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Lucy Chen: [00:00:17] Hi guys. Welcome to PsychEd, the Psychiatry podcast for medical learners by medical learners. I'm your co-host, Dr. Lucy Chen. I've recently graduated from the University of Toronto Psychiatry Residency program, but definitely most definitely still considering myself a medical learner. I'm currently working at the Centre of Addiction and Mental Health, doing a combination of women's inpatient and general adult psychiatry work. I'm joined today by Dr. Chase Thompson, a PGY3 resident.
Chase Thompson: [00:00:48] Hi, Lucy. Happy to be here.
Lucy Chen: [00:00:50] And Dr. Nikhita Singhal, a PGY2 resident from the University of Toronto.
Nikhita Singhal: [00:00:56] Thanks, Lucy. Also very excited to be here and it's my first interview, so really excited.
Lucy Chen: [00:01:03] Great. So we have a really brilliant, like, exciting episode. I'm really excited to introduce our guest and dive in. We're covering a topic that touches on the foundational psychopharmacological principles in addition to the fringes of the unknown with respect to psycho-pharm treatments for depression and exactly how they work. We are zooming in. We're on Zoom, so we are also focusing and zooming in into serotonin function and pharmacology with a focus on an excellent review article called Serotonin and Brain Function: A Tale of Two Receptors, written by our guest expert Dr. Robin Carhart-Harris. Dr. Carhart-Harris is a psychologist and neuroscientist who heads the Centre of Psychedelic Research at Imperial College London, where he conducts leading research in the field. We're really lucky to have you on the show, Dr. Carhart-Harris. Anything else you'd like to share about yourself or your work?
Dr Carhart-Harris: [00:01:58] No, but very happy to to be here and yeah, honoured to be, that people are interested in this article, so I'll be delighted to go through it with you all.
Chase Thompson: [00:02:10] Yeah. So as Lucy mentioned, we're discussing Dr. Robin Carhart-Harris's review. We chose to discuss this review on our podcast because we believe it provides a resonance in psychiatry and medical students a scaffold of knowledge about the serotonin system to further build upon throughout residency training. Our experience of learning about serotonin transmission involved a broad range of different receptors with different functional profiles and a variety of different medications that act on these receptors, all of which can be a bit confusing and dizzying to us as learners. With this discussion, we really hope to provide a slightly different and distilled way to think about these receptors. In addition, as psychedelics and MDMA enter contemporary psychiatry, some of the topics discussed today will become increasingly relevant.
Nikhita Singhal: [00:02:57] The learning objectives for this episode are as follows. By the end of the episode, the listener will be able to: understand the general anatomy and function of the serotonin system with a focus on the purported activity of the more common serotonin receptors and transporters as well as serotonin's basic mechanism of action. To describe the effects of serotonin reuptake inhibitors and how they lead to symptom improvement in mood and anxiety disorders in addition to the mechanism of action of other serotonergic medications and to consider the two-pronged serotonin system conceptualised by Dr. Carhart-Harris and understand how serotonergic agents, including SSRIs and classic psychedelics and the concepts of active and passive coping, fit within this theory.
Lucy Chen: [00:03:40] So that's a mouthful, guys. I know we're going to explore some in depth concepts and topics, but just follow along, we'll do the best that we can to condense this material for you. So I think we should just start, Dr. Carhart-Harris, before we delve into the main content of your review, it might be helpful for us and our listeners to just go over the basics of serotonin anatomy and physiology, anything that you think would be helpful for our foundational understanding.
Dr Carhart-Harris: [00:04:10] Um, well, serotonin, um, you know, it's an old evolutionarily evolutionarily old neuromodulator. So let's start by, by, I guess, clarifying what a neuromodulator is. Um, neurotransmitters are chemicals in our brains that alter the activity of neurons, um, in different ways. But, but neuromodulators, like serotonin are more about kind of tweaking the system rather than a sort of direct excitatory or inhibitory action. And so I think of these neuromodulators like serotonin as kind of, um, you know, tuning the function of the brain rather than exciting the brain or inhibiting the brain. It's a more subtle but no less sort of profound, in effect, action of these particular particular neurotransmitters. And you have, you know, similar neuromodulators in terms of tweaking the system like dopamine and acetylcholine and noradrenaline um, but serotonin is, is particularly interesting, um, for a few reasons, implicated in lots of psychiatric disorders in different ways. Um, and interesting drugs, you know, like the psychedelics work on the serotonin system, MDMA, you know, the Prozac-like drugs, the selective serotonin reuptake inhibitors, I think probably the most prescribed drugs in, in psychiatry, maybe benzodiazepines could compete with that um and so, you know, very, very important. And what surprises people sometimes is that most of the body's serotonin is actually outside of the brain, it's in our in our gut.
Dr Carhart-Harris: [00:06:19] Um, but, you know, the serotonin that is produced and released in our brains plays a very crucial function in how our brains and minds work modulating states of consciousness, so modulating sleep, plays a big role in modulating sleep architecture um, and mood classically. You know I guess to the layman people, they may have heard of serotonin as the happy hormone, they might think of the general rule that high serotonin levels equals better mood and the flip of that low serotonin levels equals maybe depression or low mood. Um, I mean, in the broadest sense, there's some truth to that, but the reality is much more complex. And speaking to complexity, the serotonin system, what arguably sets it apart from the other neuromodulators is its complexity. So these neuromodulators have a number of different receptors, which are the proteins that sit in the membrane of neurons and when they're bound to by by the chemical itself, the neurotransmitter neuromodulator itself, they'll initiate a different response. They're kind of locks that sit in the membrane of neurons and the key is the neuromodulator, the chemical, the serotonin, so that docks into this complex protein, the receptor, lots of these different receptors, and in the serotonin system there are truly lots of these receptors, I think something like 14 different receptors have been identified. And what struck me when I was studying the serotonin system, this is this was my introduction to neuroscience, really, I started my PhD in psychopharmacology, and I studied the serotonin system for four years and then I was lucky to segue into studying psychedelic drugs that work on the serotonin system in a more direct way. But yes, just the sheer number of different receptors, serotonin receptors, and then to to see that different receptors were associated with such different responses I thought was really remarkable and actually that sowed the seed for this paper. You know, I started studying psychopharmacology, um, in 2005, I think it was and this paper published in 2017, serotonin brain function. I guess the seeds were sown early on in my PhD for thinking, you know, trying to kind of, I guess, make some effort to solve the riddle of the serotonin system. I don't think I've done that at all. But, you know, I guess speaking to some of the things that puzzled me about the serotonin system, that certain receptors can do such different things and certain serotonin acting drugs like, say, a Prozac or LSD, both work on the serotonin system, but they couldn't be more different. And so I thought that was that was just incredible and process of trying to get to grips with this and, you know, writing things on on the whiteboard in my office for what different functions and behaviours are associated with, with certain serotonin receptors and what are associated with others, kind of led to the to the creation of this particular paper.
