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Peter Attia MD220 ‒ Ketamine: Benefits, risks, and promising therapeutic potential | Celia Morgan, Ph.D.
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100 min read · 19,768 words- 0:00 – 0:08
Intro
- PAPeter Attia
[upbeat music] Hey, everyone. Welcome to The Drive Podcast. I'm your host, Peter Attia. [upbeat music]
- 0:08 – 1:58
Celia’s training and interest in ketamine
- PAPeter Attia
Hey, Celia. Thanks for making time on a Friday evening to, uh, to sit down and talk about ketamine and perhaps a few other things. Uh, but great to meet you.
- CMCelia Morgan
You too. Thanks. It's my pleasure.
- PAPeter Attia
Um, so let's talk a little bit about your background, 'cause I know that you-- I think you finished your graduate training in the UK, but then you, you did a stint here in the US at Yale, if I'm not mistaken. Correct?
- CMCelia Morgan
Yeah. Um, so I did my undergraduate in psychology with pharmacology and astrophysics for a bit. [laughs] Um, but, um, then I went, uh, I did a PhD program at, at University College London, but as part of that, I spent some time at Yale, and I'd got a scholarship to do a little bit of research out, out there in the US.
- PAPeter Attia
And so what did you focus on during your PhD?
- CMCelia Morgan
Um, so my PhD was largely focused on the effects of ketamine. Um, and back then, you know, that was in the, uh, makes me feel quite old, [laughs] but nearly 20, you know, years ago. Um, we were looking both at the acute effects of ketamine as a model of psychosis. So at the time, people were using ketamine with the idea that would help us understand the neurobiological underpinnings of psychosis, because actually, from the outside, ketamine looks qui- a little bit similar to people who are psychotic. Um, and so we were using that to map the kind of cognitive processes in, um, altered by ketamine. But I was also simultaneously looking at people who take ketamine recreationally, because at the time, that was quite a big problem in the UK. Um, so yeah, I had this kind of dual focus, and when I went to the US, it was to work on, again, some neuroimaging studies, um, looking at ketamine as a model for psychosis. So it was before it really became established as an antidepressant.
- 1:58 – 7:48
The history of ketamine, medical uses, and use as a party drug
- PAPeter Attia
So l-let's talk a little bit about the history of ketamine. It was synthesized in the '60s, I believe, correct?
- CMCelia Morgan
Yeah, so it was synthesized as an anesthetic by Parker Davies, um, who-- It was, uh, synthesized as a replacement for PCP or phencyclidine, um, because obviously people know PCP as angel dust, and there's this kind of folklore around it of people running at the police and being shot down and keeping running. But I mean, really the problems with it, it had this protracted psychosis-like effects that lasted for a really long time following anesthesia. It was still a good analgesic anesthetic. They synthesized ketamine as a similar molecule, so it still works on the same receptor in the brain, the NMDA receptor, but it was 10 times, 10 times less potent. Um, and yeah, so it was synthesized back in the '60s. And r- and the drug company that synthesized it were initially really impressed by its analgesic and anesthetic effects. But then with increasing clinical experience, it was noticed that people were coming around from ketamine anesthesia, reporting a variety of quite weird effects, so things like hallucinations and out-of-body experiences, and that's what's really limited its routine clinical use. But it's still one of the most widely used anesthetics in the world today. It's on the World Health Organization list of essential medicines, so.
- PAPeter Attia
Yeah, I mean-
- CMCelia Morgan
Yeah
- PAPeter Attia
... one of the, one of the things that I remember from my clinical training was that the... you know, one of the perks of ketamine was that you didn't have the respiratory depression, and most things that we use as anesthetic agents have this problem where if you overshoot them-- And that's not an issue if you're doing general anesthesia because you have an endotracheal tube in the bronchus and, uh, in the mainstem bronchus, so you're breathing for the patient. But when you start to think about conscious sedation-
- CMCelia Morgan
Mm
- PAPeter Attia
... respiratory depression starts to become a very frightening consequence that must be managed closely. And with ketamine, you didn't have that. Now, is my memory correct that kids were less susceptible to the hallucinogenic effects? Or like, I literally this is-- 'Cause I didn't do an- much in pediatrics, but I, I can't recall if there was more flexibility in using it with kids, or am I making that up?
- CMCelia Morgan
No, I think-- I mean, it is used more with children. Um, I don't know. That's the thing I've-- We tried to do a study, actually, which never really came off, but I don't know if it's that people haven't asked kids [laughs] if they're hallucinating or maybe they have more-- they're just more-
- PAPeter Attia
It's more-
- CMCelia Morgan
... uh, open to that
- PAPeter Attia
... it, it seems less foreign to them if they are maybe.
- CMCelia Morgan
Yeah, yeah, exactly.
- PAPeter Attia
Yeah. Yeah.
- CMCelia Morgan
They are tripping all the time. [laughs]
- PAPeter Attia
[laughs]
- CMCelia Morgan
But no, maybe not that. But they're more open to, like, changes in consciousness. So yeah, I think they certainly seem to-- They, I mean, it's used routinely, whether-- I've-- I, I'm really interested, and I don't think anyone's really actually asked children [laughs] about their experiences. Um, but yeah, it's definitely-- I think it's used because it's so safe, you know? So in pediatrics, in geriatrics, also in battlefield medicine. It was the most widely used anesthetic in the Vietnam War, for instance.
