Dr. Robin Carhart-Harris: Psychedelic Psychotherapy

wonderful well thank you very much it's great to be here before um i got this invitation i'd i must have heard implicitly the term biohack but i never really thought about it but uh so i've come here with great uh curiosity to to learn and i've been learning a lot so far i'm really enjoying it so hopefully i can contribute something uh to your knowledge base that might feel relevant um to biohacking they used to call it health perhaps but uh that's where we are and i suppose uh in terms of what i do uh or rather really what these substances do psychedelic compounds is that they're hacking the mind they're hacking the brain and i suppose that's where i fit into this um this picture puzzle what are psychedelics let's start very much with the basics well we can define them by their etymology psychedelic means mind revealing so already that's hinting at a kind of hack we're getting into something that ordinarily by implication isn't fully visible to us the mind the psyche the soul and with these substances we make manifest we reveal uh aspects of the mind that are ordinarily not visible to us another simple way to define them is to give you some examples i'll give you some examples now of classical so-called classical psychedelics and then i'll give you a definition arguably the most concrete that i could offer which is pharmacological it's based on how these drugs actually work at the molecular level in our brain so examples we have psalocybin uh the pro drug of cylosine occurring in the so-called philosophy species of mushrooms grow throughout the world uh and they contain this substance psalocyvin broken down into psilocybin into salacin uh in the body uh once ingested and it's this that works on the serotonin system like all of these classical psychedelic compounds dimethyltryptamine something that occurs uh actually throughout the plant world it also occurs in in some some animals it it it can be found in our own bodies albeit in minuscule amounts it's something that's included in terms of leaf material in a amazonian tea called ayahuasca which is a combination of these dmt containing leaves and also vine that contains monoamine oxidized inhibitors that stop the oral breakdown of the dmt so it's a way of rendering dmt orally active it's something that's been used for possibly thousands of years in in a ceremonial plant medicine context and now people are experiencing ayahuasca through retreats and such like traveling to the amazon or just doing it in a more underground way lsd a uh arguably the prototypic typical psychedelic prototypical because it was only after lsd was discovered famously by albert hoffman in 1943 that we had this major wave of scientific interest in these compounds in the west and it really um spawned the first major wave of of modern scientific interest now these classical psychedelics as i've already alluded to all work by mimicking and hijacking as drugs generally tend to do an aspect of the natural system our bodies and a particular organ in our bodies our brains and they hijack a particular a particular aspect of the serotonin system first of all just looking at the molecular structure we can see how salacin dmt and also lsd do look quite similar to this naturally occurring brain chemical serotonin important for such a range of different mind um and brain functions so then following this we asked that key question what aspect of the serotonin system do these compounds hijack well we now know with a quite a high degree of confidence that it's a specific aspect the serotonin system is one of the most complex neurotransmitter neuromodulatory uh systems in our brains it has a range from 14 different uh receptors um which are kind of like the uh the locks that uh that the keys the keys being either drugs or or serotonin itself come in and they they they'll turn these locks uh in a particular way and and that will lead to a cascade of different effects and and all these different receptors do can do quite different things sometimes uh their functions sort of impose each other and we know that there's a particular serotonin receptor subtype that is critical to how these compounds work in the brain it's the so-called serotonin 2a receptor we know that because from a range of different studies if we give what we call an antagonist or a blocker that comes in and it will selectively block this particular receptor then people essentially won't trip they won't have a psychedelic experience we also know that the affinity of a psychedelic compound for this particular receptor correlates very strongly with its potency so for example lsd very high affinity and you only need tiny amounts because it's so potent so these compounds come in and like serotonin they'll stimulate the receptor they're agonists they'll provoke a response and what follows from that response well we know at a relatively low level that these compounds promote plasticity um in terms of growth of new functional units on on functional components of neurons that can facilitate communication we can take it up to a higher level and look at things like behavioral change behavioral plasticity and flexibility cognitive plasticity can take it up to an abstract level and think of things like psychedelics promoting imagination abstract thinking divergent thinking a component of creative thinking there's a kind of generalized enhancing effect on plasticity we break that down what what is plasticity essentially it's a um it's the capacity for change um so that's what that's a key function that seems to be mediated by the serotonin 2a receptor i just want to breeze through this slide because it's easy to get stuck in it but the reason why i present it is to contextualize how psychedelics fit in in terms of the the history and the developments in in psychiatry so a major event um a series of events happening in the 1950s