Chase Thompson: [00:10:14] Great. So that's a perfect segue into what you mainly discuss in your paper, which seems to be the 1A and 2A receptors. So maybe you could tell us a bit more specifically about these receptors and why your paper focuses on it.
Dr Carhart-Harris: [00:10:30] Yeah, sure. I suppose what was coming through the literature, I mean, I studied MDMA for my PTSD, for my PTSD, for my PhD. That's an interesting Freudian slip. I think there was any PTSD there, and what was coming through there was that certain behaviours that were associated with the post MDMA period seemed to be of a certain category. So there were things like impulsivity and aggression, um, and so, you know, I started, I started jotting these things on the board and with a view to, to, to writing this paper and, within the paper for those who have it in front of them, Table One is, is kind of the product of, of this, this process. And so you know certain, I guess, symptom clusters like impulsivity and aggression,anxiety, depression, low mood that seemed to be a fair bit of work on on you could say MDMA abuse you know um sort of a lot of use of MDMA, regular and high doses, there were reports of these behaviours afterwards. And so for me, this was, I think, you know, suggesting a clue as to what serotonin does, broad brush if you want. And then, um, you know, so, so these could be, you know, examples of behaviours and symptoms associated with low serotonin functioning. Um, but the inverse of them seemed to be things that were, um, promoted by stimulation of the serotonin system.
Dr Carhart-Harris: [00:12:40] So a reduction in things like impulsivity and aggression, the kind of things that you see when you yeah, stimulate the serotonin system, like with, with, with MDMA, uh, probably the most potent serotonin releaser that we, we know of. Um, and people often say, oh, MDMA, well, it releases other monoamines, but you know, the next highest monoamine that's, that's released noradrenaline, I think you get five times as much release of serotonin than you do to noradrenaline. So while people say that, you know, MDMA really is a serotonin drug, it is, you know, really hitting the serotonin system hard, spitting out serotonin into the synapse um, and, and, you know, people report this profound pro pro-social quality to the experience, you know, things like impulsivity and aggression dropping away. They describe MDMA as the kind of hug hug drug or, you know, love drug. I think hug drug is probably better and empathogen. Um, and so for me, all of this was, was kind of clue to serotonin functioning generally. But then, um, looking more into the literature, it seemed as though, uh, there was one particular serotonin receptor that arguably encapsulated these effects better than any other, and that was the serotonin 1A receptor. Now the picture is complex as it always is, um, in relation to the serotonin 1A receptor, because they are expressed in, in two key areas.
Dr Carhart-Harris: [00:14:42] So the serotonin system has its cell bodies in the midbrain, in the raphe nuclei that they're called um, and that's where the nuclei of these serotonin cells, uh, serotonin-synthesising cells are found deep down in the old brain and the fibres innervate all the way up into the cortex, really long fibres. It's remarkable how long, you know, these neurons are, individual neurons stretch all the way, their axons all the way from the old brain, the midbrain, all the way to the furthest reaches of the of the cortex. And so if we trace down to those cell bodies in the raphe nuclei where 1A receptors are expressed on on the cell bodies themselves, when they're stimulated by serotonin or a 1A-agonist, meaning stimulating, drug um then that serves to inhibit the firing of those cells and this is a feedback inhibition. It's serving a function like a kind of regulatory brake to slow things down. If there was excessive spill-over of serotonin into the synapse, this system would shut that off because it would stop the spitting out of serotonin from from the axon terminals. Um, so that's what the 1A receptors do in those cell bodies but then what we call postsynaptically, so this is presynaptically in the cell bodies, but postsynaptically on the receiving end of the synapse the effect is of 1A stimulation is, is somewhat different.
Dr Carhart-Harris: [00:16:35] It's going to it's going to inhibit the activity of those receiving cells, so it has a kind of quelling inhibitory action elsewhere in the brain. Sure, you can inhibit the cell bodies themselves in the raphe nuclei, but that's going to stop the spitting out of serotonin and that'll have lots of, you know, repercussions. Um, but what I was seeing in the literature is that postsynaptic stimulation of 1A receptors in regions like the stress circuitry, the limbic system, was associated with this inhibition and reductions in, in, in functions that you associate to associate with those stress circuitry like anxiety and stress, of course, impulsivity, aggression, you know, so for me, it started to make sense that MDMA was, you know, to a large extent and also the antidepressant Prozac-like SSRIs are to a large extent working on stress circuitry to, um, kind of smooth things out. And while it would be too simplistic to put all of that on the serotonin 1A receptor, um, it is highly characteristic of the, at least the postsynaptic serotonin receptor. Um, and for me that, that, yeah, that, that kind of got things sorted in my head to some extent about what the serotonin system is, at least in one dimension of the serotonin system. Now there's another one, the one that the psychedelics work on. But perhaps I'll pause because I covered quite a lot in relation to the to the 1A system there.