- PAPeter Attia
Yep.
- CMCelia Morgan
Um, so it's used, yeah, as you said, it's really safe physiologically, um, as an anesthetic 'cause it doesn't slow your breathing or your heart rate. Um, so when you've lost a lot of blood, it's good as well because it actually even vaguely increases your blood pressure. So yeah, I think that's why it's a widely used anesthetic. It's a really good question about kids, though, and I don't think-- I mean, I know there's some people trialing ketamine in its antidepressant use now with adolescents, so I'm sure we'll come onto that later.
- PAPeter Attia
So we'll get there.
- CMCelia Morgan
But-
- PAPeter Attia
Yeah. Yeah.
- CMCelia Morgan
Yeah. [laughs]
- PAPeter Attia
And, and, and I'm glad you made that other point, by the way. It doesn't lower blood pressure. So now you talk about it being the perfect anesthetic in trauma and shock, where those patients are hypovolemic, their blood pressure is already going down. You give them an agent-
- CMCelia Morgan
[laughs]
- PAPeter Attia
... that if anything slightly acts like a vasopressor, raises blood pressure without the respiratory depression. I mean, i-in that setting, you can understand why it, it sort of became, uh, you know, a, a turning point in, in the field medicine of Vietnam.
- CMCelia Morgan
Yeah, absolutely. I mean, the acute experience must be really unusual when you're in that setting. But I guess the dissociation [laughs] -
- PAPeter Attia
Yeah
- CMCelia Morgan
... so like, I think there's an interesting study about looking at the interaction between those acute subjective effects when you're on a battlefield. But I mean, yeah, also, like as you mentioned, not having to intubate people. That's why it's really popular in developing countries where you've got limited access, you know, to, um- Or ability to intubate patients, you know? So it's a really important medicine in anesthesia still, and I think that's something people forget, you know, with all the new, um, developments with ket- the use of ketamine.
- PAPeter Attia
Yeah. It's really interesting when you go and imagine what surgery was like before ether and-
- CMCelia Morgan
Yeah. [laughs]
- 7:48 – 19:30
Neurobiology and pharmacology of ketamine
- CMCelia Morgan
receptor.
- PAPeter Attia
So let's talk a little bit about that. Let's assume that folks don't know, um, what the, uh, NMDA receptor is. They don't know what glutamate is. They don't know GABA. Like, let's just assume people are coming-
- CMCelia Morgan
Yeah
- PAPeter Attia
... at this from a standpoint of not being completely up to speed on excitatory or inhibitory neurotransmitters. Um, explain in, in some detail exactly how these neurotransmitters work and how other, uh, neurons can amplify or attenuate the response of those and where ketamine fits into that.
- CMCelia Morgan
Um, sure. So I guess, well, do jump in as well if I'm either going too slowly [laughs] or too quickly. Um, but yeah, so, uh, glutamate's the major excitatory neurotransmitter in the brain, and it's prevalent all across the brain. And one of the, um, receptors that, um, glutamate works at is the NMDA receptor. And the NMDA receptor, the N-methyl-D-aspartate receptor, it's really important in a lot of our higher cognitive function, so it's the kind of the fundaments of learning and memory, um, particularly a process in learning called long-term potentiation, which is where neurons that, or brain cells that activate at the same time are more like... Then if you, if they both activate, then they're more likely to activate in future. So it's, it's characterized by this term that someone said, "Neurons that fire together wire together." And glutamate's really important in that and other, you know, excitatory functions in the brain. And GABA is an inhibitory neurotransmitter, so it, um, so it sh- shuts down the flow of electrical impulses across the brain. What ketamine does is blocks-
- PAPeter Attia
A- and before we do that-
- CMCelia Morgan
Oh, sorry
- PAPeter Attia
... so just to give some people some examples, right? So glutamate is excitatory. GABA is inhibitory.
- CMCelia Morgan
Yeah.
- PAPeter Attia
Um, we can give people a sense of, like alcohol. You and I were talking before-
- CMCelia Morgan
Yeah
- PAPeter Attia
... we started about, you know, GABA analogs that are meant to mimic alcohol. I mean, what are they doing? Why do people feel relaxed when they drink? It's the-
- CMCelia Morgan
Yeah
- PAPeter Attia
... GABA potentiation. Um-
- CMCelia Morgan
Yeah
- PAPeter Attia
... when you look at things like benzodiazepines, they're working-
- CMCelia Morgan
GABA [laughs]
- PAPeter Attia
... at GABA, right?
- CMCelia Morgan
Yeah.
- PAPeter Attia
So, um-
- CMCelia Morgan
Yeah, yeah.
- PAPeter Attia
Yeah. Okay. So, so, and then are there things-
- CMCelia Morgan
Yeah
- PAPeter Attia
... that c- that we can, examples we can give people that work at, uh, glutamate that are amplifying-
- CMCelia Morgan
I'm trying to think of-
- PAPeter Attia
... glutamate?
- CMCelia Morgan
... examples.
- PAPeter Attia
We tend to focus more on the opposite, right?
- CMCelia Morgan
Yeah, so like lamotrigine, so drugs used in seizures-
- PAPeter Attia
Mm
- 19:30 – 35:38
Ketamine regulation and abuse, and how it compares with psychedelics and other molecules
- CMCelia Morgan
for sure.