during the so-called pharmacological revolution included such things as the discovery of the first antidepressants the monoamine oxidized inhibitors remember that's actually a component of the ayahuasca brew as well and that uh that that has a generalized effect on brain chemicals increasing serotonin but also noradrenaline and and dopamine these pro-energy energizing monoamines and then we have a major development happening in the mid 1980s with prozac and and related drugs being discovered and now we have these compounds that are a bit more selective in their pharmacology they're increasing not just mono amines in general in general but a particular one serotonin and it's really with this that um psychopharmacology starts to believe with a bit more confidence that serotonin seems to be important in the modulation of mood and now in a way we're going full circle because psychedelics have been used as healing compounds holistic healing compounds in plant medicine context for hundreds perhaps thousands of years and it's intriguing to reflect on the fact that their pharmacology is more selective than that of the ss horizon so we could consider this in a kind of paradoxical way as as as progress in terms of the precision of the chemical pharmacology as well as going kind of full circle in sort of going back to go forwards rediscovering an ancient therapeutic approach now also the history of psychiatry in terms of psychotherapy and more specifically psychoanalysis freud for example dominating psychiatry for the first half of the 20th century and then the so-called pharmacological revolution that comes in in the 50s with drugs starting to take over and now we have this interesting synergy which isn't either just a drug or or a psychotherapy on its own but rather a drug that changes the mind the landscape of the mind in a particular way that might facilitate a certain kind uh of psychotherapy that can utilize that these developments are also helping us understand serotonin itself which has been a mystery for so long in terms of what it does what it does in the brain what it does to the mind people have offered hypotheses such as that serotonin is important for moderating stress and this ties in with how people think of of what ssris do that they can in a way sort of facilitate resilience stop the bottom from falling out um aid management of severe crises for example psychological crises and can moderate and mitigate negative affect some would wager also affect in general or intense emotion the edge can be taken off with these chemicals serotonin also aiding patients increasing evidence for that and now really intriguing evidence that puts a slightly different uh um more complex spin on what serotonin does in the brain and in the mind which suggests that it it increases our sensitivity to context so if you up serotonin levels with uh pharmacological interventions for example that will accentuate the influence of environmental factors if those factors are uh adverse if the conditions are adverse then people will do badly with a increase in serotonin levels if they're favorable if you have support then you may well do well and this ties in now to how we're thinking of a more specific aspect to the serotonin system the one that psychedelics work on and what that does what what that key function is about i've already alluded to plasticity and that ties in here we've moved on from thinking that these are compounds that are um simply psychotometic that they can mimic aspects of psychosis certainly they can and they can also be therapeutic agents but even that rule is more nuanced than that and it's more that via stimulating this particular receptor you can open a window of plasticity open a window of sensitivity to context environmental context but also in a context what's in the the agent to begin with in terms of expectations experiences memories trauma for example and making one uh more supple and sensitive to these contextual factors and so if we think of serotonin in that way mediating sensitivity to the environment i think we could think more accurately about the aspect of serotonin that's mediating that and put our focus onto this particular serotonin receptor subtype sab provides a kind of low level chemical context for uh psychedelic therapy if you want and as things go on i'll move up uh the levels to more network level and a psychological and experiential description of what this treatment seems to do but before i do that i just want to summarize the evidence base for psychedelic therapy we can begin with the safety profile that we know these compounds have a very low addiction potentials uh won't self-administer uh these compounds as they might other uh drugs of potential misuse um alcohol and such like the in in a way these these compounds are quite aversive both to animals and to humans can sometimes have you know really hellish experiences uh under these compounds and yet afterwards paradoxically they'll say they feel renewed refreshed sometimes reborn and so that's kind of useful in terms of the abuse potential of this potential medicine in that these aren't compounds that are are moorish in in the classical sense that many drugs of potential misuse are they also have a low toxicity profile um psilocybin especially uh much lower than um other um uh new interventions being used in psychiatry and in the management of depression like ketamine for example so it really has a favorable safety profile in that respect and then meta-analyses have looked at the old specters that have hung around these these compounds things like induced psychosis uh enduring perceptual uh um changes and found that the prevalence of these these cases are extremely low they can happen um but um but the the ratio of benefit to harm seems to be much more weighted in in in on the arm of potential benefit now if we focus on the potential benefit what's really exciting