Psychedelics expert Dr Robin Carhart-Harris on what exactly happens to the brain on a trip

[Music] so welcome to part one in this section we're going to address the basic pharmacology of psychedelics pharmacology being the study of drugs how drugs work and so we need to start at a very low level in scale we're looking at molecules here and we're looking at a particular brain chemical a neurotransmitter a hormone a very simple hormone an amine hormone hormones are just signaling chemicals so they cover a lot of different chemicals in in the body and we're focusing on serotonin and you'll likely have heard of serotonin probably in the context of mood you might have heard people describe it as a happy hormone maybe you've heard people say that it's linked to depression and if your serotonin levels low maybe that explains your depression of course that's massively dumbed down it's partly true but the reality is it's a little more complex and interesting than than that but psychedelic drugs psychedelic being a term coined in the 1950s by a British psychiatrist Humphry Osmond refers to a key really the key property of what these drugs do to the mind which is to reveal the mind its content it's its depth and that's quite a hopefully an interesting theme that it's a reminder to us that there's a lot of the mind that isn't so easily visible to conscious awareness and so with the coining of this term Humphry Osmond in collaboration with Aldous Huxley who we'll talk about later on I wanted to kind of capture that essential property of what these drugs do that they open the mind up they reveal its content it's true depth and so psychedelic mind manifesting mine revealing is referring to that that keep property so that's our definition of psychedelics at least in terms of the etymology where the word itself comes from we can also define these drugs based on their pharmacology how they work in the brain and that's where serotonin comes in and this this happy hormone and serotonin the signaling chemical neurotransmitter most of it is actually found outside of the brain 90% of it is found in the so called enteric system or the gastrointestinal system you got if you want and there it controlled bowel movement and motility in the gut it's generally associated with constriction similarly with the vascular system blood what it does in the brain is first of all quite complex it does a lot of different things serotonin is a neurotransmitter but it's a particular kind of neurotransmitter neurotransmitters signaling chemicals in the brain transmitting signals right and serotonin is what we call a neuromodulator so rather than being a neurotransmitter that works more like fuel in the system or some kind of inhibitory chemical so so the fuel glutamate an inhibitory chemical gaba they're more like the kind of hot and cold of the brain with serotonin we have a modulator which is more of a kind of subtle tuning of the brain and serotonin is a very complex neurotransmitter as I said you're a modulator and speaking to that complexity is the fact that it has a very broad range of what we call receptors and these are the proteins these are proteins that sit in the membrane of important brain cells and neurons that brain cells that do most of the important signaling and and passing of electrical signals and chemicals between each other and so these receptors sits in the membrane and when neurotransmitters bind to them they they initiate a signal within the cell and that signal changes the behavior of the cell and there is a number of different ways in which you can change the behavior of a cell so for example through one receptor you might initiate a signal that makes the cell more excitable and then another receptor might make the cell less excitable and so and there's a number of different varieties on that and say serotonin has we think something like sixteen different receptor subtypes speaking to that broad complexity of this system just to put that in a bit of context you might have heard of another neurotransmitter dopamine the number of receptors identified for that it's more like I think less than five so serotonin I to my knowledge the most complex neuromodulator that we have in the brain and we know since the 1980s that one of the sixteen different receptor subtypes is critical to the action of psychedelics we first discovered this because it was found that there's a near perfect correlation relationship like a straight line between the affinity or the binding potential or stickiness of a psychedelic drug whether it's LSD mescaline psilocybin for a particular serotonin receptor the serotonin 2a receptor 2a the more sticky the more potent so that relationship was discovered in the mid-1980s discovered in animals looking at head twitches which is our kind of behavioral readout of a rodent that's tripping they sort of shake their head we don't really know why but that's our readout of whether the psychedelics working or not in in animals in humans you can just ask them about the effects and there you can see that the dose required for people to feel the effects correlates extremely strongly with the drugs particular affinity for the serotonin 2a receptor and that rule that near-perfect relationship between affinity or stickiness for the 2a receptor and potency doesn't exist for any other serotonin receptors or any other receptors in the brain so it's that level of specificity that I think is quite remarkable actually and it's amazing actually that not it's not sort of common knowledge for anyone who's interested in psychedelics that we know it's such a high degree of specificity that for example if you block this receptor by giving a drug that binds to it but gets in the way of another chemical that might come in and signal that receptor just blocks we call those