#220 ‒ Ketamine: Benefits, risks, and promising therapeutic potential | Celia Morgan, Ph.D.

Hey everyone. Welcome to the Drive Podcast. I'm your host Peter Attia. This podcast, my website and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in depth content. If you want to take your knowledge of this space to the next level, at the end of this episode I'll explain what those benefits are. Or if you want to learn more now, head over to peterattiamd.com subscribe Now without further delay, here's today's episode. My guest this week is Celia Morgan. Celia is a Professor of Psychopharmacology at the University of Exeter in the uk. Celia's research focuses on the benefits and side effects of recreational drugs and alcohol on cognition, behavioral and neurobiology, and she's authored numerous publications on the potential use of ketamine and other drugs as therapies in mental health. She created her undergraduate degree and PhD at University College London, followed by a scholarship program that brought her to the United States where she studied at Yale. She conducted research at the University of Melbourne prior to returning to University College London and eventually moving to the University of Exeter where she became the Chair of psychopharmacology in 2015. In this episode we dig deep into ketamine. We talk about the neurobiology and the chemistry of ketamine, how it affects individuals, how it affects specific parts of the brains, and how it differs from other things that we might think of as psychedelics. Though I don't really consider ketamine to be a psychedelic, but we certainly contrast it with things like psilocybin and lsd. We then talk about its use case and the potential promise of ketamine, specifically around drug resistant or recalcitrant depressant and alcoholism. We talk about the importance of therapy being offered concurrently with ketamine treatment, as many people listening to this might wonder if ketamine therapy is indeed for them. So without further delay, please enjoy my conversation with Celia. Hey Celia, thanks for making time on a Friday evening to sit down and talk about ketamine and perhaps a few other things. But great to meet you.

You too. Thanks. It's my pleasure.

So let's talk a little bit about your background. I think you finished your graduate training in the uk, but then you did a stint here in the US at Yale, if I'm not mistaken.

Correct So I did my undergraduate in psychology with pharmacology and astrophysics for a bit. I did a PhD program 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 there in the US.

So what did you focus on during your PhD?

So my PhD was largely focused on the effects of ketamine. 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 a little bit similar to people who are psychotic. And so we were using that to map the kind of cognitive processes 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. And when I went to the us, it was to work on again, some neuroimaging studies looking at ketamine as a model for psychosis. So it was before it really became established as an antidepressant.

Let's talk a little bit about the history of ketamine. It was Synthesized in the 60s, I.

Believe it was synthesized as an anesthetic, synthesized as a replacement for PCP or phencyclidine, because obviously people know PCP as angel dust. And this is 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 ten times less potent. Yeah. So it synthesized back in the 60s 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.

One of the things that I remember from my clinical training was that 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 mainstem bronchus, so you're breathing for the patient. But when you start to think about conscious sedation, 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? Because I didn't do much in pediatrics, but I can't recall if there was more flexibility in using it with kids, or am I making that up?

It is used more with children. 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 if they're hallucinating.

It seems less foreign to them if they are, maybe.

Exactly. They are tripping all the time. But no, maybe not that. But they're more open to changes in consciousness. I mean, it's used routinely. I'm really interested, and I don't think anyone's really actually asked children about their experiences. So in pediatrics and geriatrics, also in battlefield medicine, it was the most widely used anesthetic in the Vietnam War, for instance, as you said, it's really safe physiologically as an anesthetic because it doesn't slow your breathing or your heart rate. So when you've lost a lot of blood, it's good as well, because it actually even vaguely increases your blood pressures. I think that's why it's a widely used anesthetic. It's a really good question about kids and people trying ketamine in its antidepressant use now with adolescents.

So we'll get there. 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 that, if anything, slightly acts like a vasopressor, raises blood pressure without the respiratory depression. I mean, in that setting, you can understand why it became a turning point in the field medicine of Vietnam.

The acute experience must be really unusual when you're in that setting, as you mentioned, not having to intubate people. That's why it's really popular in developing countries where you've got limited access or ability to intubate patients. It's a really important medicine in anesthesia still. And I think that's something people forget with all the new the use of ketamine.

It's really interesting when you go and imagine what surgery was like before ether. And I mean that's just ridiculous. And to think that anesthesia is something we've only had for about 140 years.

It's pretty crazy, isn't it A fascinating concept Anyway, when you lose consciousness and how you measure that. There's different things anaesthetists use. There's an index which relies on some EEG to look at how your consciousness drops. But I still don't think we really know what turns it on and off.

You mentioned that ketamine. Is it safe to say it's an analog of pcp?

They're all under the class of aryl cyclohexamines. And so I think Edward Domino coined the term dissociative anesthetics to describe PCP and ketamine. And also people include nitrous oxide in that category. I think based on the fact that they kind of dissociate you from your body and are characterized by these out of body experiences, which can be quite helpful. Again, I think in anesthetic use they are related compounds with similar. Their main action is on the NMDA receptor.

So let's talk a little bit about that. Let's assume that folks don't know what NMDA receptor is, they don't know what glutamate is, they don't know gab. Let's just assume people are coming at this from a standpoint of not being completely up to speed on excitatory or inhibitory neurotransmitters. Explain in some detail exactly how these neurotransmitters work and how other neurons can amplify or attenuate the response of those. And where ketamine fits into that.

Do jump in as well if I'm either going too slowly or too quickly. Glutamate is the major excitatory neurotransmitter in the brain and it's prevalent all across the brain. And one of receptors that glutamate works at is the NMDA receptor. And the NMDA receptor, the N method aspartate receptor for really important in a lot of our higher cognitive functions. So it's the kind of the fundaments of learning and memory, particularly a process in learning called long term potentiation, which is where brain Cells that activate at the same time. If they both activate, then they're more likely to activate in future. So it's characterized by this term that someone said neurons that fire together wire together. And glutamate is really important in that and other excitatory functions in the brain. And GABA is an inhibitory neurotransmitter, so it shuts down the flow of electrical impulses across the brain. Well, ketamine does.

And before we do that, just to give some people some examples, Glutamate is excitatory. GABA is inhibitory. We can give people a sense of, like, alcohol. You and I were talking before we started about GABA analogs that are meant to mimic alcohol. What are they doing? Why do people feel relaxed when they drink? It's the GABA potentiation. When you look at things like benzodiazepines, they're working at gaba. Are there examples? We can give people that work at glutamate, that are amplifying glutamate. We tend to focus more on the opposite. Right.

So like lamotrigine. So drugs used in seizures tend to reduce the flow of glutamate in the brain, particularly in the prefrontal cortex. I'm trying to think of examples, so. Good question, Peter. Do you know of any?

No, I can't think of anything off the top of my head that would do that. We normally are thinking of the opposite side of that.

I don't know if we want to get into ketamines. As you mentioned, drugs like alcohol, benzos, they all increase GABA activation. So kind of slow dampness down on the brain and reducing things like anxiety and slowing your motor function and generally inhibiting the flow of electrical impulses across your brain. It's part of the reason why we get symptoms you get when you stop drinking. Your brain kind of goes into a. It's like a seesaw, I guess. The alcohol's been pushing down on that side and keeping it dampened down. And then you release that and you go into a more excitatory state. I work a lot with alcoholics. Things from alcohol withdrawals, you can get seizures and the shakes, and that's all down to this kind of increase in excitation.

That's why withdrawal from strong GABA promoters like benzos and ethanol can be fatal if not managed correctly. So it's sort of funny. I think people intuitively know this. You can stop opioids immediately, and it might be the most painful thing in the world, but it won't be fatal. Whereas if you take a person who's on a high dose of benzodiazepines or a person who drinks a lot of alcohol and you stop that abruptly, it actually can be fatal.