Chase Thompson: [00:18:35] Yeah. So maybe I'll just make an attempt at summarising what you said, just so we understand here. So we have these serotonergic neurons with the and their cell bodies are in the raphe nuclei and they have an axon which kind of loops back and acts on itself at an autoreceptor which acts as sort of a brake or a self inhibiting mechanism. But then it also extends and acts on the stress circuitry to provide an overall overall inhibitory action on the stress circuitry. Is that sort of.
Dr Carhart-Harris: [00:19:13] Oh, broadly So. So I mean, you have the cell bodies, the the nuclei deep down in the old brain and they'll express these 1A receptors. When serotonin or a 1A-agonist drug, whenever anyone hears the term agonist, think, oh, that's a drug that's going to stimulate those receptors and they're kind of mimicking the endogenous ligand or, you know, the serotonin itself, the serotonin imposters and they'll so the 1A receptors sit on the cell bodies there. There isn't, the axon shoots off into the rest of the brain, but it's the 1A receptors on these cell bodies and when that's hit, stimulated, it inhibits now this this cell, it's going to release less serotonin. So that's the kind of inhibitory brake on on serotonin release. Is this mechanism is very relevant to how the SSRIs work, because in time this break gets sort of desensitised, it stops working so that the cell bodies continue to to spit out serotonin. Early on when you take an SSRI, activating these cell bodies and stopping serotonin release might relate to some of the irritability and worsening of symptoms that sometimes is seen early on in the in treatment with SSRIs.
Dr Carhart-Harris: [00:20:45] Now, just to to finish this thread, so here's the cell bodies with their inhibitory 1A receptors on serving as kind of brakes on the activity of these serotonin spitting cells that shoot their axons out to the rest of the brain, into the cortex and into the limbic system. So let's follow an axon now, and it's going all the way up into the brain, maybe into the stress circuitry, into like the hippocampus or something and the serotonin is going to be released from this this axonal terminal. Now, that's going to hit a receiving neuron, also in the hippocampus, because these synapses are, you know, just tiny, tiny little gaps. So here's the the cell body from the from the from the raphe nuclei spitting out its serotonin and here's the receiver and on the receiver you have 1A receptors, the serotonin is released potential you know to bind to 1A receptor here binds, inhibits this receiving cell and the activity in this region drops because the action of 1A stimulation is to inhibit the host cell. So I know it's complex, but that's it.
Lucy Chen: [00:22:04] Yeah. For sure. And like, I always, my understanding around the impact of serotonin reuptake inhibitors in treatment of depression is this idea that we're, we're down regulating 1A receptors presynaptically so that the cell can release more serotonin in the future, like it's it's not as inhibited. And that's basically like that was my kind of really that's how I grappled on to my understanding was that that's the that's the antidepressant effect of a of an antidepressant.
Dr Carhart-Harris: [00:22:39] Right. I would say that half of the picture. So you're you're desensitising these breaks, these inhibitory breaks on on the serotonin spitting out neurons so that it can start spitting out more freely. There's nothing inhibiting it spitting out a serotonin so in time that should lead to the cell spitting out more serotonin. And generally speaking, that seems to be good for mood in a sense. So that's part of the picture. The other part is that general increase in serotonin in the synapse is going to lead to more of it hitting these these post-synaptic 1A receptors. So in a sense, you're you're ramping up the serotonin system a little bit with an SSRI, dialling up a little bit the serotonin system but if you were to introduce a drug that worked directly on these inhibitory 1A receptors, you would essentially do the same thing. And that's one thing that people have tried to develop in in, you know, I guess biological psychiatry drug development, is the combination of a 1A agonist, just mimic serotonin and also reuptake inhibition to get that kind of sort of double whammy effect. So yeah.
Lucy Chen: [00:24:08] Yeah so I think this is a good transition to talk about the 2A receptors um, and more specifically, you know, I'm not sure if this is a good place to start, but there's differential expression of these receptors in different parts of the brain. They seem to be located on higher cortical areas of the brain and so we're kind of curious about that and how that sort of manifests its effect when it's stimulated or blocked.
Dr Carhart-Harris: [00:24:34] Yeah. Yeah. Well, I'm I'm really curious about that as well, because, I mean, if the listeners have the paper open and they look at Figure One, this for me was really stark, you know, and this, this tells a story. Sometimes a picture says a thousand words, for me that says a lot because we have two maps on the left. You have the in blue or at least the, you know, highlighted frame is blue, is the 1A receptor and where it is in the brain and it's hard to see the raphe nuclei, they're labelled, but you can see the the postsynaptic receptors labelled in kind of the limbic circuitry there. Um, and then look at the 2A receptor on the right and it's very much a cortical receptor. There's not much going on subcortically there, there's not much in the hippocampus really in the amygdala, not much. And yet in the cortex and particularly in association cortex, there's loads of it, loads of this this receptor and this receptor is in my mind, really interesting because of psychedelics and because psychedelics are so interesting. You know, how is it possible to to pin the the action of these drugs that can yield, you know, the most profound experiences of a person's life that leaves them just, you know, struggling to find words to describe what they've experienced. And ad yet we can pin all of that to a large extent on at least, you know, the 2A receptors, stimulating this 2A receptor is the start of all that.
Dr Carhart-Harris: [00:26:23] I mean, if you block this receptor, you don't trip. It's as simple as that. And so for me, that just screams there is something really important about this receptor because if you want to profoundly alter the quality of conscious experience, you can stimulate, you can stimulate this receptor. So we don't know why and what and you know why it's so critical, but we just know that it is, um, and a lot of a lot of, you know, little clues make sense. Like, you know, if you're going to profoundly alter consciousness, maybe it does make sense that you're perturbing receptors that are expressed in aspects of the brain that are the most developed in our lifetime as the brain develops from infancy into adulthood as well as in phylogeny or the evolution of of the human brain, Um, the expression is particularly high in aspects of, of the brain that are particularly evolutionarily expanded. I find that intriguing. There are some wacky theories about psychedelics being involved in the evolution of, of the human brain and human consciousness. Um, I don't quite buy that, but I'm intrigued by the possibility that the serotonin 2A receptor has played a role. Um, and you know, and then, you know, questions like what does it, what does it do? I mean it's again, there's wacky theories that it's there for psychedelics, maybe endogenous psychedelics like DMT, psychedelics that you can find occurring naturally in the body.