- PAPeter Attia
Okay. So, um, in the 1970s when this drug was being used pretty liberally as an anesthetic, it was... Was it unscheduled in the United States? I know now it's a Schedule 3, so it is, you know, it's a much more regulated compound. But is that-
- CMCelia Morgan
Yeah, I think it only came, oh, when was it? In the US, I think maybe 1996.
- PAPeter Attia
Yeah, I think it was the late '90s.
- CMCelia Morgan
It was, yeah, it's relatively recent.
- PAPeter Attia
Yeah.
- CMCelia Morgan
Yeah, late '90s. 2003, Putin banned it in Russia.
- PAPeter Attia
Just banned it altogether.
- CMCelia Morgan
Entirely, even for use-
- PAPeter Attia
Yeah
- CMCelia Morgan
... yeah, even for use in humans. And quite an interesting story, Brigitte Bardot, obviously the very attractive French actress, petitioned him for, to use it in animals, 'cause it's obviously widely used in veterinary anesthesia. So he removed the ban for animals, but kept the ban in place for humans, which is pretty horrendous considering what an amazing anesthetic it is. Um, in the UK it became, it was 2006. So yeah.
- PAPeter Attia
And it, and in the UK it mirrors basically the US, um, regulation around w- our equivalent of C3?
- CMCelia Morgan
Yeah, ours is Class B-
- PAPeter Attia
Okay
- CMCelia Morgan
... ketamine. So yeah, it's under the misuse of drugs scheduling, but it's, um, it's obviously what we call, you know, a Schedule 2 drug, so used for medical use. But unlike, I mean, maybe it's something we'll get into whether you consider ketamine to be a psychedelic drug, but there's not any other drugs with these kind of type of effects that can be used medically that are legal, so.
- PAPeter Attia
That, that's right. So in the United States, the other psychedelics, LSD, psilocybin, and even MDMA, which is not a psychedelic, are Schedule 1, which means they are not even used.
- CMCelia Morgan
Yeah.
- PAPeter Attia
They have no medical use at all.
- CMCelia Morgan
Yeah. And that's-- I mean, it's interesting drug policy-wise, right? Because ketamine is the most likely to be abused, I would say, of all of those compounds. [laughs] But it's the one that's, you know, legal for medical use. I mean, it has, as we've said, got an amazing number of medical uses. But you don't consider MDMA a psychedelic? [laughs] It's like-
- PAPeter Attia
I, I mean, I don't think I'm an expert to say, but no, I, I don't consider MDMA a psychedelic personally. Um-
- CMCelia Morgan
No
- PAPeter Attia
... um, I, I sort of put it in the category of an empathogen and, um-
- CMCelia Morgan
Hmm
- PAPeter Attia
... 'cause you don't really have any dissociation with it, right? You know, it's not, it's not altering perception in the way that LSD or psilocybin, uh, would. Uh, and, and-
- CMCelia Morgan
Yeah
- PAPeter Attia
... your point is an interesting one, right? Which is, you know, Schedule 1 typically implies no medical use, high potential for addiction. Well-
- CMCelia Morgan
Hmm
- PAPeter Attia
... uh, certainly, uh, I think there's medical use for psilocybin and MDMA. As you said, pretty low potential for abuse. And interestingly, while ketamine clearly has a high medical use, I want to talk to you about the potential for abuse as well.
- CMCelia Morgan
Mm-hmm.
- PAPeter Attia
Um, I've heard mixed things on this, but what, what do the data say? How, how addictive is ketamine in terms of other things for which we have benchmarks, like, for example, benzodiazepines and opioids, where we, we really have a clear sense of the addictive potential of those molecules. Where does ketamine stack up?
- 35:38 – 56:43
Ketamine as a therapeutic for depression [30:45];
- PAPeter Attia
right. So let's, let's talk about depression, because I think this is where people are really becoming interested in ketamine. It, it's certainly how it came to my attention seven, eight, maybe nine years ago was, um... God, I'm trying to think how. It was a, it was a, a physician friend of mine saying, "Hey, I..." You know, he was saying he's been prescribing intranasal ketamine to some of his patients for depression, and I thought, "None of this makes sense. Please say more." Um, and he said, "Yeah, no, this is... It's perfectly legal. We, you know, I have a compounding pharmacy, and these are the instructions that we give the pharmacy," and they give him an intra... You know, they give the patient an intranasal spray, and they use this spray. I forget the frequency with which. It was like once per... Uh, they were doing it once a week or something was the s- the, the use case. Um, and at the time, again, this is maybe 10 years ago, I couldn't find a lot of literature on it. And, and, you know, I found some, uh, and I found some interesting case reports, and I found... I remember there was one study I found based in India that looked pretty interesting. Um, but then I sort of forgot about it until maybe four years ago. And, um, and I think what brought it back to my- Uh, attention was frankly the, uh, epidemic, for lack of a better word, of ketamine clinics.
- CMCelia Morgan
Mm-hmm.
- PAPeter Attia
Um, which, which, you know, basically are almost as ubiquitous as Starbucks now. So, um, before we get into kind of the business of ketamine clinics, I, I wanna just kind of understand where the, where the idea came from. How was this something that people even thought was, you know, worth pursuing clinically? And then how does it work? Uh, who does it work in? Who does it not work in? You know, let's just go down the, the depression rabbit hole.
- CMCelia Morgan
Sure. [laughs] Yeah, I mean, that's quite... Where it came from is probably, there was a, a really early study in Iran, I think. I mean, it might even date back to some quite dodgy work by Salvador Roquet. I'm not sure if you've heard of him.
