The Peter Attia Drive - #220 ‒ Ketamine： Benefits, risks, and promising therapeutic potential ｜ Celia Morgan, Ph.D.

00:00:00.000 Hey, everyone. Welcome to the drive podcast. I'm your host, Peter Atiyah. This podcast,

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00:00:41.740 head over to peteratiyahmd.com forward slash subscribe. Now, without further delay, here's

00:00:48.080 today's episode. My guest this week is Celia Morgan. Celia is a professor of psychopharmacology

00:00:54.720 at the University of Exeter in the UK. Celia's research focuses on the benefits and side effects

00:01:00.000 of recreational drugs and alcohol on cognition, behavioral, and neurobiology. And she's authored

00:01:04.740 numerous publications on the potential use of ketamine and other drugs as therapies in mental

00:01:08.940 health. She created her undergraduate degree and PhD at University College London, followed by a

00:01:14.040 scholarship program that brought her to the United States where she studied at Yale. She conducted

00:01:18.400 research at the University of Melbourne prior to returning to University College London and

00:01:22.480 eventually moving to the University of Exeter, where she became the chair of psychopharmacology

00:01:26.640 in 2015. In this episode, we dig deep into ketamine. We talk about the neurobiology and the

00:01:33.140 chemistry of ketamine, how it affects individuals, how it affects specific parts of the brains, and how

00:01:38.100 it differs from other things that we might think of as psychedelics, though I don't really consider

00:01:42.160 ketamine to be a psychedelic. But we certainly contrast it with things like psilocybin and LSD.

00:01:47.060 We then talk about its use case and the potential promise of ketamine, specifically around

00:01:51.780 drug-resistant or recalcitrant depression and alcoholism. We talk about the importance of

00:01:57.000 therapy being offered concurrently with ketamine treatment, as many people listening to this might

00:02:02.280 wonder if ketamine therapy is indeed for them. So without further delay, please enjoy my conversation

00:02:06.940 with Celia. Hey Celia, thanks for making time on a Friday evening to sit down and talk about ketamine and

00:02:17.940 perhaps a few other things. But great to meet you.

00:02:20.640 You too, thanks. It's my pleasure.

00:02:23.020 So let's talk a little bit about your background. I think you finished your graduate training in the

00:02:26.680 UK, but then you did a stint here in the US at Yale, if I'm not mistaken, correct?

00:02:30.880 So I did my undergraduate in psychology with pharmacology and astrophysics for a bit.

00:02:37.160 I did a PhD program at University College London. But as part of that, I spent some time

00:02:42.800 at Yale and I'd got a scholarship to do a little bit of research out there in the US.

00:02:48.460 So what did you focus on during your PhD?

00:02:50.680 So my PhD was largely focused on the effects of ketamine. We were looking both at the acute

00:02:57.820 effects of ketamine as a model of psychosis. So at the time people were using ketamine with the idea

00:03:03.600 that would help us understand the neurobiological underpinnings of psychosis, because actually from the

00:03:09.500 outside ketamine looks a little bit similar to people who are psychotic. And so we were using

00:03:15.360 that to map the kind of cognitive processes altered by ketamine. But I was also simultaneously

00:03:21.120 looking at people who take ketamine recreationally, because at the time that was quite a big problem

00:03:25.920 in the UK. And when I went to the US, it was to work on, again, some neuroimaging studies looking

00:03:32.200 at ketamine as a model for psychosis. So it was before it really became established as an antidepressant.

00:03:38.120 So let's talk a little bit about the history of ketamine. It was synthesized in the 60s,

00:03:42.980 I believe.