And they are the drugs you can die from withdrawal in because of these huge then increase in excitation. Because I guess with a repeated alcohol use, your brain gets used to having all this GABA on board and then you get adaptation and your brain kind of upregulates to counteract that. And then when you remove it, yeah, you can die from withdrawals. So the people I work with, severe alcoholics, it's unsafe for them to stop straight away. So they have to cut down and use things like benzodiazepines and withdrawals. Something that I think people do think about opiate withdrawal potentially as a really difficult thing. But as you say, you wouldn't die from that. It's only from withdrawal from these inhibitory substances like alcohol and benzodiazepines.

So we have excitatory and inhibitory neurons. And the inhibitory neurons, are they the ones where you have like an NMDA receptor that is sort of globbed on to say a glutamate receptor?

That's one of the theories of how ketamine works, or were we just talking about the neurons? So I think I'm going too into the ketamine.

Yes, I'm going exactly to. Now different ideas because it's not 100% clear exactly how ketamine works, Correct?

No. And so there's a couple of theories that either ketamine blocks directly the NMDA receptors on the glutamatergic neurons and then this triggers a kind of downstream cascade and maybe it's a combination of the two that ketamine blocks NMDA receptors on these. They're called GABAergic interneurons. So they're your GABA neurons that synapse onto your glutamate. One, they put the brakes on your excitation. If you block NMDA receptor and a GABAergic interneuron, then you're going to have a net effect of increasing glutamate flow in your presynaptic cells. They're presynaptic? Yeah, it's not quite clear and it probably is a combination of the two. Increasingly, people have become interested in the downstream mechanisms, really potentially in the therapeutic effects of ketamine.

Again, ketamine is one of these drugs where the dose kind of makes the poison. I mean, I think that's true of most drugs, but it really has different effects on an individual based on how much they're getting, right?

Yeah.

Anything from mild hypnosis to some dissociation to complete anesthesia at low doses as well.

I work quite a lot with people who take Ketzeman non medically or recreationally and they lower doses, it's got kind of stimulant properties and then as the dose increases you get perceptual distortions and illusions and kind of a mild melting. People talk about floating. Higher doses still you get kind of much more profound. Maybe not hallucinations, but changes in perception of reality. And the highest dose you're completely sort of catatonic. But people are experiencing inside these really, really profound hallucinations and that there's really high doses from my work with non medical ketamine users that were actually really dangerous. A couple of people died from taking ketamine and then having a bath and they're completely dissociated from reality and they drowned. And it's like the saddest thing and it makes you, I think as a user a Ketamine users are very vulnerable to accidents at these higher doses because you are not completely dissociated from reality. Really.

Wow. So that's sort of like LSD in the sense where it really has no LD50, meaning there's no amount of LSD that you're going to take that is going to create some physiologic process that kills you the way for example Tylenol acetaminophen would poison your liver at a certain dose. But it's not to say that LSD is completely safe because you can alter your behavior in a way that is so altered from reality that you put yourself in harm's way, basically. Is that the same with ketamine? If you look at it from a purely pharmacology standpoint, there's no LD50 given that it doesn't have respiratory depression and all these other things that we worry about or how do you think about that?

Yeah. Not aware of anyone getting to like a toxic dose of ketamine. And there are problems with repeatedly taking high doses of ketamine. Physiological problems. The ketamine has a direct toxicity on the epithelial, so like the lining of your bladder, which is really interesting as something that only merge really with people using really high doses. There's no LD50 like you say. I'm much more so proud. Probably even an LSD where a lot more of your top down, higher cognitive functions are preserved with ketamine. They're not. And you are Completely, you know, catatonic. People will be kind of collapsed, anesthetized, really in a cataleptic state. So you're much more vulnerable to accidents.

And the drowning in a bathtub example, that seems tragic. And to imagine how dissociated you would have to be to slip into a bathtub, inhale water and not respond.

Exactly. You are completely dissociated. And it's really sad. It was someone that I was working with and that is not the only example I know of people who that's happened to various different accidents. It's really tragic.

While we're on the pharmacology, let's talk about the different routes of administration. I assume that most of the time when it's used medically it's intravenous.

Most of the studies, certainly in the depression field. And when it's used in anesthesia, I think people would give it intravenously. It's the best bioavailability and the most well characterized route or route, as you say in American. There are other ways of administering it which I think have been increasingly used intramuscular, has got quite good availability in the blood. And then there's people starting to use things like sublingual administration. So putting under the tongue intranasal, obviously is the route popularized by first the drug users themselves, but then patented by the pharmaceutical company Janssen, have now used that for their licensed form of ketamine and depression. Those are the main ones. And oral dosing, that's not as great in terms of bioavailability. It's obviously easy way to get a drug over and across into the system.

There's no liver toxicity with I know you're going to have a bad first pass effect, which is why you prefer to put it under your tongue as opposed to swallow it. But there's no toxicity. It just means you need a higher dose if you're going to take it orally.

Presumably, I assume people are doing detoxicity studies at the moment, because I know there's some pharmaceutical companies looking at oral dosing as a potential.

But I think for the purpose of our discussion, we're really thinking about what has been learned through intravenous and intramuscular and perhaps most recently intranasal.

Yeah, and that's where the bulk of the research is for sure.

In the 1970s, when this drug was being used pretty liberally as an anesthetic, was it unscheduled in the United States? I know now It's a Schedule 3. It's a much more regulated compound in.

The US, I think maybe 1996.

Yeah, I think it was the late.

90S, late 90s, 2003, Putin banned it in Russia.

Just banned it all together.

Yeah. Even for use in humans. And quite an interesting story. Brigitte Bardot, obviously the very attractive French actress, petitioned him to use it in animals because it's obviously widely used in veterinary anesthesia. So. 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 in the UK it became.

It was 2006 in the UK. It mirrors basically the US our equivalent of C3.

Ours is class B, it's under the misuse of drugs scheduling, but it's obviously scheduled to drugs for medical use. 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 ego.

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 have no medical use at all.

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. But it's the one that's 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 psychedelic?

I don't think I'm an expert to say. But no, I don't consider MDMA a psychedelic, personally. I put it in the category of an empathogen. And because you don't really have any dissociation with it. Yeah, it's not altering perception in the way that LSD or psilocybin would. And your point is an interesting one. Right, which is Schedule one typically implies no medical use, high potential for addiction. Well, certainly 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. I've heard mixed things on this. But what do the data say? How addictive is ketamine in terms of other things for which we have benchmarks, like, for example, benzodiazepines and opioids? We really have a clear sense of the addictive potential of those molecules. Where does ketamine stack up?

I don't know if we have really good data on that, but I would say in terms of physical withdrawals, symptoms, I mean it depends how you assess the addictive properties. Right. I struggle with things being addictive. People become addicted to things, but they're also, you know, multifunctional tools that sure.

Coffee'S addictive or whatever.

And we did a study of people that use ketamine, so they're probably at higher potential for abuse. So people who use ketamine non medically, as in what you would say recreationally, about 9% of them had symptoms of some sort of dependence or craving. 9%, 9% of a group of recreational users of drugs. So I'm finding that hard to benchmark that against opioids and benzos.

The last time I looked at the opioid data, someone listening to this will probably say no, that's wrong because I'm going by memory. My memory was about 20% of opioid users became addicted to, but that was prescription based opioid painkillers. That doesn't include heroin, where that number might be higher. But of course you're also pre selecting a different subgroup of the population. So it's not really an apples to apples comparison. In other words, what I'm saying is of 20% of patients who would be prescribed opioids for medical use could become addicted, which is a staggering number. Right. One in five people who gets an opioid prescription could go on to abuse them later. I don't know how much faith to put in that number because it seems so absurdly high, but it's plausible. So the only way we would really know this, I suppose on an apples to apples basis, is you took patients who were being treated with ketamine for another indication, such as recalcitrant depression, and you asked the question how many of those patients would go on to experience dependency? Pharmacologic, physiologic dependency.

