I'm very much a champion, but I worry that my own strong thoughts on the subject might be alienating some people. And I just started realizing this recently, actually.
Um, so I think the same things goes, you know, with, with, um, with psychedelics or, you know, any, any major thing that, you know, has the power to change the world-
DR. THEA GALLAGHER: Hmm.
DR. TANYA SIPPY: ... there is always the other side of it, right? And I think for, for psychedelics, um, you know, I, I, I very, very, very much worry about the way the drugs are being commercialized and the way they're gonna be given to people. Um, and you know, I think for, you know, the psychedelics, um, and those associated anesthetics, you know, for that matter, I really hope that the people who are prescribing these drugs are the ones who actually know what they're doing and are doing it for the right reasons, you know, not... And the right reasons are to change people's lives and, you know, to do it in a way that, you know, is important for the person, um, and that it's a good match between what the person's needs are and what the drug is doing. Um, and then it should be done with that intention.
Um, and so I think that, that's my... You know, and again, I don't, I don't, I'm not trying to, you know, put that opinion on anyone else who, who, who might have, you know, strong ideas about how this should be done. Um, but I'm just gonna say that even for me who's a trained MD, a trained PhD, I really approach this with caution, and I myself would wanna do it from a place where, you know, I'm doing the research and I understand the safety before I would ever advise or, you know, try and give this, um, to, to a patient of mine.
DR. THEA GALLAGHER: Yeah. And I think you're saying like, we, we have all this exciting information, but we have to do good work and good science and [laughs] really make sure that we know exactly what we're doing. And if we rush too soon, we might, um... you know, it could, it sounds like it could get haphazard and then we don't actually understand what exactly what is working, how it's working. Um, and that's what you're studying really.
DR. TANYA SIPPY: Look at what is happening with THC, right, or, you know, just, you know, C- CBD is fine, more like, you know, THC, I'd say. Like, again, I'm not, you know, judging, you know. I think, I think it's, you know, I think it is what it is, right? And, you know, for people to be able to, you know, have an access to a drug that could be therapeutic is a good thing, right? But where are the regulations? Like, where... like, who... you know, wha- what, at what age should you be able to, you know, buy, you know, this, this substance? And like, under what conditions should you be able to use it? I'm worried that the legislation has not caught up to the, to the legality. And this would be, I think, even worse for, you know, this class of drugs. So I think I would like to see all the, you know, litigation in place or at least have, you know, there should be a licensing credentialed process that, you know, clinicians have to go through before they can prescribe, right?
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: And it, and it cannot just be any MD who has a schedule I license.
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: Like, this is not going to go well, right? That's, I just sort of... uh, I'm gonna get off my, like, soapbox now, but that's, that's my opinion on the, on the subject.
DR. THEA GALLAGHER: Well, I think it's important. I think what you're... You know, this research is pret- fairly new, right [laughs], in some ways?
DR. TANYA SIPPY: Yeah.
DR. THEA GALLAGHER: Like, looking at psilocybin, ketamine, THC, um, and again, everyone's really excited about the work that's coming out. It all seems very positive, but I think, um, pumping the brakes for caution and understanding a little bit more about how, uh, these work in the brain and what dosage, what level, what age, long-term effects, it seems like that's also super important because in history [laughs], there, you know, you can get excited about something and then find out that there are, like, other kind of problems that maybe weren't seen at the beginning.
DR. TANYA SIPPY: Yeah. And also, just a thorough screen of the, of the, of the patient, right? I mean, someone who, who really has seen hundreds of bipolar, you know, or, you know, whatever it is, mood disorders and can identify that, looking at the history, talking to their family, making sure that this is a person who we're gonna do, um, we're gonna actually do right by and that these are actually gonna be therapeutic and not harmful. That is so important.
DR. THEA GALLAGHER: You know, in talking about that, w- with clinicians, how can... what do you think is the best road for clinicians to become apprised of what's happening in the research or to become more competent? Are there trainings? Are there... an- and maybe, you know, this is a question you don't... I don't know if you can answer, but are there ways for clinicians to kind of keep up, um, and know really, like, not just kinda like the clickbait articles, but really know what's actually happening, um, and how they could maybe get to a place where they could be a Michael Bogenschutz, you know, helping people?
DR. TANYA SIPPY: I think psychiatric training is very important.
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: Um, I think, um, at least, you know, for, for a psychiatrist, again, uh, or at least that they would be involved with the, the, the whole process, because a psychiatrist, again, can do the appropriate screening, ask the appropriate questions. And some of this is pattern matching, right, a history of psychosis. Like, somebody might come to you and they're not psychotic, right? But the only way you would know is to do, to do the appropriate, um, questions and background search. And I think, you know, psychiatrists are very much in tune to that type of thing and they're very comfortable with asking those questions and finding that history out. So I think, I think that is, that is extremely important.