00:03:43.980 It was synthesized as an anesthetic. Synthesized as a replacement for PCP or fencyclidine,

00:03:50.040 because obviously people know PCP as angel dust, and there's this kind of folklore around it of

00:03:56.220 people running at the police and being shot down and keeping running. But I mean, really the problems

00:04:00.940 with it had this protracted psychosis-like effects that lasted for a really long time following

00:04:06.860 anesthesia. It was still a good analgesic anesthetic. They synthesized ketamine as a

00:04:11.640 similar molecule. So it still works on the same receptor in the brain, the NMDA receptor, but it

00:04:16.780 was 10 times less potent. Yeah, so it synthesized back in the 60s. And the drug company that synthesized

00:04:22.280 it were initially really impressed by its analgesic and anesthetic effects. But then with increasing

00:04:27.840 clinical experience, it was noticed that people were coming around from ketamine anesthesia,

00:04:32.300 reporting a variety of quite weird effects. So things like hallucinations and out-of-body

00:04:37.760 experiences. And that's what's really limited its routine clinical use. But it's still one of the

00:04:43.140 most widely used anesthetics in the world today. It's on the World Health Organization list of

00:04:47.500 essential medicines.

00:04:49.260 One of the things that I remember from my clinical training was that one of the perks of ketamine was

00:04:54.580 that you didn't have the respiratory depression. And most things that we use as anesthetic agents

00:05:00.160 have this problem where if you overshoot them, and that's not an issue if you're doing general

00:05:06.140 anesthesia because you have an endotracheal tube in the main stem bronchus, so you're breathing for

00:05:10.680 the patient. But when you start to think about conscious sedation, respiratory depression starts

00:05:14.560 to become a very frightening consequence that must be managed closely. And with ketamine, you didn't have

00:05:20.560 that. Now, is my memory correct that kids were less susceptible to the hallucinogenic effects?

00:05:27.840 Because I didn't do much in pediatrics, but I can't recall if there was more flexibility in

00:05:33.860 using it with kids, or am I making that up?

00:05:36.780 It is used more with children. We tried to do a study, actually, which never really came off.

00:05:41.880 But I don't know if it's that people haven't asked kids if they're hallucinating.

00:05:45.620 It seems less foreign to them if they are, maybe.

00:05:48.400 Exactly. They are tripping all the time. But no, maybe not that. But they're more open to changes in

00:05:54.260 consciousness. I mean, it's used routinely. I'm really interested, and I don't think anyone's

00:05:58.640 really actually asked children about their experiences. So in pediatrics, in geriatrics,

00:06:04.560 also in battlefield medicine, it was the most widely used anesthetic in the Vietnam War, for

00:06:08.980 instance. As you said, it's really safe physiologically. It's an anesthetic because

00:06:13.440 it doesn't slow your breathing or your heart rate. So when you've lost a lot of blood, it's good as

00:06:18.040 well because it actually even vaguely increases your blood pressures. I think that's why it's a widely

00:06:22.900 used anesthetic. It's a really good question about kids. There's some people trying to get them in

00:06:26.860 in its antidepressant use now with adolescents. So we'll get there. And I'm glad you made that

00:06:31.860 other point, by the way. It doesn't lower blood pressure. So now you talk about it being the

00:06:37.300 perfect anesthetic in trauma and shock where those patients are hypovolemic, their blood pressure is

00:06:44.860 already going down. You give them an agent that if anything slightly acts like a vasopressor raises

00:06:50.600 blood pressure without the respiratory depression. I mean, in that setting, you can understand why

00:06:55.460 it became a turning point in the field medicine of Vietnam.

00:07:00.140 The acute experience must be really unusual when you're in that setting. As you mentioned,

00:07:04.920 not having to intubate people, that's why it's really popular in developing countries where you've

00:07:09.080 got limited access or ability to intubate patients. It's a really important medicine in anesthesia still.

00:07:15.540 And I think that's something people forget, you know, with all the new, the use of ketamine.

00:07:20.780 It's really interesting when you go and imagine what surgery was like before ether.

00:07:25.900 Yeah. 0.90

00:07:26.220 And I mean, that's just ridiculous. And to think that anesthesia is something we've only had for

00:07:31.840 about 140 years.

00:07:34.100 It's pretty crazy, isn't it? And a fascinating concept anyway, like when you lose consciousness and

00:07:39.500 how you measure that. There's different things on an atheist use. There's an index, which relies on some

00:07:44.480 EEG to look at how your consciousness drops, but I still don't think we really know, you know,

00:07:48.400 what turns it on and off.