antagonists people don't trip so you give the blocker block that receptor you give big dose of LSD you're not going to feel it you know it's a really solid scientific evidence for the importance of the serotonin receptor really the importance of the brain to all the weird and wonderful things that can happen with a psychedelic and so that's where we are with with serotonin and the 2a receptor being being really important we also know now through some recent brain imaging work that you can look at the proportion of these 2a receptors most of which are found in what we call the cortex which means bark actually like the bark of a tree their outer layer and in humans our brains are so weird because first of all they're massive compared to other animals and especially compared to body weight actually whales have bigger brains but they have massive bodies so in humans we have massive brains but our body you know so big not as big as a whale and what's weird about our brains is just the sheer amount of cortex that we have and cortex is associated with higher-level functioning processing computational processing thinking and in humans kind of this associative analytical thinking we have a lot of what we call Association cortex that you don't have in other animals they have the sensory cortex that does you know the hearing and you know seeing and smelling but humans have a lot of this sort of extra cortex that we think is related to our associative analytical style of thinking that's pretty unique in in our species and so these 2a receptors are disproportionately expressed in cortex that humans have so much of and disproportionately expressed in the high-level cortex associated with this high-level cognition or thinking and we know recently through using a brain imaging technique or positron emission tomography which I'll talk about later on that you can look at the proportion of available to a receptors in the brain and how much of those what percentage of those is occupied by a psychedelic that you give and this works been done with psilocybin which is the key psychedelic chemical found in so-called magic mushrooms and we know that around if you if you give a dose around 20 milligrams plus and you occupy about 60% plus of the available to a receptors you're going to get very strong effects and just recently it's been found that there's a another strong relationship in this case it's not entirely a straight line or a linear correlation like with the 2a affinity and potency but it's a nonlinear quadratic relationship between the proportion of 2a receptors that are occupied by the drug the psychedelic and the intensity of the effects that you you give a low dose you occupy I don't know 10 20 percent you're going to feel it a bit you give a higher dose 20 milligrams of psilocybin or more you're occupying now 60 70 percent you'll feel it a lot and it's not a perfect linear relationship it's sort of an inflection point there's a kind of step function you give over a certain dose and the experience becomes qualitatively and quantitatively in terms of intensity much more you know you jump up in intensity and effects and it's in that kind of 60% plus range 20 milligrams Plus that you start to get really interesting effects with these psychedelics the kind of thing that kind of things ie go dissolution and these spiritual type experiences that we'll talk about later on so all of this is really solid evidence for for the importance of the to a receptor so that's where it all begins and it's very important I think when you can get whisked away by all of magic associated with psychedelics you know visiting the spirit world and you know seeing DMT entities and all that that it grounds us and it says this like we think everything is a thing of nature the thing of these dimensions in this universe and we can pin it right down you know it's a quite a low specific level at the molecular level this particular serotonin receptor you need to stimulate to go to the spirit world you know it's one of those really grounding principles and perhaps like a reminder of the value and power of science that we know this and so a key question when you know this really the importance of this receptor is why why is it there why do we have it at all what does it do you know if you're stuck on psychedelics you might think oh my goodness maybe it's there for psychedelics and that's an interesting thought and people have entertained that that thought and there are some good reasons and bits of evidence too assume that we have chemicals swimming around in our bodies and even in our brains that can be psychedelic we have DMT dimethyltryptamine very closely related to serotonin looks a lot like serotonin as do a lot of these psychedelics there's a hint there about how they're working they're kind of hijacking the natural neurotransmitter itself serotonin they look like it they're kind of serotonin imposters and they come in that kind of hijacked that natural system and they do that thing but we have DMT dimethyltryptamine serotonin is 5-hydroxytryptamine so very closely related you look at the molecules they look almost identical and we have a little bit a very low concentration of DMT swimming around in our bodies and our brains anyway we don't really know why maybe it's just a breakdown productive of chemicals that do that have more ordinarily involved in signaling and such like in the body in the brain and it's thought that the levels of DMT that are in the body and in the brain are probably too small to be functionally important but even so just to say that that idea has been entertained and people like Rick Strassman have put forward the idea in American psychiatrist written a very impactful book DMT the spirit molecule put forward the idea that DMT might be released during extreme states