Dr Carhart-Harris: [00:28:11] But the evidence there is pretty slim. The concentrations of DMT in the body and in the cerebrospinal fluid are really, really low. They spike up during actually during induced death in, in, in rodent studies, but so does so much else, you know, so there's no specificity there. Serotonin spikes right up if you essentially induce a heart attack in a in a in a mouse. Um, and you have the complication of cells dying and spilling out their content anyway, which sort of makes for a murky picture. Um, so I don't think that's necessarily compelling evidence for, you know, endogenous psychedelics being the key ligands for these 2A receptors. I think it's a simple, you know, kind of Occam's razor go with the simplest explanation, I do think they're there for serotonin. But then, you know, what did they do? Well, increasingly, we're discovering that they promote plasticity. They promote synaptogenesis, so the generation of new synaptic connections, functional components of the synapse, the key bit where the communication is, is done in the brain. Um, uh, and, uh, yeah, so it's the especially especially fascinating receptors associated with plasticity and particularly high-level cortex and I suppose high-level aspects of of cognition and consciousness. Yes. Yeah.
Nikhita Singhal: [00:30:06] Okay. Yeah, it's very interesting just how there are these two different receptors with very different effects. Could you tell us a bit about under normal conditions, what determines where most of the serotonergic activity in our brain is going? Is it mostly involving the 1A receptors or the 2A receptors? And are there different factors?
Dr Carhart-Harris: [00:30:30] Yeah, I'm glad you asked that question, Nikki, because that's a key component here. If you were to look at where the serotonin transporters are, in fact, this this paper that I got, these maps from Beliveau et al 2016 is worth looking up because it's a kind of nice atlas of of different aspects of the serotonin system are the receptors and also the serotonin transporters. And what you find when you look at the transporter map is that a lot of the transporters, which are kind of like hoovers, you know, hoovering up serotonin from the synapse to kind of recycle it, essentially. Um, uh, these transporters are heavily expressed in the stress circuitry and in the sort of older brain, quite, quite high subcortically and they overlap to a fair extent with, with the distribution of the 1A receptors. Now there's a so for me this is a bit of a clue that the serotonin 1A receptor might sort of dominate the serotonin picture, so to speak, broadly. You know, this question, what does serotonin do in the brain is more dominated by what the 1A receptor does than the 2A receptor. Otherwise, if we tweaked serotonin levels with Prozac or MDMA, we would trip out, you know, and you might a little bit with MDMA, but not really to the same extent as what you do with a drug like LSD. So for for me, you know, it is it's this this sort of stress related, um, um, you know, mollifying, taking the edge off thing, action of serotonin that seems to be mediated by these 1A receptors. Another key consideration here, and I'd love to find more literature on this, we cite something in our paper, but I was really on a quest to find more because it seems like such a critical question.
Dr Carhart-Harris: [00:32:37] And the question is this what is the what is the relative affinity of serotonin itself for its different receptors? I mean, you might just think it has a uniform affinity. First of all, what's affinity? Well, it's stickiness. It's the binding potential of serotonin for its different receptors. You might just think, well, you know, these are all proteins that recognise serotonin. It's just going to be a uniform thing. Serotonin sticks to them all equally well, but that there's some suggestions that that's not the case. And actually serotonin has a higher affinity for its 1A receptor than its 2A and its natural affinity for the 2A receptor is quite low. And for me that's kind of intriguing because that could suggest that, again, if you're going to modulate serotonin levels with a drug like, you know, Prozac or another SSRI Citalopram, um, uh, you're not really going to have a big impact on the 2A receptor in its, its functioning because if you did, you might feel something more akin to a psychedelic experience with, with those, with those SSRIs and you don't. So that seems to be a key question. And, and there seems to be some evidence that, yes, the affinity of seratonin itself is higher for the 1A receptor than the 2A.The 1A receptor is also very heavily expressed and expressed in regions that have a very dense innervation from those serotonin fibres coming up from the from the, the cell bodies. Um, so again, that that might be suggestive to this principle of the 1A receptor kind of dominating the serotonin picture in a, in a general sense.
Chase Thompson: [00:34:35] We just want to take a moment here to pause to provide some context for the upcoming discussion. We are about to discuss some theoretical positives and negatives of taking serotonin reuptake inhibitors, as well as classic psychedelics for the treatment of depression. It is important to note that this discussion is purely academic and no clinical decision should be made based upon it. Further to this, we are also not recommending that anyone pursue or undergo psychedelic therapy outside of a rigorously controlled medical setting. One should be aware that there are medical and psychiatric risks from taking these drugs in uncontrolled environments.
Lucy Chen: [00:35:08] And, you know, you've talked about in your paper that, you know, 1A seems to be a mechanism for passive coping and sort of this degree of like a degree of kind of like release under stress or punishment. And then the 2A receptor having a differential like mechanism by which it causes plasticity or kind of improves the depressed state. So can you kind of talk about, I guess, the bipartite model?