Um, and then I think, you know, for, um, for let's say, you know, potentially at some point, you know, this could be a family practice doctor or, you know, an anesthesiologist, let's say. It makes me a little bit less comfortable, but I think it could be, right? But there, I think you would need, you know, extensive training-
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: And, you know, what, how... What are these drugs doing, what to expect, you know, what are the effects on, um, on the body, you know, not just the mind. Um, and also, um, I think probably specific trainings for each substance.
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: MDMA is not gonna be the same as psilocybin, which is not gonna be the same as the next thing. Um, so I think, you know, kind of thorough and very, um, well-thought-out, um, trainings would also be something that I would be, um, really supportive of.
DR. THEA GALLAGHER: Mm-hmm. Yeah, and I think, you know, and also like an understanding of any potential interaction effects and such?
DR. TANYA SIPPY: Absolutely.
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: Yeah.
DR. THEA GALLAGHER: Yeah. And to kind of go back to people being faced with their own death, do you think that, you know, I'm just thinking about someone who is in that place, right, and obviously could be really terrifying. Is there... Do you... is there a place for ultimately, like, some sort of compassionate use, like, in the future so it, like, these people aren't waiting 50 more years [laughs] so like, you know, um, for something like that to be allowable?
DR. TANYA SIPPY: I would hope so.
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: This is a better question for Michael Bogenschutz and Stephen Ross. Um, I know that, um, it, it could be possible in, like, a limited way, um, for, you, clinicians to apply for licenses to, um, use these drugs as a, as an extension of current, um, clinical trials. Um, I myself have not done this, but I know that, you know, I, I'd spoken to, um, I think one of them previously about, um, this being, you know, a possibility. But that would not reach the, you know, a very large population.
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: So the only way I think to do that is, you know, continue doing the research, um, continue, you know, having open conversations, you know, with the FDA, with the government, um, and, um, you know, just everyone getting on the same page about what would the benefits be for these types of drugs.
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: And I think that's the, you know, the proper way forward. And you know, it will take time, but I do think we will have these moments where, you know, we make a lot of progress and then hopefully, um, you know, get there. My hope is within the next 10 years.
DR. THEA GALLAGHER: Yeah. That leads me to my, my next kind of question. What are you hoping to see from your research or y- you know, in the next five to 10 years?
DR. TANYA SIPPY: I have different goals for each project.
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: Um, but I think I would, I would like to have a very good understanding at least of the basal ganglia and associated circuits that are important for linking, um, sensation to action, um, in the normal physiological setting. Um, and that's gonna involve, you know, all the approaches, you know, that I, that I've told you about, um, earlier. Um, and it's also gonna be, you know, a combination of these two projects because, um, you can't just look at, you know, the striatum alone. You have to look at inputs coming from other brain areas, um, and you also have to look at the role of dopamine. Um, so that, that would be really wonderful. And ideally, if we could then apply that to a disease model, um, such as, you know, addiction, which is, you can study very, very well actually in rodents, um, that, that would be, you know, really great.
And on, on the side of the, you know, the, the psychedelics, I would like to use everything that my lab has learned from those two projects, um, to really establish powerful biomarkers for what the psychedelics might be doing and then study those processes during and before, um, psychedelic, uh, treatment.
DR. THEA GALLAGHER: It seems like more and more patients are kind of, er, er, you know, they have access to the internet. They're very interested in how things are working. Um, I feel like more and more patients, like, want to be educated, want to understand. Um, they don't just wanna be told by a doctor, "Here, take this, do this." And so I'm thinking in connecting the work that you're doing, 'cause I've even learned so much just talking to you, for clinicians who are, you know, working with patients every day, um, and patients are wanting to understand more as well, how... where would you advise, you know, clinicians to go to kind of continue to learn and to learn maybe more about these mechanisms and how, um, some of these, you know, newer m- medications are working or, you know, w- what would you... where would you advise them to go to kind of continue to grow in that area?