So far the data suggests it's pretty low. So we know that a little bit from the trials that have gone on so far, but it's a really early stage. And I guess if you're doing Apple's Apples opioids, is that daily or benzos? I don't know frequency. Also, how you're defining addiction is quite hard because if it's physical withdrawal symptoms or is it impacting on your everyday functioning or is it seeking beyond your prescription dose escalation? I mean I know from having worked with ketamine, people who are addicted to ketamine that a small proportion of people do become Addicted to. As we mentioned, it has these really serious physical consequences of having toxicity on your bladder. You know, I was working with 16 year old girls who've had their bladders, had to have a cystectomy. So you have your bladder removed and then they're having to wear a colostomy bag. Really dire consequences. And I think that's quite rare. I was thinking about other drugs that have got like a direct physiological.

So just to make sure. I understand. So these are 16 year old girls that were not using ketamine for. For medical indications such as depression. They became addicted to it recreationally.

Yeah. And this was kind of an epidemic in the UK in the 90s, early 2000s when we were researching it, because people didn't really know anything about ketamine.

I was in medical school in the 90s. We learned about it as Special K. That's what it was referred to. I don't know if that was the San Francisco name cause that's where I was going to school. Was it called Special K in the UK also?

Yeah, I think people called it that. Some of them called it kiddie Smack. It was basically like heroin for kids.

I see. So it's kind of the JV or junior version of heroin. Not quite as bad for those people.

But there was zero information about it at the time. And they were not taking the drug the way it's given for depression. They were taking grams and grams of it every day. So these serious. Something important to say.

We'll come back and do the math on what that means. But if they're taking high doses of this stuff daily, were they taking it and then basically passing out in their apartments for hours and just dissociating on trips?

They would just tolerate it because it is. The tachyphylaxis is like the rapidly developing tolerance. And if you do administer ketamine repeatedly in a short time window, you do need to give higher and higher doses. With these people. They were going, they were functioning, you know, walking around on doses that, yeah, would floor an elephant or certainly a horse.

But what was the drive with opioids? The drive is that high. There's a really, really profound high that comes from that Mu receptor being hit. What was the high that they were getting even once they were into that high state of tachyphylaxis?

We actually did some research on this. I think we spoke to about 120 Ketman users doing some interviews of why they took it. So some of them said very pragmatic things. I think because it's Very cheap. So things like it's cheap. It gets me really off my head. I think the escapism of it. There's some slight opioid actions of Ketzerman. Maybe we can come on to that, talking about the different isomers of ketamine. But. Yeah, so some people are taking it just for the escapism. Some people talk more as we'd see them, kind of psychonauts, but almost addicted to chasing the consciousness and the insights they felt they were getting. And they were just taking more and more to try and get more insights. I mean, there's some really high profile examples of that. I don't know if you've heard of John Lilly, who was the neuroscientist based in California of the film Altered States is about him. And he did quite a lot of unusual research, you know, giving LSD to dolphins. He invented flotation tanks, I think. And he writes in his book, the scientist clearly documents becoming completely addicted to ketamine to the extent that he was having an intravenous drip of ketamine pretty much 24 hours a day. So he really heavily escalated his dose and became kind of psychotic where he had these revelations and went to tell the president of the USA about the world being taken over by computers. So, I mean, it's a really fascinating book if you're interested in reading an account of ketamine addiction.

And how did that story end for him?

Did he manage to get off ketamine in the end? I'm trying to remember. That's a really good question. I can't remember the end of it. I know there's some sad ends. There was another book called Journeys to the Bright World by someone called Marcia Moore. Her husband was an anaesthetist and she experimented with Ketterman. It's actually quite interesting. They are very different subjective experiences. So John Lilly's one's very machine state and he's experiencing hallucinations very related to being in a computer. And hers were very soft and round and going back to the earth. But she sadly, I think, froze to death. She took some ketamine outside and again that thing where you are completely dissociated in your. Yeah. From your body. And she'd gone outside one evening and actually froze to death. That's really sad. They were people taking really high intravenous doses of ketamine. It's got a rapidly developing tolerance.

And why is it different? So pcp. I'm trying to think. I don't really think I took care of any patients that were Strung out on pcp. But I certainly remember the lore of the drug and it struck me as a much more aggressive drug. People that were on pcp, as you alluded to earlier, they seemed almost bulletproof. Right? They'd punch their hand through a glass window, be unfazed by the fact that they just broke every bone in their hand. Given that these drugs have such a similarity, why did PCP seem to produce that phenotype? Or is that just lore and that really wasn't what was happening?

Yeah, I think that's law. I mean, I think it produce a protracted psychotic state. I think they gave the police nets even to catch people on pcp. There was a lot of police brutality, these special PCP nets, police brutality associated with pcp and maybe the people taking pcp. Some people have suggested kind of a degree of racism or against kind of people in poverty. So I've looked for examples of this kind of bulletproof phenomena and I can't find any in the literature. Certainly there's definitely examples of people having a protracted psychotic like symptoms, having hallucinations, having to be hospitalized. But this whole running police and the kind of violence aspect I find hard to imagine.

And is PCP still being used? Is it still a street drug?

It's never really been a street drug in the uk. I'm not aware there's many reports in the US either. It's interesting and it's interesting in the context of the new use of all these substances. Nobody's really thinking about using pcp, but maybe that would be something to investigate.

So speaking of kind of the resurgence of these drugs, how would you contrast ketamine with psilocybin and lsd? So psilocybin and lsd, of course, are much more similar to each other. How does ketamine differ? I mean, obviously it differs in use case, but do you have other senses of how it produces a different experience?

Obviously it has completely different action where they work on the 5ht2a receptor. And ketamine, as we were talking about, works on these kind of glutamatergic receptors. And there are some similarities in the acute experience, which is people talk about EO dissolution and ketamine causes that quite profoundly, so you lose your sense of self. And that happens to a degree as well. On psilocybin mushrooms and lsd, I think you get much, you can think more clearly on LSD and psilocybin. Ketamine impairs some of your higher cognitive functions and causes that kind of analgesia, which is associated with ketamine's got an anxiolytic effect. So even at higher doses, people don't report anxiety, whereas they can describe things, as some of our patients describe things that sound scary but they don't feel the kind of physiological anxiety. Whereas drugs like lsd, psilocybin, people can report being absolutely terrified by the experience. Maybe that's the dissociation that happens more on drugs like ketamine, where you have the sense of being separate and everything's kind of emotionally numb, as I guess you'd think with it being an analgesic or an anesthetic.

And that might be due to the greater inhibitory effect potentially of ketamine is probably why you maybe can short circuit some of the anxiety. That can definitely happen with LSD and psilocybin if the setting isn't right or if the dose is too high.

Yeah, we were talking before about the abuse potential. Maybe why it's got a higher abuse potential. Because that's right.

It has less of a negative feedback loop. I think anybody who's tried the other psychedelics will say, look, if you go back to the well too many times, you can get stung.

It's unpredictable in that sense, if you're looking for kind of escapism, you don't want to escape into absolute terror.

Well said. Let's talk about depression because I think this is where people are really becoming interested in ketamine. It's certainly how it came to my attention. Seven, eight, maybe nine years ago, it was a physician friend of mine 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. It's perfectly legal. I have a compounding pharmacy, and these are the instructions that we give the pharmacy and they give the patient an intranasal spray and they use this spray. They were doing it once a week or something was the use case. And at the time, again, this is maybe 10 years ago, I couldn't find a lot of literature on it. You know, I found some and I found some interesting case reports. I remember there was one study I found based in India that looked pretty interesting, but then I sort of forgot about it until maybe four years ago. And I think what brought it back to my attention was frankly, the epidemic, for lack of a better word, of ketamine clinics, which basically are almost as ubiquitous as Starbucks. Now, before we get into the business of ketamine clinics, I want to just kind of understand where the idea came from, how Was this something that people even thought was worth pursuing clinically? And then how does it work? Who does it work in? Who does it not work in? Let's just go down the Depression rabbit hole.