like dying and actually now there's some evidence that the concentrations of DMT do indeed leap up when you induce a heart attack in in a rodent for example the problem there is that a lot of chemicals leap up because your animals dying and it's about its cells start to break down and they spill their content so serotonin its concentration leaps right up I don't know what it is something like four four hundred times its ordinary concentration is found in in the brain during during these conditions when the animals dying but that aside that possibility that should never be ruled out you should never really rule anything out let's address that question again why are these serotonin 2a receptor z' there what do they do they could be there for a naturally occurring psychedelic like DMT or maybe they're there for serotonin and there's this rule in in so rational thinking Occam's razor that you should tend to go with the simplest most plausible explanation picking from a range of different possibilities yeah maybe not the one that makes your your spine tingle with excitement that we have a naturally occurring psychedelic there's this there and and that's why we have these two a receptors but perhaps it's there for serotonin you know that's probably the most simple and plausible reason for these receptors being there and so then what does it do what does it do and we know that the most reliable way to release serotonin and this might sound a little counterintuitive at first when you think of serotonin as a sort of happy hormone the most reliable way to release serotonin is to stress an animal or cause some kind of pain but if you think about it a bit more maybe it does make sense because the most reliable way to release endorphins naturally-occurring pain relievers is to cause pain and so maybe there's a clue there that you release the serotonin and it's going to counteract it's going to address it's going to be a response to stress maybe that's its function and and this is a useful way I think of thinking about a bit of a mystery really in in psychopharmacology drugs in the mind in the brain mystery and science what serotonin for but a strong candidate is there is that it's there in the brain at least for some kind of response to stress and adaptive responses to stress might take a few different forms and maybe there are different serotonin receptors that address those different responses to stress but because we're interested in psychedelics and we're interested in the to a receptor what might it's signaling do that's functionally useful as a response to stress and to answer that we can look at a lot of evidence that we have the first of all that stress paradigms a number of different kind of varieties of ways in which you can stress an animal quite sad in some ways of course that this research is done but it's done we have this information stressing animals you you you don't just release serotonin but you increase the availability and also the functioning generally speaking of the to a receptor it's quite a specific and very reliable relationship stress an animal the more intense the stress and the more chronic or long-lasting the stress the bigger the effect and what what happens is it's a term we refer to as an upregulation just means an increase really we up regulate the functioning of the to a receptor so another kind of clue that that this receptor is involved in in a response to stress so to focus in now about the specific response you can look at different evidences that show that stimulating the to a receptor the serotonin 2a receptor increases plasticity in the brain and we can have a number of different markers of plasticity you boil that term right down what does it mean really it's about the ability to change and plasticity could mean that you you you change your behavior or maybe you're just supple and you reinforce your behavior so it's not always like the breaking of patterns of behavior or thought it can be the stamping in of patterns or thought it just means that you've got a supple mind and brain or system that you can that's pliable that's malleable that you can move in a particular direction and that's what - a receptors seem to do they seem to be strongly associated with plasticity the potential for change and so that's another clue about why they're there there's also strong evidence that the - a receptor is involved in learning learning and plasticity go hand in hand another component of learning is what we call extinction learning or unlearning so you've stamped in some kind of behavior like an addiction for example what can you do to sort of rewrite that learning well you can induce plasticity the ability to change and then you can try and break associations you know and so that's extinction learning and if you can enhance that maybe you can treat addiction for example and so if you're inducing plasticity through the - a receptor you have a system that is very sensitive and it's sensitive to the conditions that it's it if you provide conditions that are going to stamp in a certain kind of behavior you're going to stamp it in more easily because you have that supple plastic system but if you provide conditions that are going to shift you in a particular direction guide you in a particular direction then that's going to be enhanced so there's a really important rule here that's starting to emerge in relation to serotonin itself but particularly this serotonin 2a receptor that is hijacked by psychedelics and the rule is that serotonin and serotonin 2a receptor specifically is strongly associated with our sensitivity to context sensitivity to the conditions that we're in at any given moment and a lot of different things you can bring in here like strong evidence that the 2a receptor is involved in brain development as we