about this treatment modality is that the therapeutic effects appear very quickly so we've seen drops in our depression scores just a day after the the intervention and these this is in people who've had their their depressions for on average over 15 years they've tried um some of them 11 different antidepressant medications without that affecting their depression in a significant way also different psychotherapies close to 90 percent of the sample had tried at least some form of psychotherapy often multiple therapies and that hadn't budged their depression either so we see these rapid changes and we also see them enduring the maximal effect size was actually at five weeks after this isolated four to five hour experience so that's really quite paradigm shifting in the context of a pharmacological what you might interpret as a pharmacological intervention uh uh in in mental uh health uh that uh rather than being on a drug you know consecutively chronically medicated uh it's that you have a particular kind of experience a profound experience that then seems to endure so that's been demonstrated quite nicely by the by the likes of roland griffiths and his team at johns hopkins where they've given quite a high dose of psilocybin to people who'd never taken a psychedelic drug before and they found these enduring increases in psychological well-being um that uh remained um significantly increased over a year on from that single um uh uh time limited experience of just four five six hours under the psilocybin they also found that people would rate their experience as being among the most profound of the whole of their lives they would put it up there with things like the birth of their first child and and that sense of meaningfulness of the experience is something that also um endured as well some people would describe their experience as being mystical you might think of a synonym for that a more secular synonym as a peak experience uh whatever your your favored uh perspective on this um uh what seems to be um uh compelling is that the experience is is is very profound and is felt as meaningful so population studies have looked at um different mental health outcomes peter hendricks at in alabama has looked at suicidality in a in a large cross-section of the u.s population some close to 200 000 people looking at different factors and then looking at their relationship to mental health outcomes he looked at psychological distress and he also looked at suicidality and he found that use of psychedelics was an anomaly among use of drugs of potential misuse so the general rule is the more you take the drug the worse your mental health whether it's alcohol whether it's heroin that rule stands up but not with psychedelics so those who reported psychedelic use i think within the last year actually had significantly lower rates of suicidality and psychological distress when controlling for other potentially confounding variables now the modern wave of controlled clinical research with psychedelics was really kicked off in 2006 with a modest study looking at salazar in a single treatment session with psalocybin for obsessive compulsive disorder finding promising outcomes there but those researchers being really a lot of pressure put on them by by stigma and regulation and their work was was um uh wasn't really allowed to to continue and flourish but the signs were promising and this has since been followed by uh more recent work looking at psalmist for end of life distress so people given terminal diagnoses experiencing exercise existential anxiety and depression in relation to that and then being given psalocybin with psychological support on either just one or two occasions and then these consistent findings of rapid and enduring improvements in these mental health outcomes and crucially again these these responses appearing to be significantly mediated by the kind of experiences that people were having under the psilocybin others have looked at addiction smoking addiction 80 abstinence rates after two treatment sessions with psilocybin at 12 months on so really remarkable outcomes uh in the context of leading treatments others looking at sully simon for alcohol dependence again very promising and exciting drops in drinking behaviors um with with stylistic therapy for for alcohol dependence we've looked at depression i've already described some of those results treatment resistant depression others have looked at ayahuasca for severe depression uh we're now looking at psilocybin versus a leading ssri in the context of major depressive disorders so people will either get six-week six weeks of escitalopram very selective serotonin reuptake inhibitor one of the leading ssris um and people will either get that or they get to full dose treatment sessions with psalocybin so we're really now trying to put our um our resources uh where our mouth is and put this to the test because we do believe there is major potential here as do others as do investors some private money coming in now several millions of dollars um for a multi-site trial potentially pivotal registration trial in europe covering at least 13 different countries similar work being planned for north america so things are really starting to happen now and how importantly does this uh does this work and so here i would refer us to arguably the leading model of how the mind and brain works more generally outside of the context of psychedelics just what's dominating cognitive neuroscience at the moment what's dominating psychology and psychiatry more generally as well and it's this predictive processing model it's a model of the mind that says that much of what the mind and the brain does is to is to impose internal models on our experience of the sensorium and really that our experience of the world is very much dominated by these internal models they might to some extent be innate and that and and