- PAPeter Attia
Mm-mm.
- CMCelia Morgan
Yeah. His, um, he was a psychotherapist. Yeah
- PAPeter Attia
But I do wa- I do wanna compliment you on the use of dodgy. That word cannot ever be overused.
- CMCelia Morgan
[laughs] Often.
- PAPeter Attia
So any, anytime you wanna just throw in that that's a dodgy scam or that's-
- CMCelia Morgan
[laughs]
- PAPeter Attia
... it was just dodgy work-
- CMCelia Morgan
Sure [laughs]
- PAPeter Attia
... please, please feel free to insert that.
- CMCelia Morgan
Thank you. [laughs] It's not a very scientific word.
- PAPeter Attia
No, no, it's-
- CMCelia Morgan
But thanks, Peter. [laughs]
- PAPeter Attia
It, it belongs here. It belongs here.
- CMCelia Morgan
Okay. Yeah, no, and he definitely was a dodgy guy.
- PAPeter Attia
[laughs]
- CMCelia Morgan
So there we go. Um, he was a, he was working for the Mexican government actually, I think interrogating people, and he took some of the techniques from that, I think, and tried to... He's a psychoanalyst, kind of psychotherap-peutic practice, and he was giving ketamine with other psychedelics, um, to try and produce changes in people's brain state. But I guess that's probably the first documented cases of people using ketamine in a kind of psychiatric therapy sense. But really-
- PAPeter Attia
And this is what? This was in the '80s or '90s?
- CMCelia Morgan
No, that was back in the '60s.
- PAPeter Attia
Oh, wow.
- CMCelia Morgan
In, um, yeah, so way back. Maybe the '70s there was this study out of Iran. Um, but really, yeah, the work that's kind of caused this whole explosion in ketamine depression research, 'cause I don't think anyone was really watching those areas of research, came out of, um, a group at Yale and a guy called Robert Berman, um, who did a, did an early study in 2000, um, giving ketamine, a single ketamine infusion to patients with treatment-resistant depression. And they showed this thing which was kind of groundbreaking in that, and that's, was that you could get this rapid reduction in, um, depressive symptoms, not as are traditional SSRIs. You know, your, the Prozacs and your traditional antidepressant drugs have got a delayed onset of action, and it was just kind of accepted that they take two weeks to work, and, you know, there's various ideas of why. But, um, this, this ketamine works immediately and, and in people with treatment-resistant depression. This isn't mild depression.
- PAPeter Attia
And, and tell me, tell me how it was administered in those early studies. Was this... It-
- CMCelia Morgan
So that was... Yeah, sorry.
- PAPeter Attia
No.
- CMCelia Morgan
So that was intravenously.
- PAPeter Attia
Intravenously.
- CMCelia Morgan
Yeah.
- 56:43 – 1:07:56
The brain under the influence of ketamine and theoretical mechanisms for its anti-depressive effects
- CMCelia Morgan
I mean, you probably wouldn't be responding to them I guess. So-
- PAPeter Attia
... this works? What, what, what do you think is the mechanism of action?
- CMCelia Morgan
Oh, yeah. So I mean, that's where I think potentially the therapy and targeting the therapy is really important. I mean, people have talked about ketamine and, and indeed the other psychedelics as psychoplastogens. I'm not sure about the term, but maybe the idea that they provoke this kind of cascade and there's studies showing they increase synaptic plasticity in the, in the prefrontal cortex. Well, certainly ketamine does. Um, so increases the growth of new synapses and, um, dendrites and so the basically the ability of the brain to form new connections and that that is correlated with, um, the antidepressant effect. Um, and so we kind of wanna... We're doing some work at the moment to sort of chart the time course of that in humans by looking at EEGs, so that's kind of electrical sim- signals from the brain and trying to target the window of this synaptic plasticity. 'Cause we know from animal studies this might be kind of starting four hours following the ketamine dose, peaking about 24 hours. So we just sort of track the antidepressant effects, which is quite interesting. I think the idea, you know, for me as a psychologist is that you could time your psychological therapy when your brain is most plastic, most able to learn new things. And we know actually, you know, this kind of plasticity is impaired across a whole range of like psych- sort of psychiatric disorders, so not just depression, but also in alcohol and addiction and, and trauma. So actually stim- being able to stimulate the brain to kind of learn new things that while it's really plastic, then actually giving some psychological therapy that uses that process, because we know that's what we're asking people to do really in psychological therapy, is to think differently about things, learn new ways of thinking about old problems. Um, so yeah, that's, that to me is, seems like an intuitively appealing mechanism. I mean, there's some problems with it in that neuroplasticity happens from all sorts of things, so what some might argue, you know, is this like specific enough as a process? Um, other drugs produce neuroplasticity that we wouldn't say were necessarily potential treatments for mental health problems and psychiatric disorders, so.
- PAPeter Attia
Such as?
- CMCelia Morgan
We need to find out more about it. Well, like cocaine. So people say the neuroplasticity produced from cocaine-
- PAPeter Attia
Mm
- CMCelia Morgan
... is used, um, is why it becomes addictive. Like, there's this kind of stimulation of that from an acute cocaine dose. So I do think we need to find out a bit more about it, and maybe it's down to something really specific and neurobiological. Um, so I leave that to my kind of preclinical researchers, but, but yeah, it's, it, it's fascinating.