Sure. There was a really early study in Iran, I think. I mean, it might even date back to some quite dodgy work by Salvador Bocay. I'm not sure if you've heard of him. He was a psychotherapist.

Yet I do want to compliment you on the use of dodgy. That word cannot ever be overused. So anytime you want to just throw in that that's a dodgy scam or that's dodgy work, feel free to insert that.

Thank you. It's not a very scientific word, but thanks, Peter.

No, no, it's. It belongs here. It belongs here.

Okay. Yeah. And he definitely was a dodgy guy. So there we go. 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 psychotherapeutic practice. And he was giving ketamine with other psychedelics 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.

This is in the 80s or 90s.

No, that was back in the 60s.

Oh, wow. Yeah.

So way back, maybe the 70s, there was this study out of Iran. But really, the work that's caused this whole explosion in ketamine depressant research, because I don't think anyone was really watching those areas of research, came out of group at Yale, and a guy called Robert Berman, who did an early study in 2000 giving a single ketamine infusion to patients with treatment resistant depression. And they showed this thing which was kind of groundbreaking in that you could get this rapid reduction in depressive symptoms, not as traditional SSRIs, Prozacs, and your traditional antidepressant drugs have got a delayed onset of action. And it was just kind of accepted. They take two weeks to work. And, you know, there's various ideas of why, but ketamine works immediately. And people with treatment resistant depression. So this isn't mild depression.

Tell me how it was administered in those early studies. Was this.

So that was intravenously.

Intravenous. Okay. And what kind of doses were they using?

0.5 milligrams per kilogram.

So an 80 kilogram person is getting 40 milligrams intravenous over 40 minutes. Over 40 minutes. So not an IV push, but a pretty quick drip.

Pretty quick. Like mild dissociation, I would say, from my experience of using different doses and some kind of peripheral subjective changes. Yeah, we've used that dose in acute studies.

And then just for reference, what would a recreational drug user who's not completely habituated, so they're not way up the tachyphylaxis curve. But if a recreational person went to their drug dealer and said, I want some ketamine because I want to blast off, what dose would they be given?

That's really variable, I'd say, but maybe more on like at least 100, if not 200 milligrams, I would say.

So they're going to be given two and a half to five times the dose. And they would blast off with that? They would probably take that intramuscularly.

Intranasally, I think, is the typical route for ketamine users.

And is the bioavailability similar? I'm sure the onset is different with intranasal versus intravenous versus intramuscular. But does the same amount of drug basically get to you with each of those routes?

Slightly less than intravenous is obviously the optimal route for that. But, yeah, it's pretty good way to get it across, which is why it's now been taken forward as a treatment in depression, I guess.

So going back to this patient that's getting 40 milligrams, that's a dose that they know something is happening. They're not getting a placebo, they're not being blown out of the water.

It's really variable. Through all my work, I guess I must have given hundreds of people ketamine in research studies, and response is really variable and not necessarily predicted. So we weight adjust all of our doses.

So give me the range. What's the sort of interquartile range? Are there some people that literally feel nothing? At 0.5 mgs per kg, I don't.

Know that anyone would feel nothing but maybe feel more like slightly drunk and feel a bit disoriented, you know, that kind of feeling, like intoxicated, basically, and slightly dissociated.

And at the other end of the spectrum, are there people that are just tripping?

People have gone down a canoe in their mother's eardrum, like doing really weird stuff like having frank hallucinations, basically. We can talk about that in a bit. We've found out a little about what predicts that, I think.

Now tell me. I'm very curious because I just know myself with any single agent that I've ever ingested in my life. Anything that ranges from alcohol to acetaminophen to a psychedelic agent, I need like three times what anybody else needs to feel it. And I've always been curious as to why.

The things that we found out from our research is that people with a family history of alcohol problems, they have a greater acute response to ketamine, they're.

More sensitive to it, they're greater response.

To the therapeutic effects, They've actually got less of the response to the acute. Sorry, I said that completely wrong. And what are the other things? Bmi, which is kind of obvious, I suppose, is so higher bmi, body mass index is predictive of a higher acute.

Effect, but that's because they're getting a higher dose.

Well, in a way. But then the BMI is slightly different and I suppose maybe that's something to consider. Similar with alcohol. Right? Like your lean muscle versus your fat.

That's not surprising, right, Because BMI really speaks to how much lean mass and non lean mass you have. It doesn't really speak to your organs and it certainly doesn't speak to your brain.

No, no, it doesn't speak to your brain. So no, these are really obvious things. I mean, and this is why we haven't got very far in predicting how people respond. And therapeutically we know with depression, the more suicide attempts, people have a better response, so they're more likely to respond, which probably maybe means they're more severe. I guess we know. Not very much at all really. There's some kind of.

So let me ask another question. Does the acute response that you are watching during the. Call it two or three hours that they're in your chair being administered the drug? Right, because it's a 40 minute infusion, presumably it's another couple of hours while they're under the effect of the drug. We call that the acute response. Is that predictive of what you're really after, which is the abatement of depression?

Yeah, that's a really good question. I think the field is pretty divided. So the way that the acute effects have typically been measured is, is with a scale called the Clinician Administered Dissociative State Scale, which basically looks at dissociation, but it was designed to look at dissociation from people having flashbacks, from traumatic experiences. So it asked some questions that are relevant for ketamine, but some that are not. So it's like things moving in slow motion. Have colors changed? Do you have a sense of forgetting chunks of what have happened? A lot of it is Relevant, but people who've looked at other aspects of the acute experience. So with these dissociative effects, some studies, I'd say about 25% find they predict the therapeutic effects. We've actually done a systematic review on this, but the others don't. I think in general psychiatry there's a feeling that these acute effects are a nuisance. And there's a whole research effort has been devoted to finding drugs that don't have these acute effects with kind of limited success. And actually when you look into the data, people who use a bit more nuanced ways of looking at the acute effects. So there's some scales that look at some of the bit more, I guess you'd say, trippy effects and things like mystical experiences in the sense that you can't explain the experience that's gone on. And those do seem to predict. So it's quite interesting.

Wow. First of all, just try to unpack that. It's not crystal clear that the person who's sitting there feeling slightly drunk is going to have a lesser outcome or a greater outcome than the person who's on the canoe in their mom's Eustachian tube. So the second point I would extract from what you said is we're probably using too crude an instrument to try to tease out exactly what effects in the acute phase matter. And it's either because we don't know what questions to ask them in that window, or we're not doing our analyses on a fine enough gradation of symptoms. Is that a fair assessment?

Yeah, that's what I'm saying. Basically, I think we need finer, more nuanced understanding of the effects. So we're doing some stuff now just recording what people say and getting them to describe it and then using artificial intelligence machine learning algorithms to find patterns in that to see if that might predict it. Because I mean, that seems like a bit of a no brainer now that we've got quite a long way with just using natural language to predict outcomes.

By the way, does ketamine produce amnesia?

Yeah, it's got some amnesia, but people can remember the experience. You might forget aspects of what's happened and it certainly impairs your episodic memory. But people do remember the experience. So we do interviews with people about the salient points of the experience they'll remember. But I guess it's through a bit more of a fuzzy haze than maybe your classic psychedelics. So a bit less accessible, I would.

Say after you've done this, the patient wakes up and it's three hours later. Wake up is the wrong word. But the patient sort of returns back to their baseline state. Do they immediately feel the alleviation of the depression? Is that how quickly it can onset?

People can feel just, yeah, quite considerably better. A colleague of mine, Rupert McShane, he set up the first NHS treatment Resistant depression clinic here in the UK and he likened it, you know, the film Awakenings, which is actually about Parkinson's. These people are really severely depressed, often can't get off bed and that they suddenly come alive. Some people, you know, not everyone responds to it, but that is pretty rapid and people just feel a kind of sense of clarity, a bit more interest in the world, I would say, almost like you're able to detect novelty where you weren't before. You know, it's quite a great thing to see.

What is the mean and median duration of how long that lasts?