Dr Carhart-Harris: [00:35:39] And yeah, so, you know, the principle here would be there's multiple roads to Rome. Is that how the saying goes? Or more than one way to swing a cat? You know, you can you can get to the same sort of, you know, end goal by different by different means and and here so you know, what's the end goal? Well, it's an antidepressant effect. You can either take your Prozac for two, three, six months, years, whatever, and it's going to just take the edge off things, help you get through less of the intense anguish that you can see in all sorts of disorders. Or you can undergo a psychedelic experience, maybe just one and first of all, think about how different that that is, the model there, you know, years, I don't know, maybe a thousand administrations ofof your SSRI daily administrations or one versus one potentially one or a small number anyway of a of psychedelic administrations. And so this must be radically different. I mean, if psychedelic therapy, and I'll unpack that in a moment, works for depression then it works in a radically different way. It's got to yet it's working on the serotonin system but the serotonin system is is a chimaera. You know, it's a it's a at least, you know, certainly has more than one face and these faces are radically different to each other.
Dr Carhart-Harris: [00:37:26] Um, and so and so for me, you know, tackling that in a sense, the less exciting side of serotonin, the one related to taking the edge off things, was something I felt I needed to do to properly understand the system, or at least get a bit of a handle on it. Whereas the other one was more naturally exciting and interesting, the psychedelic side and the 2A side. Um, and for me, you know, I came across these terms active and passive coping and I just found that a really useful phrase, active and passive coping. Here it is, Puglisi-Allegra and Andolina. Yeah and so for me, I was like, well, this is kind of speaking to the principle here. You know, if you're on your SSRI for six months, a year, years, and it's taking the edge off things, you've gone to kind of doctor and said, I'm struggling, I need some help and the prescription comes and in a sense it's quite a classic medical model. It's quite passive: Doctor, fix me, give me, give me medicine, I just need to take medicine, medicine makes me better kind of thing. Sorry for being sort of so kind of simplistic about it, but you get what I mean. Whereas the psychedelic model is quite different.
Dr Carhart-Harris: [00:38:54] It's, um. You know, Doctor, what have you got for me? Well, let's talk. And I guess that's how it starts. It's like, let's talk, you know, tell me about yourself. You build a relationship of rapport and trust. You get to know the kind of nooks and crannies of the individual in front of you on a much more intimate and personal level to build that rapport and trust. And then you're going to have this huge, I would say, hugely destabilising experience potentially um, that's in a sense the, it speaks to the complexity and maybe the limitation of psychedelic therapy is that the experience can be damn hard, you know, really, really tough and weird, weirdest experience that you might ever have um, at least you're conscious of, um, and can remember, because birth's got to be pretty weird. Um, and, um, yeah, and you're in a state of vulnerability and so, you know, how do we, how does your clinician, your supporter, your guide, your sitter, whatever, therapist, how do they look after you? And so that critical role of the therapist or guide in Classic Model, it's two individuals that are doing the prep work, then the facilitation or support during the session itself and then the integration, the landing afterwards, talking through the experience. Um, you know, as you land, if you follow the arc of the experience from, from prep and then the intense experience itself, then trust the arc, you know, you always come down and then the, the work that's done afterwards to kind of to allow for space to talk through insights that might have arisen during the experience, moments, periods of perhaps cathartic release, crying, sometimes floods of tears, um, sometimes serious anguish, sometimes serious confusion as well.
Dr Carhart-Harris: [00:41:16] But to allow space for talking through all of that weirdness and wonderfulness and, you know, the richness of the experience is so critically important. And that's why earlier on I intentionally put some emphasis on therapy. So one is a classic medical model. Doctor, what have you got for me? Medication, you know, take your pills and off you go. And the other one is this engagement where, okay, there's some work to be done here. It's drug doing something in my mind and brain, opening it up and now this is ripe, ripe conditions for some deep therapeutic work. So for me, when I came across these terms of active and passive coping, which I think were outside of the context of the serotonin system I think, I have to remind myself, they resonated with this, these different properties of the serotonin system and serotonin drugs, antidepressants.
Lucy Chen: [00:42:25] So I'm wondering because it's interesting that you're kind of talking about the 2A receptor also in this psychotherapeutic process where there may be like a profound realisation or working through of some past traumatic content. So is that sort of the mechanism of action of certain types of therapeutic processes that are more sort of expressive or they're more sort of exploratory?
Dr Carhart-Harris: [00:42:51] Yes, there is some evidence that processes like destabilisation can actually paradoxically be a good thing in in psychotherapy. So there's empirical evidence to back that up. So but but this, you know, intrinsically is a more complex model than the much simpler, and this is the merit of the of the classic medical model, you know it's simple. You don't, you know the complexity of human beings and interactions and relationships areare not so much involved. Uh, whereas here you, with psychedelic therapy, you have a model that depends on the therapeutic work that is combined with the drug action. You can't pull these things apart because if you try to you, you can get adverse events and you know, even iatrogenesis meaning things get worse rather than better. So it's the point I always emphasise, you know, not through any sentiment as such, only that sentiment in the sense that it just follows from the science and everything about what these drugs seem to do in my mind is saying they are um, sensitising the, the individual to experience to environment. Um, and therefore, you know, logically, scientifically, one needs to pay very careful attention to environment. And while you can't change the past, you can, you can, um, you can engineer the present and the future to some extent and so you have a therapeutic duty, based on the science and the logic, to do that when you're making someone exceptionally sensitive to environment. And another little qualifier that's important, environment doesn't, in my mind at least, doesn't just mean external environment. There's an internal environment that often we're not aware of, and it runs so deep, you know, because there's aspects of our minds that we are remarkably unaware of, and yet they're revealed under psychedelics. And the psychedelic therapy model is typically lying with your eyes closed. So there's not much, you know, visual input from the environment at all. Yet the experience is so experientially rich and content rich. So where is that material coming from? Well, it's coming from our minds, of course. And so that's just evidence for the the depth and the richness of our minds that we're unaware of ordinarily.