00:07:50.100 So you mentioned that ketamine, is it safe to say it's an analog of PCP?

00:07:53.980 So they're all under the class of arrow cyclohexamines. And so I think Edward Domino

00:07:58.820 coined the term dissociative anesthetics to describe PCP and ketamine. And also people include nitrous oxide

00:08:05.640 in that category. I think based on the fact that they kind of dissociate you from your body and are

00:08:11.380 characterized by these out-of-body experiences, which can be quite helpful. Again, I think in

00:08:16.060 anaesthetic use, they are related compounds with similar, their main action is on the NMDA receptor.

00:08:22.400 So let's talk a little bit about that. Let's assume that folks don't know what NMDA receptor is.

00:08:27.800 They don't know what glutamate is. They don't know GAAP. Let's just assume people are coming at this

00:08:31.360 from a standpoint of not being completely up to speed on excitatory or inhibitory neurotransmitters.

00:08:37.060 Explain in some detail exactly how these neurotransmitters work and how other neurons can amplify or

00:08:45.900 attenuate the response of those and where ketamine fits into that.

00:08:49.760 Do you jump in as well if I'm either going too slowly or too quickly? Glutamate is the major excitatory

00:08:57.140 neurotransmitter in the brain and is prevalent all across the brain. And one of the receptors that

00:09:02.880 glutamate works, that is the NMDA receptor. And the NMDA receptor, the N-methyl-diaspartate receptor,

00:09:08.060 which are really important in a lot of our higher cognitive functions. So it's the kind of the

00:09:12.600 fundaments of learning and memory, particularly a process in learning called long-term potentiation,

00:09:19.180 which is where brain cells that activate at the same time, if they both activate,

00:09:24.200 then they're more likely to activate in future. So it's characterized by this term that someone

00:09:28.780 said neurons that fire together, wire together. And glutamate is really important in that and other

00:09:33.360 excitatory functions in the brain. And GABA is an inhibitory neurotransmitter. So it

00:09:38.940 shuts down the flow of electrical impulses across the brain. Well, ketamine does.

00:09:43.260 And before we do that, just to give some people some examples, glutamate is excitatory. GABA is

00:09:48.540 inhibitory. We can give people a sense of like alcohol. You and I were talking before we started

00:09:53.640 about GABA analogs that are meant to mimic alcohol. What are they doing? Why do people feel

00:09:59.380 relaxed when they drink? It's the GABA potentiation. When you look at things like benzodiazepines,

00:10:05.940 they're working at GABA. Are there examples we can give people that work at glutamate that are

00:10:12.040 amplifying glutamate? We tend to focus more on the opposite, right?

00:10:16.080 So like lamotrigine, so drugs used in seizures tend to reduce the flow of glutamate in the brain,

00:10:21.760 particularly in the prefrontal cortex. I'm trying to think of examples. It's a good question,

00:10:25.240 Peter. Do you know of any? No, I can't think of anything off the top of my head that would do

00:10:28.620 that. We normally are thinking of the opposite side of that. I don't know if we want to get

00:10:32.260 into ketamines. As you mentioned, drugs like alcohol, benzos, they all increase GABA activations

00:10:39.240 and kind of slow dampeners down on the brain and reducing things like anxiety and slowing your motor

00:10:45.140 function and generally inhibiting the flow of electrical impulses across your brain. It's part of the

00:10:50.540 reason why we get symptoms you get when you stop drinking. Your brain kind of goes into a,

00:10:56.600 it's like a seesaw, I guess. So the alcohol has been pushing down on that side and keeping it

00:11:02.500 dampened down. And then you release that and you go into a more excitatory state. I work a lot with

00:11:07.340 alcoholics. So things from alcohol withdrawals, you can get seizures and the shakes, and that's all

00:11:12.680 down to this kind of increase in excitation.

00:11:14.580 That's why withdrawal from strong GABA promoters like benzos and ethanol can be fatal if not managed

00:11:23.820 correctly. It's sort of funny. I think people intuitively know this. You can stop opioids

00:11:28.540 immediately and it might be the most painful thing in the world, but it won't be fatal.