It's really variable and obviously some people don't respond at all. So it's important to say that what.

Fraction do not respond at all?

I don't think we have a good handle on it. Basically we need more real world data because if you look at people in trials, it's often very different, but I think it's around 50, 50, 60%.

Oh my God, I had no clue it was that high. So you're saying half the people that show up with completely treatment resistant depression and go through this experience under the well controlled setting of the lab in the clinical trial have no benefit from it?

Yeah, I think that's what's happened over time. So the early studies, like Carlos Verrarte's study, it was 75% and this typically happens with any new treatment. As more and more studies come out, the rates of response reduce. Maybe I'm being overly conservative, so I should probably have that figure to hand. But I will say I think the duration is probably about two days to a week often and some people have longer will have two weeks. But that's the bit where my research comes in really, because we've been looking at how you might extend that response and that's something that does seem to be coming out now. If you give it alongside psychological therapy of some kind, you can really extend the response to ketamine and the antidepressant effects as well. As my trials have been looking at ketamine in the treatment of alcohol, but we found still reductions in drinking six months following just three infusions.

How far did you space those three infusions?

Either a week or two weeks, probably on average with seven Sessions of psychological therapy. So quite a limited treatment program, really.

Let's define treatment resistant depression for somebody. It's not defined by duration, is it?

No. I mean, that's a tricky one because it's defined differently depending on different trials. Often people define it as not responding to two conventional antidepressants in the current depressive episode or having had multiple different treatments. Some people take a more conservative definition of that to have maybe three failed responses. So it is pretty variable in the trials.

And depression requires at least two weeks of the set of symptoms that we typically associate with depression. Would it be classified as depression if there is an obvious externality? So loss of a child, you know, if your child died and a month later you can't get out of bed, is that considered depression?

No, that's natural sadness.

What I mean by that is like, how does that get classified, given that there's such a clear explanation for the.

Why, if that continued for a really prolonged period of time? But then even that in itself is maybe contentious. There's a clear boundary between grief, what we would anticipate from grief, and natural sadness, and then depression.

Let's keep it this one sort of simple and say that this is not something that's clearly associated to a trigger such as grief, but instead a less obvious to explain form of depression. It's been going on for at least a couple of weeks. Let's make it interesting and say it's been going on for months. So that this person has gone through one ssri, they've taken it to a therapeutic dose, they've had no benefit, they've then progressed and moved to a different SSRI or a different class of drug, an SNRI or something like that. And similarly they're just not getting the benefit. Do we assess how much psychotherapy they've been doing at the same time?

I'm just thinking about the clinical trials or the reasons we give for prescribing off label ketamine here in the uk. Typically it would be the antidepressants, like not responding to two antidepressants. You could say failed response to cbt. In a lot of the trials they would have non responders to cbt. I know particularly some of the psilocybin studies, but that's cognitive behavioral therapy.

So now the person comes in and again, we've just said 50% of those people are not going to respond. That's pretty sad. So what are we saying to those 50% of people? We're going to go back to trying more and more conventional therapies or do we say we should try this again and maybe the second time we use a higher dose or something like that.

There's some evidence that people take maybe three. This is in depression might not respond to actually three ketamine doses, but maybe the fourth one. There's some evidence that having an extra beyond three doses might increase the response. I mean, certainly unlabeled ketamine, which is this bravato, this is the Janssen version of ketamine, which is intranasal, that's indicated for repeated dosing. So you start out twice weekly, I think it's for a month and then move to weekly. And what they're finding with the long term studies is that people are staying on the dose. I think there was an idea that people might progress off or drop down to. I think they dropped down to fortnightly, but they're staying on it for a number of years now, I think is the kind of long term data. So it is a maintenance.

So the plan is to keep people on ketamine or let's go back to somebody who responded. So let's go back to a patient whose depression is profound and they've been through all the treatments and nothing's worked. They do their first ketamine infusion and they feel remarkably better and it lasts four days and then all of a sudden the depression sets back in. Is the thinking that we're going to repeat this treatment and get longer and longer periods of benefit, during which time we can work more on psychotherapy to try to wean off the need for ketamine?

That would be my thinking, and that's some people's thinking, is that targeting the therapy during that time is really important if you don't want to keep someone on ketamine as a maintenance dose.

By the way, do patients need to stop their traditional antidepressants when they are coming to these trials? Because most of them are probably on SSRIs and not doing well. Do you at least get to keep them on that?

In our trial, we were, our funding body, which is the UK state, didn't want us to include people on ssris. But actually most of the studies, the depression studies, people are still on them and there's no interaction. It's not like some of the other novel substances like psilocybin, where you'd. It's working in a completely different way in the brain, there's nuisance. I mean, you probably wouldn't be responding to them, I guess.

Why do we think this works? What do you think Is the mechanism of action.

That's where I think potentially the therapy and targeting the therapy is really important. People have talked about ketamine and indeed the other psychedelics, psychoplastogens. I'm not sure about the term, but maybe the idea that they provoke this kind of cascade and the study showing they increase synaptic plasticity in the prefrontal cortex, or certainly ketamine does so increases the growth of new synapses and dendrites and basically the ability of the brain to form new connections, and that. That is correlated with the antidepressant effect. We're doing some work at the moment to chart the time course of that in humans by looking at eeg. So that's kind of electrical signals from the brain and trying to target the window of this synaptic plasticity. Because we know from animal studies this might be kind of starting four hours following the ketamindos, 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. He's able to learn new things. And we know actually this kind of plasticity is impaired across a whole range of psychiatric disorders. So not just depression, but also in alcohol and addiction and trauma. So actually being able to stimulate the brain to learn new things, well, 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 definitely about things, learn new ways of thinking about old problems. That's. To me, it seems like an intuitively appealing mechanism. I mean, there's some problems with it in that neuroplasticity happens from all sorts of things. Some might argue, you know, is this specific enough as a process? Other drugs produce neuroplasticity that we wouldn't say were necessarily potential treatments for mental health problems and psychiatric disorders.

Such as?

Well, like cocaine. So people say the neuroplasticity produced from cocaine is why it becomes addictive. There's a stimulation of that from an acute cocaine dose. I do think we need to find out a bit more about it. And maybe it's down to something really specific and neurobiological. I leave that to my preclinical researchers.

When you think about things like MDMA and psilocybin, a lot of the therapy takes place while under the influence of the drug, Whether it be for PTSD or depression. Is that Happening also with ketamine when that patient is in the aftermath of the infusion or are they basically just left alone during that period of time and the psychotherapy takes place immediately following the next day and the next day and the next day trying to take advantage of them being less dysthymic in our work.

Certainly we wouldn't be trying to do any therapy under the influence of ketamine. I think people are too dissociated, the memory is impaired. There are some ketamine therapists who do use this what's called kind of psycholytic approach where they use mild doses to be able to to some therapeutic process. There's a really interesting study actually from a guy. Where is he? In Texas, I think. I had some correspondence with him. He's actually looking at complex ptsd, really severe multiple traumas and he was treating complex regional pains and drain on top of that. So these are really traumatized people who've got really severe pain. And he was giving continuous, quite low dose over 96 hours, so continuous infusion. And he was doing very basic psychological therapy during that time and found massive reductions in capscore, which is our measure of PTSD symptoms. It was a really small study, but I thought that was quite interesting approach. 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 and when they're having the acute experience is really just supporting them and the.

Work happens and then it's the integration afterwards where with psilocybin.

Well, 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. But I don't know, we're kind of lacking in research from that side.

What do we know about the brain under the influence of ketamine? Have people done FMRI or fdg PET and looked at either the metabolic state of the brain or the activity of the brain? You've obviously mentioned the prefrontal cortex, but can we get even more granular than that? Are there certain sections of the PFC that are more active than others?

There's quite a lot of really interesting work. I guess as you'd imagine, the default mode network.

Tell folks what the default mode network is. It's very important in this space.