to a large extent they're also learnt and perhaps in certain psychopathologies they could be overlearned and become over dominant we can think of biases in depression for example a pessimistic bias a negative cognitive bias how this can become kind of entrenched and then dominate the way we think and really the way we feel as well other examples phobia where we might know our beliefs our internal models which our beliefs their predictions their assumptions their expectations we might know that they're entirely irrational and yet we're compelled by them because of the dominance of these internal models similarly eating disorders which was talked about uh earlier in the context of fasting for example but when when this happens it's it's it's so clearly pathological that people look in the mirror they think they're fat and they're not at all um but um yet these these irrational beliefs become stamped in for whatever reason i'll suggest a reason in a moment but i'll also suggest right now a potential solution to aberrant beliefs which quite simply would be to relax those beliefs let's say in a time limited plastic state and then work on their revision and that's what i would submit is what psychedelic therapy does essentially so we know predictive processing rules supreme we just need to look at things like optical illusions or the way we can fill in this kind of garbled text and read it relatively coherently even though the at the granular level the the units the letters that are jumbled up we can still see the gestalt and we can make sense by grouping by our internal models of what this text is saying so predictive processing has been described as a kind of handshake between internal models or beliefs and data which might include things like what comes in from our sensorium through our different senses our eyes our our ears our touch but also feelings feeling states what's coming up uh in terms of bodily sensations uh within us and so this kind of handshake as i've already suggested is is overweighted it's biased to the side of beliefs that's what happens ordinarily this cognitive aspect of of modern humans is arguably more dominant now than ever and perhaps we're starting to realize this and thinking that we should think more carefully about harmonizing with our sensations and with data but that top-down top-heavy aspect of our minds i would submit is a large part of psychopathology of mental illness it might arise because of conditions of uncertainty that are very difficult for us to tolerate where might that be especially extreme well perhaps in the context of trauma for example so i just offer this this sort of loose kind of throwaway model um let's see it's if it's of any use as we go forward but i call it tiber i could go into why um but i won't but uh it's a it's an acronym that stands for tightened beliefs in response to uncertainty and we can use uncertainty and trauma it's kind of interchangeable there perhaps a solution and perhaps a desired end state we might want to get to is a situation where the mind and the brain isn't so top-heavy but there is a more harmonious handshake between internal models and our experiences of the world and so this is how i propose we get there with psychedelics and i call this one the rebus model relaxed beliefs it's not tightened like in pathology but relaxed beliefs under psychedelics i know it's a bit of a fudge the acronym but it sort of works for me i think it might be memorable as well and so it all starts with stimulating this particular aspect to the serotonin system the 2a receptor initiating this window of plasticity i call it an entropic hot state a state in which things get kind of jumbled up there's more uncertainty and and at least for a period and like i said it's not often not pleasant the acute psychedelic experience but in this state we can have a relaxation of of beliefs at multiple levels uh including at the highest levels particularly with high doses where people will experience a a breakdown of internal models as high as our own sense of self and people realize have a realization a profound realization that they have constructed their self their identity as an internal model and it's not something that's absolute as they perhaps assumed before they had this experience and then out of this kind of flattening of the mind's landscape and opening of the mines landscape people often report spontaneous insight and it's this insight that seems to mediate to a large extent the revision and the recalibration of people's beliefs so that they can be more in tune and more harmonious with with what i call data experience in the world that all sounds a bit abstract it's a model and all models are wrong um so let's see how wrong it is and whether we can improve it going forward but i provide it as a sort of heuristic i think it's useful um and uh in time we can test it we can scrutinize it um and see um see whether it helps us or not but if we just listen to our patients what are they telling us and how can that inform how how we understand this treatment might be working they often use analogies that are quite mechanistic they'll talk about their minds and their brains feelings if they've been rebooted reset here's a patient from our depression trial saying it was like when you defrag the hard drive on your computer referring to their mind and their brain now if we look at what happens to the brain under a psychedelic acutely so this is within the experience itself we see a couple of principal things we see if we look at large-scale brain networks sub-serving different distinct functions whether they're vision or hearing or movement motor action or higher level things like thinking cognition or even introspection arguably that highest level function for for humans that's so um so especially advanced in our species and there is a particular network that's quite closely associated with