DR. TANYA SIPPY: That's a very difficult question. It might be the hardest question you've asked me, which, which is, you know, sad in a way, I have to say. But, um, I, I personally trust very few people with, um, being able to advise, um, the public on, on these drugs. So, uh, what we really need is we need more, um, people who are, uh, very, very capable in this area who are, you know, psychiatrists or doctors doing research, scientists. Um, we just need more of those doing this work, um, who are willing to do the work but also talk to people about the work. Um, and the, and the only way to do that is in, like, mass number because, um, each of us has, you know, only a certain amount of time to dedicate to public outreach-
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: ... or to dedicate to, you know, seeing our own patients. Um, and so if we can get, you know, you know, I don't know, at least, you know, 10,000 or 20,000 of us across... maybe those numbers are too big, I'm not sure. But basically, you know, um, uh, a critical mass, um, then I think, you know, people will have many people to go to. You know, you'll have, you know, you know, 12 or 20 in New York, you know, who you can talk to and then, you know, we collaborate on, you know, establishing, you know, a place where we can put information that we really think is, um, important and relevant. Um, and you know, of course, you have, uh, very, very, you know, well, very, somewhat... you can edit this out, maybe.
DR. THEA GALLAGHER: [laughs]
DR. TANYA SIPPY: But you have some, you know, reputable, um, news outlets, of course, as well, um, you know, who, who are trying to responsibly publish, um, articles on this that I think the public is looking into. But I think those articles tend to be, you know, have either one side or the other.
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: And depending, like, on what, you know, the, the state of mind the person is in when they're, when they're reading the article, it's either gonna feed into their fear or feed into their excitement, but not actually get them, you know, real, the real, um, information, um, in an unbiased way. So that, that's my worry about, um, those, those articles, although I think they're fantastic to, you know, kind of spread the, the knowledge that this work is happening. You know, it, um, yeah, I think it has its limitations.
DR. THEA GALLAGHER: Yeah, but it sounds like going, like, reading the publications of the people that you have referred to in this podcast and, and kind of getting back to, um, the, the studies that have happened and that we know about, um, and, and taking all that information, it sounds like also, with a grain of salt, not the research study itself, but, you know, what the plans are for the future because we don't have tons of studies yet.
DR. TANYA SIPPY: Yes, exactly. So I think, you know, we definitely need, um, we need more studies, but let's, like, just look at ketamine for an, as an example, right? So, you know, ketamine I think is, is, uh, a very, very interesting drug, right? It's one of the only drugs that we, we have right now in psychiatry, um, that can actually treat acutely, um, depression and, potentially, suicidal ideation in an acute setting. So that is powerful, right?
DR. THEA GALLAGHER: Hmm. Mm-hmm.
DR. TANYA SIPPY: Now, I don't really... There are a lot of ketamine clinics in this city, right? Many and many capable doctors who have used the drug who are now using it for mental health, for example, anesthesiologists, um, and, um, mostly anesthesiologists [laughs], actually. But I just think that with the emerging research, we will realize that there is so much more that you can do with this drug if you actually go into it thinking you're gonna treat, you know, a mental health problem-
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: ... um, potentially provide the right environment, provide the right therapist, all in combination, um, I, I just think that that's the direction that this is going. And I'm happy that, you know, people can, can go and get the treatment 'cause that by itself probably is helping.
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: But it's just an example of, like, how much further you could potentially go, um, with these treatments I think with the right team.
DR. THEA GALLAGHER: Mm-hmm. Yeah. I didn't know that ketamine clinics were run by anesthesiologists. I just assumed psychiatrists.
DR. TANYA SIPPY: Some are run by psychiatrists, um, and in fact, a friend, uh, and colleague of mine, um, is, is doing ketamine-assisted therapy. And I'm confident she's doing a great job, um, but many are not. Many are, are run by anesthesiologists and many, um, are run by, um, people who don't have medical degrees at all, but they hire, you know, a team.
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: And I, I don't know. I'm not saying that those are, they're not, you know, qualified or they're not great centers.
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: Um, I'm just saying that I just don't know, and I know that there are many of them.
DR. THEA GALLAGHER: Mm-hmm.
DR. TANYA SIPPY: And there's very few psychiatrists who I know that are doing, you know, this, this treatment in their, in their offices.
DR. THEA GALLAGHER: Yeah. And so one of the themes I think that [laughs] we've talked about is this is all exciting, there's a lot to keep looking forward to, but proceed with caution a bit.
DR. TANYA SIPPY: Definitely.
DR. THEA GALLAGHER: Well, thank you so much. This was a really, um, exciting conversation and looking forward to, um, hearing and seeing all that you continue to do.
DR. TANYA SIPPY: All right, thank you so much.
DR. THEA GALLAGHER: Thanks so much, again, for that conversation, Dr. Sippy. If you enjoyed this episode, be sure to rate and subscribe to NYU Langone Insights on Psychiatry on your podcast app. For the Department of Psychiatry at NYU Langone, I'm Dr. Thea Gallagher. See you next time.