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 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. Repetitively think about something good, but repetitively thinking about something bad or mind wandering. So that's where the default mode network has been shown to be disrupted following psychedelics, this kind of background normal kind of chatter of your brain. And also similarly with things like mindfulness. So there's been studies looking at that. You mentioned the prefrontal cortex. There's some really interesting studies looking at prediction error signalings. The idea that your brain is basically making predictions all the time about the world. And that's how we understand everything perception. We know that there's 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, then I'd have like a massive shock of surprise because 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 attention and activity in your brain. And there's some work showing that ketamine basically disrupts. There's a bit of the dorsalateral prefrontal cortex in your prefrontal cortex, but a bit back and a bit to the side really associated with this prediction error processing. And that's disrupted with ketamine. Things that aren't surprising become surprising. The things that shouldn't be surprising and are completely predictable and things that aren't predictable are no longer surprising. So basically noisy signal, just quite an interesting way of understanding maybe the subjective experiences from a lot of these drugs that you turn off some of that forward prediction from the brain and make noisier signals. I think that's quite interesting way to think about the subjective experiences.

And is the brain hyper metabolic under the influence of ketamine?

The idea is that it's more hypo in some ways get an increase in prefrontal glutamate. And we know that as well because you get attenuated and an increase in prefrontal function. So I don't know that that's particularly clear, I guess. And the neuroimaging as I've done it as a method in the past is not my area of expertise.

How many patients do you think, when relieved of their depression during these ketamine trips, will need to stay on ketamine as a long term treatment and if so, at what frequency?

That's what's really frustrating in a way, is that there's all of these ketamine clinics, as you mentioned, that have sprung up all across the us. We don't really have that in the UK because we have a state healthcare system.

So in the uk, any patient who is receiving ketamine for depression is doing it through the nhs. It's paid for by the nhs.

There's a couple of private clinics now that have sprung up giving ketamine. I'm involved with one, actually. Mainly there's five centers prescribing on the nhs, but it's all off label because our state healthcare regulator have not recommended yet Spravato, which is the intranasal ketamine for use. And so there's no licensed ketamine for depression. So it's all prescribed for treatment resistant depression.

But if the physician prescribes it off label, is it paid for still by nhs?

Some of these clinics, yeah, that have sprung up, maybe five of those at the moment, potentially. There's a lot of data out there that we could be looking at, but we don't have a good registry of all the patient. In answer to your question, there would be a number of people that probably might respond in all of these clinics. My sense is that not everyone has treatment resistant depression. I think, particularly in the us, it's been given for a wide range of indications.

My guess, in looking at the way it's being done in the us is there is no indication. The only indication is, do you want to pay for it?

Yeah. That's why I think it would be amazing if we could have a international registry rate and then we could look at this data. We'd have the data to be able to say with this presentation how long someone would likely be on ketamine. Because speaking from the trials data is one thing, but actually is already being given out there for all manner of things. It's a shame because I think these data would be really helpful and also it would add a level of safety, potentially for the patients and for the clinicians. I know there's a couple of case reports of people going across state lines, ketamine seeking. I don't think it's a huge problem, but we don't know. We must be mindful of the potential of these things. I've seen some Slightly worrying trends. Recently I've organized a ketamine conference with some colleagues, some of them from the us we had a few pharmaceutical companies coming in and developing ketamine for oral daily dosing. To me that's a bit of a worry, Having worked for 10 years researching ketamine users, because even if you're using very low or daily dosing, you're going to have to dose escalate. So where's the end point 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 I mean, I'm going to 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 a greater profit motive without enormous consideration for the downside. I don't know what it is about ketamine that has me sort of cautious and maybe it's just the anecdotes and that's a bad frame. But, and this is going to sound really silly, but have you ever seen people with these sort of ketamine eyes sunken, distant? This person has taken too much ketamine in their life and their brain doesn't work as well anymore. 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 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. 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 again, it's just anecdotal, but you see some of these people where you get the concern. It's not just the bladder. I mean, the cystitis is a very obvious 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. Am I just sort of making this up? And it's possible I am and that I'm just over extrapolating from something else, but you've been around this more than almost anyone. Do you have A concern around that.

Yeah, no, we've done a lot of studies on that as well. And we haven't studied the sunken eyes, but we have looked at the brains.

I mean, it sounds silly to say it. It's not physically sunken like you would with hypothyroidism. It's a vacancy is more what I'm.

Describing, a kind of dullness. 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 the spark has gone out of life. Which is odd, right? Because what we're giving ketamine for is 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 cognitively, we found cognitive impairments and with planning we found actually reductions in your hippocampus which is involved in processing novelty and encoding memories. And 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 this kind of symptoms. So people who take it occasionally. But yeah, really, really, really heavy doses, I think that's possible. I don't know because seeing the way that it's administered in clinics, the idea of it as a rapid acting antidepressant, and I think the promise was that it's not a maintenance medication 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. Some of these people, this is life threatening, right? Like people who are really heavily suicidal.

Say, has anyone done that study where you. Because that's the closest way to get to a quality adjusted life year analysis, which is going to 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?

There's people who have definitely done work with patients with Suicidal ideation. Yeah. And you get reduced mortality with ketamine. I mean, these are tough studies to do, right?

Yeah, of course, they're ethically difficult as well when you know that you have a treatment. So what does your intuition say is probably the sweet spot for what the intermittent Call it transient but fixed use of ketamine is as a bridge to go from completely treatment resistant to depression to treatable depression.

Just from our data. But there we used three doses and.

Seven sessions of therapy, three doses separated.

By seven days each, seven days to two weeks. And then that was a 0.8 milligrams per kilogram, a slightly higher dose than in depression because you get a sort of cross tolerance with alcohol because alcohol also works on the same receptors, ketamine at higher doses. So that's when people get really intoxicated and feel like they're spinning out. That's kind of your alcohol working on your NMDA receptors. So, yeah, we use that three doses. And these people with alcohol problems have depression as well and can be quite severely treatment resistant. What we found, I think is interesting is we were still seeing impacts on reductions in rumination, which I meant that repetitive negative thinking and reductions in anhedonia, which is a hallmark of depression, but also across multiple disorders. And that's an inability to experience pleasure in the world. So we saw reductions in that at three months, but they were back to baseline at six months, whereas they were still showing reductions in drinking, which I thought was really interesting. So it might suggest certainly in depression, that maybe that would be the time, maybe weekly or fortnightly doses.

That model makes a bit more sense. If you could say, look, this is a treatment that you need to do once a quarter every three months. So you have a loading phase where you do the infusion weekly for three or four weeks and then you're onto kind of a quarterly schedule. That to me is very interesting. What's less interesting to me and what I'm seeing certain people do is twice a week, ketamine infusion for life. A, I worry about the toxicity of the drug and B, it would have to really have an enormous efficacy to justify it seems. And I look at the short term studies where they're comparing ketamine to Versed, it's not that much better. Not that Versed is a good option, by the way, but when you're using Versed as a control and you're seeing, well, basically that's telling you there's a pretty big placebo effect from doing this as well.

No, exactly. I mean, that's my intuition as well. This is a positive thing if we're maintaining people on this twice weekly for life.

So tell me why you think it's working in addiction and do you primarily work in alcohol addiction or do you also look at opioid addiction?

We want to look at opioid addiction as well. And actually there's some other work going on in the US looking at opioid addiction. And this work dates back to some work by a Russian psychiatrist, Jenny Kripitsky, who did work with heroin addicts and found a similar dosing regime, which was just three infusions with this psychological therapy around it, produced reductions in heroin use at 12 months. You know, quite significant.

Do you know how much, how much of a reduction?

I know in alcohol? There was a 40% reduction in relapse.

Rate at 12 months.

At 12 months, yeah.

Is the control doing pharmacotherapy or behavioral therapy, such as 12 step programs?