- PAPeter Attia
Now, now when you think about, when you think about things like MDMA and psilocybin-
- CMCelia Morgan
Mm
- PAPeter Attia
... uh, the, the real... A lot of the therapy takes place while under the influence of the drug, uh, whether it be for PTSD or depression. Um, is that happening also with ketamine when that patient is, uh, um, in the aftermath of the infusion, or is that, are they basically just left alone during that period of time and the psychotherapy takes place immediately following, you know, the next day, and the next day, and the next day, trying to take advantage of them being less dysthymic?
- CMCelia Morgan
Yeah. I mean, in, in our work certainly, um, we wouldn't be trying to do any therapy under the influence of ketamine. I think people are too dissociated, you know, their memory's impaired.
- PAPeter Attia
Mm-hmm.
- CMCelia Morgan
To me that's... 'Cause I know there are some ketamine therapists who do use this what's called kind of psycholytic approach, which is where you use mild doses to be able to, um, do some therapeutic process. There's a really interesting study actually from a guy, where is he? Um, in Texas I think, working one of the VAs. I've had some correspondence with him. He's actually looking at complex PTSD, um, which is, you know, really severe multiple traumas, and he was treating complex regional pain syndrome on top of that. So these are really traumatized people who've got like really severe pain, and he was giving continuous ve- quite low dose, um, I can't exactly have at the, my fingertips the dose, but ketamine over 96 hours, so continuous infusion.
- PAPeter Attia
Mm.
- CMCelia Morgan
And he was doing very kind of basic, um, psychological therapy during that time and found massive reductions in, you know, CAP score, which is our measure of PTSD symptoms. Which I, I mean, it was a really small study, but I thought that was a quite interesting approach. Um, but no, in o- to answer your question, we do the therapy outside of that, and I think most people with ketamine do do that. I think really with psilocybin as well even, people would argue what you're doing in that- But now having the acute experience is really just supporting them-
- PAPeter Attia
Yeah, yeah. That, that's fair
- CMCelia Morgan
... in the way it happens
- PAPeter Attia
And then, and then it's the integration afterwards where with psilocybin. Yeah
- CMCelia Morgan
Yeah. Well, there's, there's very little research on what integration is or what the key fundaments are. It's kind of accepted that it's this thing that you have to do. [laughs] But I don't know. We're kind of lacking in research from that side. Um, but yeah.
- PAPeter Attia
And what do we know about the brain under the influence of ketamine? I mean, have, have, have people done fMRI or FDG PET and, and kind of looked at either the metabolic state of the brain or the activity of the brain? I mean, you've obviously-
- CMCelia Morgan
Yeah, I mean there's-
- PAPeter Attia
... mentioned the prefrontal cortex, but is it e- can we get even more granular than that? Are there certain sections of the, uh, of the PFC that are more active than others?
- CMCelia Morgan
Yeah. There's, I mean, then there's quite a lot of really interesting work. So there's the kind of, I guess as you'd imagine, the default mode network, which is, you know, being the dumping-
- PAPeter Attia
Tell, tell folks what the default mode network is. It's very important in this-
- CMCelia Morgan
So it's kind of your b- it's basically what happens in your brain when you're not doing anything active. So when you're in a scanner and we don't give anyone anything to do, then that's a resting state scan, and you look at how the brain networks connect. So people say it's kind of, yeah, the task, the, the kind of background activity of the brain, and have likened it to things like rumination, which we know are important in depression, which is like where you repetitively think about something. You can have positive rumination as well, you know, pos- repetitively think about something good, but repetitively thinking about something bad or kind of mind wandering. So that's where the default mode network has been kind of shown to be disrupted following psychedelics. So this kind of background, normal kind of chatter of your brain. And also similarly with things like mindfulness. So there have been studies looking at that. But you mentioned the prefrontal cortex. There's some really interesting studies looking at prediction error signaling. So the idea that your brain is basically, like, making predictions all the time about the world, and that's how we understand everything perceptionally, you know? We know that there's, like, whatever behind your computer screen, there's a world behind that. I would predict that. If I put my laptop screen down and found there was a gap in reality, [laughs] then I'd have a s- like a massive shock of surprise 'cause that would signal to my brain that I had to learn something new. So every time a prediction that we make based on our learning is violated, then you get this increase in learning and, and attention and activity in your brain. Um, and there's some work showing that ketamine basically disrupts. There's a bit of the dorsolateral prefrontal cortex, so sort of in your prefrontal cortex but a bit back and a bit to the side, um, that's really associated with this prediction error processing, and that's disrupted with ketamine. So things that aren't surprising become surprising. [laughs] The things that shouldn't be surprising and are completely predictable, and things that aren't predictable are no longer surprising. So basically a kind of noisy signal, um, that I think it's like, it's just quite an interesting way of understanding maybe the subjective experiences from a lot of these drugs, that you turn off some of that kind of forward prediction from the brain and make a kind of a noisier signal. So I think that's quite interesting way to think about the subjective experiences. But yeah, I mean, there's quite a lot of neuroimaging work, um, being done. I've... Yeah, we've done some of it as well, looking at kind of hippocampal function.
- PAPeter Attia
And, and is the brain hypermetabolic under the influence of ketamine?