Chase Thompson: [00:46:01] So it sounds like with action at 1A, we're kind of talking about, you know, an individual learning to tolerate their current circumstances or at least experience less stress in their in whatever they're already doing. But with action at 2A we're talking about kind of like an expansive or neuroplastic type changes or someone really learning to cope with their environment rather than just tolerate it. I guess I'm just wondering because, you know, when we're talking about the action of psychedelics at 2A, do we know that the new beliefs or the plastic changes are always in a more positive direction, or are there cases where it's really not a good idea for someone to undergo that type of experience?
Dr Carhart-Harris: [00:46:54] Uh, yeah. So. So first of all, um, you know, we can look at the aggregate data, whether from control studies or population studies or observational survey type studies and say, well, at the aggregate level, at the average level, the psychedelic experiences, even actually outside of an obvious context of therapeutic care and support, the outcomes appear to be positive. Now, there might be some, some there may well be some biases in in in data from certain sources, but generally that is a very, very clear picture, you know, large effect sizes in the direction of positive. But that's not to say this is an absolute rule and that somebody could come to have a psychedelic experience and be negatively affected by it. And this is a really critical point that, you know, again, speaks to this principle that psychedelics are not intrinsically healing, in my view. Now, some would even challenge that, but I would sort of challenge them back and say, maybe you're being slightly naive here. Um, you know, most of the time the large majority of uses of psychedelics, people are taking them, especially these days, with some forethought and planning and so, you know, the outcomes are skewed in this positive direction.
Dr Carhart-Harris: [00:48:30] But I do still emphasise that, um and sometimes I oscillate on it because I could see how this process of breakdown and reconfiguration could could be healthy, you know, or it could be intrinsically healthy, speaking to, you know, a mechanism of a recalibration. You know, you take someone who has, um, crystallised, set into a pathological mode of being, you may well think, well, this isn't working or this, this isn't right so we're going to destabilise and the, the hope I suppose is that you return recalibrating into a healthier state. And, you know, maybe there maybe there is something to be said for for that model but I just think it's a bit of a dangerous model to to have too much faith in that psychedelics are intrinsically healing and sort of work in this sort of resetting way because most of the time and most of the evidence is is backing up, you know, careful intention for the experience and, um, and, you know, directing it in a particular, in a particular way with therapeutic support.
Lucy Chen: [00:50:10] I'm curious about sort of the longitudinal impacts of like the 2A stimulation treatment model. Like, is it the neurogenesis? Like what is it? What is sort of what is a longitudinal impact of that treatment model?
Dr Carhart-Harris: [00:50:26] Yes, I'm curious about it, too and I would say we're yet to really have the answers. There hasn't been that much done in the way of brain imaging work, for example, on the longer term changes in brain anatomy and function from from psychedelic use. We have some data that we're processing currently and I suppose the principal, if there is a principal that's coming through, it's that the kind of changes that you see during the experience itself, you will see in the opposite direction afterwards into the longer term. And so for example, if you were to look at our, um, I mean this is limited data to extrapolate from to an extent, but in our depression trial, this is a paper published in scientific reports, we scan people a day after their second treatment session with psilocybin and, whereas, we know now with a high degree of confidence that during a psychedelic experience itself, brain networks break down, they kind of disintegrate. But it's a transient disintegration as the drug effects wear off, they spring back and reconfigure. And we saw this in the default mode network, a network associated with, um, well, actually it's a network that's the regions that make up the default mode network have very high expression of serotonin 2A receptors and it's a network associated with high level cognition, self-reflection, imagination, daydreaming, theory of mind, thinking about the future and the past, mental time travel. So these really high level, arguably species specific, at least to the extent that we do these things, functions, um, is associated with the default mode network.
Dr Carhart-Harris: [00:52:22] We see it break down under psychedelics and this correlates with the intensity of the psychedelic experience but then a day afterwards, at least, the network seems to spring back and actually the magnitude of this springing back and, and there was a we're not sure how salient this is, but we noticed it, there was a slight expansion in the spatial extent of the default mode network um, one day after the treatment in our depressed patients who weren't depressed when we rescan them, a good majority of them were feeling well. Um, and that actually predicted, that was prognostically predictive meaning that those who were responders out at five weeks later were those who showed this slight expansion in the spatial extent of the default mode network. That's a bit arguably a bit too much detail I would say. But generally the rule is that disorder during the trip and a return to order afterwards and maybe there is a kind of um at least a lot of this is sort of theoretical, but maybe there is a kind of, um, uh, kind of, um, sort of spring cleaning of the system. It, it springs back simpler. Um, there's some of the redundancy has been, has been lost, uh, into the longer term maybe, which might make for a kind of cleaner, crisper style of, of, of being, dare I say.
Chase Thompson: [00:54:07] It kind of sounds what you're talking about with the psychedelic experience of being broken down and then rebuilding back up, a little bit like the model of therapeutic action that some people talk about, where the goal is kind of integrating a bunch of diverse experiences into sort of one unified whole person. Do you think that that maps on in this case?
Dr Carhart-Harris: [00:54:35] Well, there's suggestive evidence that that it does. I mean, you know, to many people, this might feel almost, I don't know, it might speak to to the way sometimes people push back about the reductionism of science, where if you were to say, look, you know, these these profound mystical type experiences, these this sense of, you know, mystical union or spiritual union sense of interconnectedness relates to some, uh, you know, alteration in brain function during the experience itself, where, for example, the brain is operating more as a, you know, coherent whole unit. It's more globally interconnected, and you see correlations with that effect and ratings of things like ego, dissolution. Um, it's quite easy to say, ah, you know, those are the neural correlates of ego dissolution and those are the neural correlates of the unitive experience, that sense of profound interconnectedness. Now, if I was really pressed on it, I would say I do actually think that that's, that's the way things are um, but I also acknowledge that that's just one piece of the puzzle um, and there's, there's so, so much more to the story that we've yet to really flesh out um, I would say and you know, part of it is that in a sense we're, you know, inching our way forwards with a model of, um, in a sense, what's lost under a psychedelic experience in terms of the, the usual sense of stability and familiarity of one's self and the world that's lost, um, and that relates to a breakdown in familiar systems that are usually stable in their functioning.