For context, this is in the 80s in Russia, they were inpatient alcoholics in locked wards. So I remember saying to Evgenie, did anyone drop out? So they can't drop out, they're locked in. So I think it wasn't in the normal consent and ethics processes we have now, but still a really important study. And Both groups had 100 people in. It wasn't a randomized control trial. He asked people if they wanted to be in this ketamine and psychotherapy group or just have stand.

So I'm sorry, I don't understand. The trial. You have an inpatient trial where all the patients are given trial. Yeah, trial in quotes. This would constitute a dodgy trial.

Yeah, this is dodgy.

It's inpatient and they're all given unlimited access to alcohol.

No, no, no, no, no, no, they're not. They don't have any excess alcohol.

So how do we know what the relapse rate is?

So they do do their detox, they get given their ketman treatment, they're discharged, and then when followed up at 12 months.

Oh, I see. So 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.

They couldn't drop out of the treatment. What I was asking him about was, do people tolerate the treatment? Well, but they just did the treatment, so I guess, yeah, they didn't get shot by the kgb. No, they were really important studies. Jenny asked people if they wanted to have this group psychodynamic psychotherapy with just three infusions of ketamine. He was using Higher doses and intramuscular to 1-2mg per kg, quite strong.

But we haven't done the head to head of ketamine plus behavioral therapy versus pharmacologic plus behavioral therapy for alcohol.

No, we haven't. I've done ketamine plus therapy plus compared to ketamine with therapy control compared to placebo and therapy compared to placebo. So I did a four arm trial.

Tell us about that trial.

What we found, I mean, which was great because that's what we hypothesized and that's quite rare. I wasn't expecting to get. What we hoped for was that we saw the strongest, greatest reductions in drinking and greatest abstinence in ketamine and therapy group. 86% abstinent at rates at six months. And then the second best effect was in our ketamine and education controls. We wanted to look at the effects of therapy, ketamine within and without therapy. But there's really nonspecific effects of just spending hours with a therapist who's quite nice. Bit like medication management, which is used in a lot of the US trials.

That's a very elegant trial design because you get away from what's called the performance bias of the therapy. The therapy itself, you have to make sure you're controlling for just the fact that an hour, three times a week they have to go talk to somebody. So tell me what they do. In the education arm of that, people.

Were doing calculation about alcohol, talking about how alcohol affects the body. And we did some relaxation. But just as we thought, as a bare minimum of what we wanted to do with people going into ketamine session, you know, a ketamine infusion was to have a bit of a relaxation. Maybe the relaxation helps with the blinding.

And then for the non ketamine group, did they get versed or what type of a control do they get? What's the placebo?

Just got saline, basically.

Also no dissociative effects.

No, I know, which is a bit of a shame in retrospect. We should have used something. Yeah, like midazolam or we just use the saline placebo.

But it's still a very elegant two by two study, perhaps only limited by the fact that the control didn't get some sort of active substance. But nevertheless, at 12 months, or. Sorry, at six months, you said that the double positive group. Double positive meaning ketamine plus actual psychotherapy dedicated towards alcohol reduction. Did you say 86% were still alcohol.

Free at six months abstinence rates, which is good. Really?

What about in the other three groups?

The response were quite good in all of the groups, but it was statistically significantly different. 96 patients. It didn't feel like a small trial because only 24 patients per arm, so we weren't powered for the full interaction. Actually, we're taking it forward now into a phase 3 with 280 patients, again funded by the UK state, which is great. So we get to run it in NHS settings and hopefully see it as a medicine in those contexts, because. And I don't know what you think of the psychedelics world and I think some of the therapies are amazing, but for our state healthcare system, those things are not ever going to happen. You're never going to have two therapists for 40 hours. So I wanted to come up with a therapy that was deliverable in our state healthcare system. It's a great idea that you could do, have that kind of system, but we've got these kind of slightly lower level trained therapists and there's a lot of them in the NHS here. And so we designed our therapy to be quite manualized so that they could deliver it and it take a short amount of time.

How much therapy were they getting in the active therapy group?

In total? About 11 hours in six months. Yeah. So they just get. For the treatment part, they check in.

Oh, so just in those first three weeks or two weeks when they're getting. It's three doses separated by seven days.

Yeah, for a total. So they have a therapy session before their infusion, immediately before. And so if they were in the therapy group, they would be doing kind of mindfulness practice and then in the education group, there's some relaxation and then they have the ketamine session and then they just recover as you work from an anesthetic and they go home, come back the next day, where we think the peak of the synaptic plasticity effects are, and they have another. So these are longer sessions of an hour and a half therapy. So it's kind of a ketamine infusion sandwich between two therapy sessions and they repeat that three times.

What is the therapist talking about? I don't really know much about alcohol addiction in particular. When that patient comes in the day after their first ketamine infusion, when they're, as you said, at their maximum neuroplasticity, I assume the therapist has a very clear playbook for how they want to work with that patient in that 90 minute block. What's in that playbook?

Some of it's very pragmatic things. Like what are your most risky situations for drinking? Like trying to preempt situations where they might relapse. But some of it's more about how you want to live your life and the values you want to embody. So trying to think about, think about your life without alcohol, how would you structure that? Things about thinking about your thinking around drinking, which is more cognitive behavioral therapy based. What are your thinking biases? Let's identify those and then planning. So they have quite a lot of activities to do in the week or weeks in between the sessions and I guess like standard homeworks, but planning their days, journaling, keeping track of those things. We teach mindfulness techniques to enable people to deal with cravings, to get a bit more of a space between them and their kind of addictive impulses. So there's a whole range of stuff really. We threw the book of the evidence based therapies at them.

Tell me about the inclusion criteria. I mean obviously you're dealing with a patient who's motivated, who says I want to stop drinking. They actually come and do a pre infusion therapy session. Is there anything that in that session the therapist says we're not going to include this patient. Is there another decision that's made of a go no go based on that pre infusion session?

Well, the go no go's normally made before that. So they had to go through like a number of screenings basically to get as is with a clinical trial, which is kind of a problem with clinical trials that we end up with quite pure populations. But we needed people to be abstinent when they started. As we were talking about right at the beginning with a lot of people who are drinking, they can't stop straight away. So they either need to go through a medical detox in most cases. Most of those are in the community now. So you can work with people's health care providers to support them as they doing that. So we keep checking in with them until they're ready to start normally, maybe two weeks after if they've done a full detox. If someone's drinking really heavily, but they're at levels that we think we can help them cut down over a four week period, we would do that. So normally be a kind of pre screening where we check all the medical contraindications for people and psychiatric ones. So we don't include people with psychosis or psychosis in a first degree relative people with uncontrolled blood pressure because of ketamine increasing. So uncontrolled hypertension is. Ketamine increases your blood Pressure and a variety of other things. We would exclude people from the study and then we have to access their medical notes. And so, yeah, it's quite a process. But the main bit is getting people abstinent. The therapy is all around supporting people with their new life and using the ketamine experience really to get that perspective, a perspective they might not have had for a while, a kind of new perspective to think about their life in a new way and try and focus on how they want to go forward, really. So it's really using the ketamine as a catalyst for the therapy rather than purely focusing on the pharmacological properties of it.

Remind me, how much does blood pressure go up in that type of a therapy when you're at 0.8 mgs per kg, what's the raise? What's the increase in systolic and diastolic blood pressure?

It really varies. So some people are really minimal, some goes up about 10. I'm trying to think a psychologist, I guess. We have anesthetist there for the whole thing, so they're probably checking that. And there was someone. We had to stop the infusion because it went above. I think it went over 180. That's pretty rare. And that's. Do you know why we exclude people then? My anaesthetist colleagues say if people in theater, we just give them ketamine, irrespective of this. They're, I guess, because of the way anaesthetists are, the people that kill you, ultimately, of all the medical professionals, they're quite desensitized, I guess, to risk, whereas.

We'Re like, oh, so again, tell me what the response rate was in the double negative group. So the group that didn't get the ketamine and only got the education, but without therapy, what was their six month?