- CMCelia Morgan
Um, I di- a hyp- I think the idea is that it's more kind of hyp- more hypo in some ways. Um, so-
- PAPeter Attia
Mm
- CMCelia Morgan
... you get an increase in sort of prefrontal glutamate. Um, and we know that as well because you get attenuators, so, um, so, and an increase in kind of prefrontal function. But then there's... Yeah, so it's... I, I don't know that that's particularly clear. Um, I guess, and the neuroimaging, as I've done it as a, as a method in the past, it's not my area of expertise, [laughs] so yeah.
- PAPeter Attia
How many patients do you think, um, when, when relieved of their depression during these ketamine trips, um, will need to stay on ketamine as a long-term treatment? And if so, at what frequency?
- 1:07:56 – 1:16:39
Risks and concerns with overusing ketamine, and what an intermittent or maintenance dose might look for a patient
- CMCelia Morgan
don't know, right? So we must be mindful of the potential of these things. I've seen some slightly worrying trends recently. Like I've organized a ketamine conference with some colleagues, um, some of them from the US, and, uh, we had a few pharmaceutical companies coming and they're developing ketamine for all daily dosing.
- PAPeter Attia
Mm-hmm.
- CMCelia Morgan
And to me that's a bit of a worry having worked, you know, for 10 years researching ketamine users because I feel like if you, even if you're l- using very low or daily dosing, you're gonna have to dose escalate, right?
- PAPeter Attia
Yeah.
- CMCelia Morgan
So where's the end point? And if you, if you aren't giving it in a supportive therapy, is the idea that people are just on ketamine all the time? I don't know. To me it seems a bit worrying. Maybe there's something I'm missing about the drug development pathway there, but [laughs]
- PAPeter Attia
No, no, I don't... I mean, I'm gonna just take the skeptic's point of view on that. I don't think you're missing anything. I think it's a land grab for, uh, a greater profit motive without-
- CMCelia Morgan
Mm
- PAPeter Attia
... enormous consideration for the downside. Um, you know, so, so I, I mean, I, I would, I would share your... I don't know what it is about ketamine that has me sort of cautious. Um-
- CMCelia Morgan
Mm
- PAPeter Attia
... and maybe it's just the anecdotes and that's a bad, um, that's a bad frame. But, um, y- you know, it just, do you th- is there... I mean, this is gonna sound really silly, but do, do you, do you have a sen- have you ever seen people with these sort of ketamine eyes? Like these sort of sunken, distant, like this person has taken too much ketamine in their life and their brain doesn't work as well anymore? And I think you can have that with, I'm sure there are lots of different drugs that can produce that phenotype. I'm sure somebody that's taken far too much cocaine can experience something. But-
- CMCelia Morgan
Mm-hmm
- PAPeter Attia
... but the, but it, I, I think it has, it's, it's something that you see more commonly, I would assume, with ketamine than you would with LSD or psilocybin because as you said, the frequency of use is much harder with those other drugs. Like-
- CMCelia Morgan
Mm
- PAPeter Attia
... no one is going to, I mean, I shouldn't say no one. I'm s- someone can do anything. But it's far less likely that a person is going to take heroic doses of LSD or psilocybin over and over and over again, whereas you could get down that path with ketamine. And-
- CMCelia Morgan
Mm
- PAPeter Attia
... again, it's just anecdotal, but you know, you see some of these people where you, you get the concern, it's not just the bladder. I mean, the cystitis is a very obvious and, and, and tangible objective side effect that can be devastating. This is much more subtle. It's just something's changed in that person's brain and it's not for the better. Uh-
- CMCelia Morgan
Mm.
- PAPeter Attia
So, so am, am I just sort of making this up? And it's possible I am, and that I'm, I'm just over-extrapolating from something else. But h- have you, you've been around this more than almost anyone. Do you have a concern around that?
- CMCelia Morgan
Yeah, no, we've done a lot of studies on that as well, and I guess maybe, I don't know, we haven't studied the sunken eyes [laughs] but we have looked at the brains.
- PAPeter Attia
Yeah. And it's not, it's, I, I mean it sounds silly to say it. It's not physically sunken, right? Like, like you would with-
- CMCelia Morgan
Yeah
- PAPeter Attia
... hypothyroidism. It's just, it's a vacancy is more what I'm-
- CMCelia Morgan
Yeah
- PAPeter Attia
... describing.
- CMCelia Morgan
A kind of dullness.
- PAPeter Attia
Yeah.
- CMCelia Morgan
And that, I mean, I guess like any addiction, one thing I noticed, and again anecdotally, was just like a lack of, you know when people lose their sense of humor, and that seems to be like a thing in addiction. It's like the, the spark has gone out of life. Which is odd, right? Because what we're giving ketamine for describes quite a paradoxical drug in depression is to like put the spark back. But then it makes sense. You do it too much and maybe that spark is gone. And we found that, you know, cognitively we found cognitive impairments and with planning, and we found actually, um, reductions in, you know, your hippocampus, which is involved in processing novelty, um, and encoding memories, and that's the function of that is reduced in some of our brain imaging studies with people who, these are people who take daily heavy doses of ketamine. So I'm not saying even your non-medical recreational user would show, show this kind of symptoms. So people who take it occasionally. But yeah, really, really, really heavy doses, I think that's possible. Um, I don't know because seeing the way that it's administered in clinics, I mean, originally it was not, never really, the idea of it as a rapid acting antidepressant, and I think the promise was that it's not a maintenance medication, you know?
- PAPeter Attia
Yeah.