Dr Carhart-Harris: [00:56:57] But the thing that we haven't yet cracked and for me is the most tantalising sort of next frontier for psychedelic research is how do we explain the more, the stuff that comes in when something is lost? You know, the emergent order, how can we explain these visions of of, you know, seemingly timeless motifs that, um, you know, enter enter our minds um, and so, you know, stark um, or memories that flood back that are felt you know, as if one is re-experiencing something and um how do we explain the order amidst the disorder or the emergent order from, from the disorder. And we're not there yet. And, you know, we've got ideas about how to try and do it. It's going to be how to be a kind of, um, oh gosh, a sort of, we're going to have to capture these things as they play out in real time, and that's a challenge. But yeah, that's the kind of next frontier, I would say. Yeah.
Chase Thompson: [00:58:23] So maybe I'll just bring us back a little bit to the original model you discussed related to 1A and 2A. Earlier on, you had talked about MDMA being a potent serotonin releaser and with the potential to act on both of these receptors. But I guess the kind of phenomenon you're talking about under a classical to a experience is quite different than what one might experience with just MDMA. Is there a way to explain that or.
Dr Carhart-Harris: [00:58:57] Yeah. Yeah. Sorry. In the sense that, you know, why doesn't MDMA produce these psychedelic-like experiences?
Chase Thompson: [00:59:06] Right.
Dr Carhart-Harris: [00:59:08] Yeah. And I think part of that is that MDMA isn't a direct agonist of the serotonin 2A receptor. It doesn't really have any appreciable affinity stickiness for the 2A receptor. So any action at the 2A receptor that's being caused by MDMA is being caused through its increase in the endogenous ligand, serotonin. So you might think, well, you know, if you're if you're whacking up the the serotonin levels in the synapse profoundly with MDMA and and as I said earlier, you know, MDMA, maybe mephedrone could compete and not much more else, all these things are dose dependent, of course. But, you know, for sheer big release of serotonin, it's hard to beat MDMA, really. Um, and so why doesn't it produce, you know, trippy psychedelic effects? And I think part of the explanation for that is that, well, there's a lot of serotonin receptors and some of them counteract each other um, and you're not just increasing activity at one receptor, you're increasing activity at 1A receptor and the 1A receptor in particular has a counteracting effect to the 2A receptor. And 1A receptors are found in, even though they're heavily expressed in the limbic circuitry, they are expressed in the cortex and they're often co-expressed with 2A receptors. And so the assumption, and there's a little bit of evidence to back this up, Rick Strassman did some related work, um, there's a bit of evidence that the 1A activation, 1A activation say with uh MDMA-induced serotonin release might counteract the the effect of any 2A agonism through the serotonin release. So it's kind of like a diluting, you know, having a diluting effect on what otherwise would be a big trippy effect through the release of serotonin.
Chase Thompson: [01:01:27] Just in follow up to that, you know, when we are prescribing these medications that promote passive coping, namely, you know, SSRIs, do you think that that limits the individual's capabilities to actively cope in some sense?
Dr Carhart-Harris: [01:01:44] Maybe. And, you know, it's a dangerous question because of the implications of it, given that millions of people are prescribed SSRIs. You know, you might think on a sort of policy level like, you know, what are we doing? Are we doing a good thing here? And I mean, that's a very complex question because you you know, you have people on the cusp of just complete breakdown and and just turmoil and often suicide and so, you know, if you can get through the initial rough ride of going on an SSRI, this can really smooth things out for a period and help you get through a crisis that otherwise might have led you to do something drastic, like, you know, attempt on your own life. Um, and so, uh, it's a complex one.
Dr Carhart-Harris: [01:02:44] You know, so but, but, but let's be honest in our opinions, in my opinion um, yes, I think probably that would be the implication that instead of, you know, really getting to the nitty gritty of of, often there's not a clear, obvious solution to why one is suffering, you know, very, very complex, but, um I'm not sure it's helping to, to in terms of insight and self-development, I'm not really sure it's helping to, to actively cope, to, to, to be just smoothing things out with an SSRI. Might help you engage and be willing to go and talk to someone, a therapist and the evidence of the combo SSRI-time-psychotherapy suggests a bit of an additive effect, but not much. It's quite modest. Um, and so, you know, might just get you out of the house and, and so it might just be helping in that respect.
Chase Thompson: [01:03:51] Yeah, absolutely. And definitely don't mean to suggest to anyone that one way or the other is better that they should seek out one style of treatment. I think it it's a selection issue or who should really pursue each type of treatment at this point.
Dr Carhart-Harris: [01:04:07] Yeah. Who and when. You know.
Chase Thompson: [01:04:09] Right.
Dr Carhart-Harris: [01:04:10] In the throes of, you know, period of real serious turmoil in your life. Is it right to go and have a big, you know, dose of ayahuasca? I'm not sure. Um, so yeah, who and when I think.
Lucy Chen: [01:04:28] I'm actually really curious about whether people have thought about like developing guidelines for approaching treatment, like in a staged model or stage approach to care, you know, is there a way to determine sort of readiness for, you know, a psychedelic treatment-based modality, and how is that determined? And I wonder about your kind of your study criteria, too, and who you decide to recruit?
Dr Carhart-Harris: [01:04:54] Yeah. Um. Well, that's something that we're trying to crack. We've been doing these surveys for a long time, collecting data prospectively from people taking psychedelics in the wild, so to speak, you know, whether they're microdosing or LSD in the bedroom or, you know, uh, mushrooms at Burning Man or whatever, or ayahuasca at a retreat. Um, and so for us, there's an advantage in doing that naturalistic work because people are taking the psychedelics in all sorts of novel contexts. So we can look at, you know, set and setting, we can look at, um, how ready people feel simply by asking them, um, and if you do this with a tracker, you know, that's going to capture data before the event as well as afterwards, then you can do that and, and grab more useful data you know. If you try and do it in retrospect, it's always just in retrospect so you're, you're not really predicting things. You need to make your prediction ahead of time or collect the data ahead of time to really predict. But we've made a stab at that. We've got a couple of publications that have tried to predict or do predict response and a lot of our assumptions about set and setting were consolidated by that work. Um, but we're still getting to grips with it and getting to grips with the relative weighting of different factors like for example, emotional support and trust appears to be particularly heavily weighted as a predictor of the kind of experience that you have, which is the mediator of the longer-term outcomes.