mature it's involved in modulating and mediating how the brain matures and develops levels are very high early on in life and drop as we hit sort of middle age whether that's associated with a kind of sort of ossification or you know rigidity of thinking and behaving as you as you went to that part of life is an interesting question maybe so that's where that's where we are serotonin that's what psychedelics are working on they're working on that aspect of the serotonin system that is associated with plasticity and they're inducing a state where we're very sensitive to our conditions and those conditions might be right there and then in the environment but there's another environment to think about and that's the inner environment it's what's in your head to begin with and if these compounds are psychedelics are so flattening the the hierarchical nature of the brain so much of nature is organized hierarchically and there are different things that sort of enslave things you know a level down a kind of mastery slave relationship is found throughout nature and it's very much found in the brain likely explains a lot of of how the brain works but through this to a receptor you're there's good evidence that you're relaxing that kind of enslavement and and and so in that kind of open playing field you have this supple system that's going to be sensitive to what's out there but it's also going to allow for what's in there to be more easily accessible and all of this might intuitively bring you to that theme that was emphasized initially actually by by Timothy Leary who we'll talk about in the next section of set and setting set is your mindset it's that inner environment it's what you bring to the experience you know in psychoanalytic terms you might think of it as the unconscious mind or Aldous Huxley refer to it as the mind at large you know the mind sort of beyond ordinary sort of conscious access that's that's the set that's the unit includes more superficial things like your expectations but maybe it also includes things like you know what happened in your childhood or maybe even further back you know what happened in in you as a human being you know in terms of your your ancestry these the collective unconscious as Col Col Jung would refer to it so all of that can become more available and accessible that's just set and then the setting is simply what's there in the environment people that you're with the music that's playing maybe the stress that's in the environment and so you know let's come back again serotonin serotonin 2a receptor plasticity sensitivity to context that's likely what this receptors there for and good evidence that if people whatever your being whether you're a rodent being stressed in someone's laboratory or you're a human being encountering the ordinary stresses of life perhaps they get really intense and you've got some existential threats to your very existence or sanity what's going to be happening in your brain is that you're to a receptor is increasing in availability and functioning you're getting very plastic very sensitive and context-sensitive and you could you could sadly enter a psychosis and go in that direction you hit a fork in the road and you can move off to madness or you can have some kind of existential revelation and transformation and maybe you find God and you start to take up spiritual religious practice you have a conversion experience or you know so it's a fork in the road and and these are supple plastic states I like to call them pivotal mental states because they could either move towards pathology or they can move towards I think they call it a pathology but wellness so it's an opportunity and we'll talk about this later on how you can harness that opportunity therapeutically to try and treat mental illness or just generally move someone towards a state of enhanced psychological wellness so just to rehearse what we covered there we talked about what psychedelics are mind revealing we talked about how they work at the molecular level that we know that and we know it quite precisely that they work on a serotonin system very complex neuromodulatory system in our brains they work on a particular receptor subtype the to a receptor serotonin 2a receptor found in high concentrations in the cortex that aspect of brain that humans have so much of and especially so in the highest-level aspect of cortex in the association cortex that's where you see these key kind of gateways that psychedelic work through molecular kind of gateways the serotonin 2a receptor where it all begins they're there they're in high concentrations in hierarchically the highest aspect of brain the to our knowledge we know even exists anywhere in the universe so far and yeah and by stimulating these receptors we induce a state of plasticity ability to change and so in a state of high sensitivity you have a system that is capable that can be guided in a particular direction and if that state emerges arises naturally through stress for example adversity then sadly you might move towards illness and maybe something like a psychosis in an extreme case but perhaps you induce that state so for example with the psychedelic drug or maybe even some kind of ascetic practice that creates a kind of stress to the system but you've intended for that stressing of the system and you utilize the the subsequent plasticity to move you towards wellness so that's where we are in the next section we're just going to rewind a little bit and cover the history of the science of psychedelics so maybe a little lighter and hopefully interesting you

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Keywords: psychedelics, robin carhart-harris

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Length: 30min 13sec (1813 seconds)

Published: Sun Mar 22 2020