- CMCelia Morgan
And how empowering that is for patients to not be on a daily medication. And that's why I feel a bit sad that there's not more research effort going into looking at enhancing the antidepressant effect with therapy, so we don't have to give people hundreds of doses of ketamine. Or maybe some people will just need that, and that's a cost-benefit analysis I guess you make when you're prescribing any drug, you know? 'Cause these, some of these people, you know, this is life-threatening, right? Like people who are really heavily suicidal, so I guess-
- PAPeter Attia
Has anyone done that study where you, y- and 'cause that's the closest way to get to a quality adjusted life year analysis, which is gonna be that cost-benefit analysis. Has anyone taken that group of patients who are the most treatment resistant and randomized them to continuing to try to treat even though it's resistant versus ketamine and looking at really hard outcomes like differences in suicide rate?
- 1:16:39 – 1:35:49
Treating addiction with ketamine: Celia’s studies of alcohol dependance
- PAPeter Attia
So tell me why you think it's working in addiction and, and, and do you primarily work in alcohol addiction or do you also look at opioid addiction?
- CMCelia Morgan
We want to look at opioid addiction as well, and actually there's some other work going on in the US, um, looking at opioid addiction. And this work dates back to some work by a Russian psychiatrist, Evgeny Kropitzky, who did work with heroin addicts and found a similar, you know, dosing regime, which was just three infusions with his psychological therapy around it, produced reductions in heroin use at 12 months. You know, quite significant.
- PAPeter Attia
Do, do you know how much? How much of a reduction?
- CMCelia Morgan
I know in alcohol there was a 40% reduction in relapse rate-
- PAPeter Attia
At 12 months?
- CMCelia Morgan
... in these Russian... At 12 months, yeah. I mean, which is-
- PAPeter Attia
And what's the control group, which I assume is doing... Is the control group-
- CMCelia Morgan
They would-
- PAPeter Attia
... gr- doing pharmacotherapy or behavioral therapy such as 12-step programs?
- CMCelia Morgan
They were... I mean, so this, for context, this is in the '80s in Russia. They were inpatient alcoholics. And, um, so they were lock- in locked wards. So I remember saying to Evgeny, "Did anyone drop out?" It's like they can't drop out. [laughs] They're locked in. So I think it wasn't in the normal consent and ethics-
- PAPeter Attia
Yeah
- CMCelia Morgan
... processes we have now. Um, but still a really important study. And both groups had 100 people in. And so, and it wasn't, you know, it wasn't a randomized control trial. He asked people if they wanted to be in this ketamine and psychotherapy group, which is half-
- PAPeter Attia
So, so I'm sorry. I'm not sure I understand the trial. You have an inpatient trial where the-
- CMCelia Morgan
Well, trial
- PAPeter Attia
... all the patients are given... Yeah, trial in quotes. It's, this, this-
- CMCelia Morgan
Yeah [laughs]
- PAPeter Attia
... this would constitute a dodgy trial. Um-
- CMCelia Morgan
Yeah. [laughs] This is dodgy. No, you're kidding. [laughs]
- PAPeter Attia
So, so, so it, but it's inpatient and they're all given unlimited access to ac- alcohol, but they're-
- CMCelia Morgan
No, no, no, no, no. No, they're not. They don't have any access to alcohol. [laughs] Sorry.
- PAPeter Attia
So how do we know, how do we know what the relapse rate is?
- CMCelia Morgan
No, so they do, they ha- do their detox.
- PAPeter Attia
Uh-huh.
- CMCelia Morgan
They get given their ketamine treatment. They're discharged.
- PAPeter Attia
Oh, okay.
- CMCelia Morgan
And then when followed up at 12 months-
- PAPeter Attia
Oh. Oh, oh, I see. So they're out-
- CMCelia Morgan
Yeah
- PAPeter Attia
... they, they behave as outpatients, but they're not allowed to drop out. In other words, if you drop out, the KGB bring you back in.
- CMCelia Morgan
Well, yeah, they couldn't drop out of the treatment.
- 1:35:49 – 1:42:40
Advice for people considering the therapeutic use of ketamine
- CMCelia Morgan
[laughs]
- PAPeter Attia
Um, [laughs] um, so what's your, what's your... Uh, there's one other thing I wanna talk about before we, we, we, we, we wrap this up. So I wanna... But I wanna sort of put a bow on the ketamine story. Um.
- CMCelia Morgan
[laughs]
- PAPeter Attia
What would you say to people here in the US, right? So where, where ketamine clinics are ubiquitous, and as far as I can tell, I think you can just walk into them. I don't think you need a referral. I don't think you need a medical referral to go to a ketamine clinic. Um, although I think there are therapists who do make referrals and say, "Look, this is-
- CMCelia Morgan
Mm
- PAPeter Attia
... a reputable clinic," and I'm sure that there are many reputable clinics, and, you know, your depression is recalcitrant or, um-
- CMCelia Morgan
Mm
- PAPeter Attia
... you know, you're having this problem in your life, and I think it could get better here. So I, so I suspect that there's a, a really good conduit of therapists sending patients appropriately to good ketamine clinics. But let's also posit that anybody can walk into a ketamine clinic, which I, I really do believe is true, um, and sort of tell the persons there, "Hey, I'm having this issue. I wanna do it." But there's a bit of a conflict in that model because the, y- when you walk into the clinic, they're in sort of incentivized to do what they do, right? When you're a hammer, everything's a nail.