Dr Carhart-Harris: [01:06:48] And so, for example, let's, let's do a quick sort of back of the envelope algorithm here. If you feel, uh, you report feeling ready, there aren't distractions in your life you're ready to do this, you're willing to let go to this experience, surrender to the experience, you're in the company of people who you trust and you feel emotionally supported then these are all, you know, green lights, meaning the these are good signs. These are good signs. Um, uh, now ahead of time, there's not much else, I said a back of the envelope algorithm here, so what what's this going to predict? Well, it's going to predict a stronger chance, not a done deal, but a stronger chance of a of a mystical-type experience, a peak experience if you want to put a more sort of obviously humanistic spin on it, you know, sense of bliss, a sense of interconnectedness, sense of timelessness um, and if you have this, this is another kind of green light or good sign that the longer-term outcomes are going to be favourable. And, and then things can come in, and I would say it's a bit too early to put any empirical data on this, but again, there are strong assumptions about integration, you know, to help sustain the positive effects that you got from the experience. And you know, this great phrase from Jack Kornfield, "After the Ecstasy, the laundry", you know, after the big experience comes the work, you know, the work never stops. Uh, doesn't have to be painful, but it's the work needs to continue.
Dr Carhart-Harris: [01:08:39] And so I think, you know, very, very simply that's a kind of back of the envelope algorithm that at least, you know, helps us put a lot of emphasis early on, which is critical and that helps me address, I could try and do it briefly, the other part of your question, which is the screening, you know, how do we screen? And I suppose in a sense, you know, in our clinical studies there is a bit of selection bias because we are looking for people where we feel that we've developed some rapport. There is a sense of trust. We're picking that up from, from from the people that we're talking to um, and those are kind of ideal for psychedelic therapy it seems. Uh, but so, you know, people see the results of these small studies and they get very, very excited and think psychedelics are the big breakthrough treatment in mental health and while they may well be, um, also it's healthy to have some critical acumen and think, well, there may be a selection bias in the patients that come into those trials. Um, maybe a bit of confirmation bias. The patients really want to get the psilocybin and believe it's going to work, you know, so well that doesn't mean that, you know, that will never be part of the treatment effect and always is, you know, that positive expectation at least just be conscious that that's part of the vehicle that can that can be producing these really impressive outcomes.
Nikhita Singhal: [01:10:15] Thank you for that. I think it's really exciting to hear about some of these benefits of possible future therapies coming out and I guess just one more question, coming back to this idea of the receptors. So the 2A agonism seems to be able to induce these very positive changes. I just wonder about some of the medications that we prescribe people for depression that are actually 2A antagonists such as Mirtazapine. How like how can we reconcile the the fact that they may both, 2A agonism and antagonism, have positive effects on depression.
Dr Carhart-Harris: [01:10:52] Yeah. Again really key question. And that brings us back to the you know many roads to Rome analogy that what 2A antagonism might do. So now we're blocking these these receptors rather than stimulating them um, what that might do is to work more in the direction of passive coping. You know, again, it's sort of maybe anxiolytic, flattening people out, less, less scope for any extremes in emotion. Um, and you know, Mirtazapine is kind of a bit of a sedating medication often I think taken just before sleep and it's it's probably that that that mechanism it also promotes sleep as well so you have deeper sleep so less awakenings and that can be a problem in depression, poor sleep, you know, waking up hyper aroused. Um, and so it's a it's a, yeah a different road to ideally a similar effect, but more just passive coping, taking the edge off things rather than, you know, getting to the, to the root, um, maybe the root cause of the suffering and promoting insight and therapeutic development.
Lucy Chen: [01:12:18] Um, well, thank you so much, Dr. Carhart-Harris. You know, a goal of our podcast is to not only cover like fundamental key concepts in psychiatry, but also to stimulate curiosity and to create opportunities for depth of understanding and to allow for expansive thinking when it comes to learning about treatments and treatment options in psychiatry. Your article and your ideas most definitely facilitate these values and goals for us, um we truly appreciate your time and your your valuable expertise. Um, I just wanted to know if you have any parting thoughts or ideas to leave our audience who are comprised from a variety of learners, um they're mostly sort of senior medical students and junior residents in psychiatry.
Dr Carhart-Harris: [01:13:03] Oh uh no, just to say that I appreciate your appreciation. I guess that's why, you know, people like me, write these things and do this work is that hopefully it should inspire others. And so I suppose one passing thought might be improve on this. You know, this isn't by any means the end of the story. It's just everything's iterative in science. So I'd love to see some bright young people come along and take this on to the next the next stage and develop our understanding.
Lucy Chen: [01:13:35] All right. Thank you so much.
Chase Thompson: [01:13:40] PsychEd is a resident driven initiative at the University of Toronto. We're affiliated with the Department of Psychiatry at the University of Toronto, as well as the Canadian Psychiatric Association. The views endorsed in this episode are not intended to represent the views of either organisation. This episode was produced and hosted by Drs Nikhita Singhal, Lucy Chen and Chase Thompson. This episode was audio edited by Chase Thompson. Our theme song is Working Solutions by Olive Musique, and a huge thank you to our incredible guest expert, Dr. Robin Carhart-Harris. You can contact us at psychedpodcast@gmail.com or psychedpodcast.org. Thank you very much for listening. Bye.