introspective function it's called the default mode network it's exciting a lot of interest in cognitive neuroscience at the moment especially over the last 15 years or so since its discovery and what we find is that when this network breaks down under psychedelics and as a rule networks do appear to break down under psychedelics but when this network breaks down people will describe some of the more profound aspects of of of their experience they'll refer to a sense of ego dissolution and we see a strong correlation there between ratings of ego dissolution and the breakdown of this particular network or system which is arguably the leading candidate as a sort of functional dynamic system uh that can correlate with with our sense of self and self functions so there's a principle that these networks break down there's a disintegration if you want within large scale brain networks under psychedelics brain networks also appear to lose their the extent of their separateness and so in a sense their their their um specialization their difference their level of um of uh distinction um uh segregation from each other and so this this desegregation of brain networks is something that we've seen quite reliably and other teams have now here we're looking at the visual system that's the blue blob at the back of the brain the primary visual cortex and a particular aspect of it that does very low level visual processing we're asking the question with this analysis where in the brain is activity correlated to that blue region we find that ordinarily activity is quite constrained and restricted to the visual system so part of the visual system is just talking to other parts of the visual system there's high specialization there under lsd and as we've seen with other psychedelics that rule breaks down and much more of the brain now starts to kind of bleed in to visual function influencing visual function that's something that we've depicted a number of different ways people tend to quite like this image which shows different communities of regions so the colors are communities of regions which are the the small blobs and then the lines between them are communication patterns that are above a certain threshold for significance and we can see ordinarily most communication goes on in a kind of cliquish way within certain um communities certain systems of function and yet under psychedelics there's a much open more open conversation going on between different um systems in the brain so that's what we see acutely but but what do we see post-acutely after people have had their profound potentially mystical type experiences peak experiences under these compounds what happens when they come down well there when we look the next day and it should be said that we i think we're just scratching the surface here this is really just the first bit of data that we have on this um it's from our depression trial it's just one day post-treatment but we want to ask you know given these enduring effects what happens weeks months after this treatment but this is all we have at the moment we look the next day and we found something quite different to what we see acutely so instead of networks breaking down we see that they reintegrate we make that assumption knowing that they break down acutely that they're reintegrated post-acutely with actually a slight um expansion in the spatial extent of the network at least in the context of the default mode network what that means um in terms of the big picture we don't know but in terms of the we have some ideas but in terms of um uh the therapeutic meaning of it well it does seem to relate to therapeutic response so those patients who responded to the intervention and had significant drops in their depressions that rendered them classifiable as responders at five weeks at a key end point when the effects were maximal were those who showed this reintegration to the largest extent so it seems to be useful it seems to be important in mediating uh the therapeutic response so what i've given you um in this talk is a kind of very mechanistic account of how how psychedelics um work in general and therapeutically but i don't think it entirely does justice to the very rich um phenomenology of the psychedelic experience and one component that i've left out that i just want to address now in the last five minutes or so is insight remember we started off by reminding ourselves that psychedelic means mind revealing making the mind more visible to itself the mind revealing itself to itself and what we found in our therapeutic work is that the magnitude of people's ratings of insight acutely is predictive of the therapeutic response in the longer term i have a patient here and there's you know very many examples of similar things and and much richer accounts of course but here just the patient saying i had fresh insight into things it was as if the scales dropped from my eyes so the this is kind of alluding to dissolution i would suggest of of a kind of occluding uh quality to the mind and and because of that um that breakdown of the kind of blockage and obstruction um the one can experience a broadening of the mind and be more fully aware of things that perhaps previously were kept from consciousness why perhaps because they were hurtful uh and difficult to integrate so that's the therapeutic model you can see the correlation there drops in uh depression scores correlating with insight here's just a schematic to refer us to brain dynamics it's it's an attractor landscape an energy landscape it's a way of depicting a dynamic system dynamical system with a static image and we can imagine this ball having having dynamics being able to move around and in this landscape it's going to fall into that dip into that depression and it might get stuck like in treatment resistant depression and find it difficult to get out everything's pulling them back into this