- CMCelia Morgan
Mm.
- PAPeter Attia
When you're a ketamine clinic, you're incentivized to give ketamine. Um, how would you caution people around ketamine, uh, use liberally in that context?
- CMCelia Morgan
I suppose I'd say that it, the evidence, you know, that we've gathered, and not just us, there's an- another group at Yale, Sam Wilkinson, has looked at, you know, therapy and ketamine, and there's another trial starting in depression, is that actually it's a bit of a waste if you just If you just do the ketamine, you should certainly try it embedded within therapy and you probably don't need, you know, all of those doses. I think interrogating what you're trying to get out of that experience and that actually it's, you know, I think it's, it's, that's great to hear that therapists refer people to ketamine clinics. Like we've got so far with therapy then we're gonna use this as a boost so we can continue the therapy. To me that just seems much more appealing model because really do people want to-- I don't think people wanna be kind of stuck on a drug. Even if you're not, you know, addicted-
- PAPeter Attia
Mm
- CMCelia Morgan
... but you're going in twice a week or even once a week, like that's so disempowering for patients. We know that, right? And speaking to patients, one of the things they said was great about the, our treatment approach is, you know, rather than being on daily meds, things like, like other treatments in alcohol, like the Campral say you have to take three times a day. They feel pretty liberated, you know, and they know they're doing the healing themselves which I think is a really important part of the process. So I'd say, yeah, get, get, kind of get a therapist, think about using a really minimal number of doses. I mean, I do-- Um, yeah, it's, it is worrying. There's some really worrying practices that you hear about, you know, some mail order ketamine clinics. I don't really worry about them from the abuse side. Maybe I'm wrong not to, but just because it's so expensive, I think [chuckles] unless you're, you know-- You have to have a lot of money to be able to afford that ketamine. I j- but I just think it, where it's unsafe because if you're-- Certainly don't take ketamine at home when you're not supervised, you know? This drug makes you completely dissociated from your environment. If you, if something happens, there's a fire or-- And all sorts of things could happen. You can't take it unsupervised, but I think there's a lack of kind of clinical care and supervision in some of these models, um, that, yeah, I find that really worrying. But it's expensive as well. [chuckles]
- PAPeter Attia
So, so yeah, you, you, you sort of answered what my next question was going to be which was not at all to, to say do you condone the, the use of, of, of non-medical or recreational ketamine, but more to say if someone is going to use ketamine recreationally, what, what is the [clears throat] -- what is the instruction set you provide them to make sure that they don't harm themselves psychologically and physically? So one of them is, I, I, if I'm just gonna extrapolate, it's like if people are gonna do ketamine recreationally, there really needs to be somebody around watching them, right? You can't-
- CMCelia Morgan
Yeah
- PAPeter Attia
... you can't trust yourself to be under the influence of this drug at least at a high dose, which I'm guessing based on what we've said is, you know, depending on your size, 100 to 200 milligrams would be considered a high dose.
- CMCelia Morgan
Uh, yeah, really high. And I think, you know, start really small doses and I guess is the advice that you'd always give to people with any non-medical use of a drug. Yeah, and do it in a s- you know, safe place with someone who's not under the influence of any substances and start with a small dose. But yeah, I mean, it's not-- I don't know so much them in the US. You rarely get ketamine particularly cut with other things, but it can happen, so that's something to be careful of as well.
- PAPeter Attia
Wow, that's interesting.
- CMCelia Morgan
Like with you and the input.
- PAPeter Attia
What would it typically be cut with?
- CMCelia Morgan
I don't-- Um, people-- I mean, there are ketamine analogs which people have shown. So there's a drug methoxetamine, um, so they're the kind of research chemicals that have come out of labs in China, Israel. Um, so it's an analog of ketamine, but it's got-- studies have shown more toxicity to the bladder, um, and slightly maybe higher abuse potential. But yeah, typically, I mean, I, yeah, I don't, I don't think it's, it, it's normally particularly cut with things, but it's something to be mindful of and why it's really important to take a small dose, you know. But ideally, yeah, obviously I think cautionary non-medical use.
- PAPeter Attia
Well, Celia, that's-- I mean, this is super interesting. I mean, this is-- I, I've sort of been deliberately sort of ignorant of ketamine. I don't know why. I've, I've sort of gone down the rabbit hole on trying to understand as much as possible about these other, uh, agents which ironically are-- tend to be the one that are Schedule I and therefore not really readily available for clinical use. Outside of trials, we do have many clinical trials here in the United States looking at, uh, uh, in particular the use of psilocybin and MDMA. Um, but, but ketamine's been a bit of a black box to me, and yet it's the one that I probably have seen the most people use because of course-
- CMCelia Morgan
Mm
- PAPeter Attia
... it can be used legally. Um, so I found, I found this discussion very helpful. I found this discussion really insightful, um, and it, it sort of, uh, clarified for me a lot of the, the use case, the neurobiology, the risks, and, and perhaps most importantly what the promise of this agent is. Um, so I wanna thank you for your time. And again, I know it's late there in the UK at the moment and, uh, and more importantly I think thank you for the work you're doing. This is really fascinating, uh, and I, and I, I kind of love the model.
- CMCelia Morgan
Oh, thanks for having me, Peter. [chuckles] [upbeat music]
Episode duration: 1:42:40
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Transcript of episode fNFnr8UTGI4