Still really high. So about 68%, I think.

What do you attribute that to? So it means there's a 20% difference between the two extremes, which is still great. But how do you attribute a 68% abstinence rate in people that didn't get ketamine and didn't really even get therapy? They just sat down and talked with somebody about alcohol biochemistry.

I think that was pretty extraordinary for any clinical trial. And we did have a really lovely team. So partly put it down to that. It's something you see in clinical trials. People just do better. They've gone through this whole rigmarole process with this really strong intention to stop. So they've been through quite a lot of hurdles. The Trial was pretty demanding, so if you stuck with it. We also had things which I hadn't mentioned, like we had a scram. I don't know if you've ever seen them. They're using criminal justice more. Lindsay Lohan had to wear one when she had some DUIs. It's basically like a tag that you put around your ankle that measures your alcohol through transdermally because you excrete about 1% of alcohol and sweat. So there were things that we were using to measure alcohol that might have actually acted as an intervention on their own. Now we're using a much more discreet wearable, but then really clunky thing. You know, you had to say, you're not going to do swimming for six months. All these things. I think that in itself was an intervention. A lot of these people don't have a lot of social connections. Some of them did. But the fact of having people looking after them, checking in on them all the time, people just showing you general human kindness, I think can have obviously a really positive effect in a group that might be quite isolated.

That's amazing. I think these are really staggering insights because you have everything from the monitoring of compliance to just the interaction. I don't say any of this to diminish the fascination I have in both two components of this. One being the effect of the ketamine in therapy producing 88% abstinence at six months, but also just looking at the control group and realizing it didn't take much to move the needle. And what can we learn from that? Sort of more big picture. It's a bit of a sad statement, it really is.

Our alcohol services here in the UK are just so dysfunctional at the moment. People, by the time they get to any sort of treatment, people that are really seriously, complexly with multiple health problems or people have been through multiple treatments and they've not worked. And it's really hard to access therapists. So it's multiple things just like, oh, yeah, it's really sad. It doesn't actually take that much to shift something that's pretty entrenched.

Well, the other thing too is it makes me wonder about less responsive cohorts down the line, where you would expect the response rate to be lower. But let's say you took an individual who's less interested in not drinking. I don't think you could treat someone who says, I'm going to keep drinking, but someone who maybe hasn't fully hit rock bottom but says, you know, yeah, maybe I'm drinking too much and Yeah, I probably meet the criteria for being an alcoholic. I haven't destroyed my life yet. I just sort of wonder if you have these places for earlier intervention as someone is on the path towards really destructive alcoholism. Lots here. So in the phase three, obviously you said 200 plus patients, so that's going to be great. You're still going to do the same. Four arms.

It's funded by the NHS Department for Health here, so we've gone down to take the two most extreme arms. In an ideal world of infinite resource, I would definitely have the four arms because I really like that design. And I think something's really missing from the broader psychedelics world, is teasing apart the impact of the therapy and the drug, but speaking to clinicians. So we've got like a patient advocacy group involved from the start that actually given some of the risks with ketamine, that we wouldn't really want to give it without a therapeutic container. So having found these promising effects for this efficacy study, which is more of a definitive study, then we would just take the most extreme arms. We're looking just with the therapy and then the various other more discrete variables compared to our placebo. But we're using a low dose ketamine this time instead to manage expectancy and the same education protocol.

What will that low dose be? Will the high dose still be 0.8 milligrams per kilogram?

Yeah, and the low dose is low, like 0.05 was of working out with some piloting, but.

And why is that? Because at 0.5 they will, or 0.05 actually, they'll experience nothing. I mean, they shouldn't feel anything.

But we've done some other studies. I mean, we've done some studies with morphine and childhood trauma. So looking at people's. I mean, it's completely different area of research, looking at how childhood trauma seems to sensitize the brain to respond to opiates. And there we found actually using a very low dose morphine was kind of a better control than another drug. I think it is actually helpful in expectancy. So you tell people you're getting the.

Drug no matter what, you're getting one.

Of two doses of ketamine. Also because we had patients actually drop out. Well, two patients, they knew that they hadn't got the ketamine, they hadn't got the active. So we're saying you're getting one of two doses of ketamine. It's kind of easier to maintain people in that, I feel.

The other thing is you might be able to Recruit some KGB officers to help with that dropout. Right?

Exactly. No one drops out. We're not doing any dodgy stuff.

This is a non dodgy trial.

Non dodgy.

There's one other thing I want to talk about before we wrap this up, but I want to sort of put a bow on the ketamine story. What would you say to people here in the US 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, although I think there are therapists who do make referrals and say, look, this is a reputable clinic and I'm sure that there are many reputable clinics and your depression is recalcitrant or you're having this problem in your life. And I think it could get better here. So I suspect that there's 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 really do believe is true, and sort of tell the persons there, hey, I'm having this issue, I want to do it. But there's a bit of a conflict in that model, because when you walk into the clinic, they're incentivized to do what they do. Right. When you're a hammer, everything's a nail. When you're a ketamine clinic, you're incentivized to give ketamine. How would you caution people around ketamine? Use liberally in that context, I suppose.

I'd say that the evidence that we've gathered, and not just us, another group at Yale, Sam Wilkinson, has looked at therapy in ketamine and there's another trial starting in depression. It's a bit of a waste if you just do the ketamine. You should certainly try it embedded within therapy and you probably don't need all of those doses. I think interrogating what you're trying to get out of that experience, I think it's great to hear that therapists refer people to ketamine clinics like we've got so far with therapy. Then we're going to use this as a boost so we can continue the therapy. To me, that seems much more appealing model. I don't think people want to be kind of stuck on a drug. Even if you're not addicted, you're going in twice a week or even Once a week. That's so disempowering for patients. We know that. Right. And speaking to patients, one of the things they said was great about our treatment approaches. Rather than being on daily meds, things like other treatments and alcoholic, the campus that 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 a therapist. Think about using a really minimal number of doses is worrying. There's some really worrying practices that you hear about. 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, you have to have a lot of money to be able to afford that ketamine. But I just think it was unsafe because certainly don't take ketamine at home when you're not supervised. This drug makes you completely dissociated from your environment. If something happens, there's a fire or all sorts of things could happen. You can't take it unsupervised. But I think a lack of clinical care and supervision in some of these models that I find that really worrying.

You sort of answered what my next question was going to be, which was not at all to say, do you condone the use of non medical or recreational ketamine? But more to say, if someone is going to use ketamine recreationally, 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, if people are going to do ketamine recreationally, there really needs to be somebody around watching them. 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 depending on your size, 100-200mg would be considered a high dose.

Yeah, really high. 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 in a safe place with someone who's not under the influence of any substances and start with a small dose. I don't know so much. In the US you rarely get ketamine particularly cut with other things, but it can happen, so there's something to be careful of as well.

Wow, that's interesting. What would it typically be cut with?

I mean, there are ketamine analogues which people have shown so There's a drug methoxetamine, so they're the kind of research chemicals that have come out of labs in China, Israel, so it's an analog of ketamine, but studies have shown more toxicity of the bladder and slightly maybe higher abuse potential. I don't think 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.

Well, that's super helpful advice. I've sort of been deliberately ignorant of ketamine. I don't know why. I've gone down the rabbit hole in trying to understand as much as possible about these other agents, which ironically tend to be the one that are Schedule 1 and therefore not really readily available for clinical use outside of trials. We do have many clinical clinical trials here in the United States looking at in particular the use of psilocybin and mdma. 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 it can be used legally. I found this discussion very helpful. I found this discussion really insightful. It clarified for me a lot of the use case, the neurobiology, the risks, and perhaps most importantly what the promise of this agent is. I want to thank you for your time and again, I know it's late there in the UK at the moment and more importantly, I think thank you for the work you're doing. This is really fascinating and I kind of love the model.

Oh, thanks for having me. Peter.

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Sam.