rut into this deep depression and so what might we need in order to remediate that situation well we could flatten the attractor landscape flatten the energy landscape in that way the ball would be able to move out it would have freer dynamics it may well be felt as a as a freeing up of the mind and that's an analogy that i just want to leave you with and also with this theme of reconnection i talked about a healthy handshake between internal models in the world that can happen with successful treatment and again this is something that people will describe with the treatment and i just want to give you some of these quotes we've written about this in a more formal way from qualitative work and then proposing certain experiments we can do to test this more concretely but let me just read you some of these quotes this one and these are from patients in our trial other trials here's the first one this connection it's just such a lovely feeling we are all interconnected you hear that kind of thing in all sorts of contexts with psychedelics i was being reminded of things i already knew i was learning without being taught there had been i felt an opening of the heart i was convinced in that moment i'd figured it all out it was right there in front of me love the only thing that mattered now this sounds kind of platitude and all it can sound wishy-washy but you hear this uh from people and and it's so compelling for them and it does seem to be what's mediating their wellness when it works and i'll just leave you now with this last quote which comes not from the context of psychedelics but from a an astronaut taking part in the lunar missions uh being up there and experiencing the overview effect looking back at the earth seeing it in its totality and then in having that big picture being perhaps able to put things in perspective i think that's a very useful an analogy for thinking about how psychedelic treatments can work in my cockpit window every two minutes the earth the moon the sun the whole panorama of the heavens and suddenly i realized that the molecules in my body the spacecraft the body of my partners were all manufactured in some ancient generation of stars i've heard carl sagan's quote earlier it's very much related i felt an overwhelming sense of oneness of connectedness and insight and epiphany so i'd just like to thank those who've supported this work the uk medical research council shamil chandaria and his foundation who are really opening things up for us now in the uk with a new center at the university of oxford that will run in parallel with things at imperial alex mosley charitable trust and to thank you very much for your attention thank you thank you very much dr carhart harris for such an insightful overview you very well gave an overview of the different positive therapeutic interventions and their implications now there is some concern with the use of some psychedelics especially on a repeated basis for example lsd seems to have high affinity on 5 hd 2b which has been linked to increased risk for uh while or heart disease so you can basically grow tissue in your heart that can be problematic so there is a lot of discussion on micro dosing and if that's safe compared to having high dose experiences that seem to break down the default mode network and all of that so what is your take on micro dosing and the potential risks because i know that there are several medications that have been taken off market because of this particular effect yeah no sure we should we should think about uh all of these things lsd has comparatively uh quite a low affinity i think for 2b um it has especially high affinity for 2a 1a i don't think it lsd has such a high affinity for 2b solicit might the thing about lsd and particularly microdosing is uh you know what's suggested by the name microdosing there's such tiny amounts of the chemical and when the chemical has preferable affinity for 2a that's where we can think in those very very low doses the effect is going to happen and there's probably going to be negligible functional effects at something like the 2b receptor those kind of medications that caused issues there include things like femploramine that was taken off the market as a a dietary suppressant there's some questions that hang over ssris because in general increasing serotonin levels are gonna cause issues um in terms of serotonins up it's gonna serotonin itself is gonna hit 2b it's going to have effects there and so you know let's put this in the context people prescription rates of ssris are going up on at record levels and so if there was really major major concern here how how could that happen of course we could think of you know market forces and and and dark forces like that um but um but uh that kind of helps um put things in the context another really important thing to say is that unlike traditional um pharmacotherapy taking drugs um these treatments and and let's push micro dosing to this to the side for the moment because that's not really our focus it's something that's happening out there as a kind of meme i would you know caution people uh let's see the evidence first because it's not there yet there's just a lot of anecdote and this kind of meme that's been created but our model is to give an isolated experience and and so in that context if there is significant 2b i mean it's there in just one one shot and it's very unlikely i think to be causing any kind of valveopathy right so you are pretty much in line with the traditional use which also promotes more of uh ceremonial use uh specific mods for specific reasons uh rather than just going on with it every day for performance reasons or for mood reasons etc so thank you very much dr carhart harris that was excellent big hand

Channel: Biohacker Summit

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Length: 41min 39sec (2499 seconds)

Published: Sat Dec 12 2020