00:11:33.040 Whereas if you take a person who's on a high dose of benzodiazepines or a person who drinks a lot

00:11:39.920 of alcohol and you stop that abruptly, it actually can be fatal.

00:11:44.380 And they are the drugs you can die from withdrawal in because of these huge then increase in excitation

00:11:50.140 because I guess with repeated alcohol use, your brain gets used to having all this GABA on boards

00:11:55.840 and then you get adaptation and your brain kind of upregulates to counteract that. And then when you

00:12:02.540 remove it, yeah, you can die from withdrawal. So the people I work with, severe alcoholics, it's unsafe

00:12:08.000 for them to stop straight away. So they have to cut down and use things like benzodiazepines and

00:12:12.360 withdrawals. So it's something that I think people do think about opiate withdrawal potentially as a

00:12:16.900 really difficult thing. But as you say, you wouldn't die from that. It's only from withdrawal from

00:12:22.080 these inhibitory substances like alcohol and benzodiazepines.

00:12:26.460 So we have excitatory and inhibitory neurons. And the inhibitory neurons, are they the ones where you have

00:12:35.200 like an NMDA receptor that is sort of globbed on to say a glutamate receptor?

00:12:41.580 That's one of the theories of how ketamine works. Well, we were just talking about the neurons. So I think I'm

00:12:46.860 going too into the ketamine.

00:12:48.080 Yes, I'm going exactly to now. Different ideas because it's not 100% clear exactly how ketamine works,

00:12:53.580 correct? No. And so there's a couple of theories that either ketamine blocks directly the NMDA

00:13:00.000 receptors on the glutamatergic neurons. And then this triggers a kind of downstream cascade. And maybe

00:13:06.460 it's a combination of the two, but ketamine blocks NMDA receptors on these, they're called GABAergic

00:13:12.400 interneurons. So they're GABA neurons that synapse onto your glutamate ones. So they put the brakes on

00:13:19.540 your excitation. So if you block NMDA receptor and a GABAergic interneuron, then you're going to have

00:13:25.340 a net effect of increasing glutamate flow in your presynaptic cells. So they're presynaptic.

00:13:30.740 But yeah, it's not quite clear. And it probably is a combination of the two. Increasingly, people

00:13:35.400 have become interested in the downstream mechanisms, really, potentially in the therapeutic

00:13:39.960 effects of ketamine. Again, ketamine is one of these drugs where the dose kind of makes the

00:13:45.860 poison. I mean, I think that's true of most drugs, but it really has different effects on an individual

00:13:52.260 based on how much they're getting, right? Yeah. Anything from mild hypnosis to some

00:13:58.760 dissociation to complete anesthesia? At low doses as well. I work quite a lot with people who take

00:14:04.960 ketamine and non-medically or recreationally and they, at lower doses, it's got kind of stimulant

00:14:10.400 properties. And then as the dose increases, you get perceptual distortions and illusions and kind of

00:14:16.440 a mild melting. People talk about floating. Higher doses still, you get kind of much more profound,

00:14:22.300 maybe not hallucinations, but changes in perception of reality. And the highest dose,

00:14:26.580 you're completely sort of catatonic, but people are experiencing inside these really, really

00:14:30.440 profound hallucinations. And that is really high doses from my work with non-medical ketamine users

00:14:37.480 that were actually really dangerous. A couple of people died from taking ketamine and then having

00:14:42.140 a bath and they're completely dissociated from reality and they drowned. And it's like the saddest

00:14:46.400 thing. And it makes you, I think as a user, the ketamine users are very vulnerable to accidents at

00:14:53.040 these higher doses because you are not completely dissociated from reality, really.

00:14:57.760 Wow. So that's sort of like LSD in the sense where it really has no LD50, meaning there's no amount of

00:15:05.920 LSD that you're going to take that is going to create some physiologic process that kills you the

00:15:10.860 way, for example, Tylenol, acetaminophen would poison your liver at a certain dose. But it's not

00:15:16.600 to say that LSD is completely safe because you can alter your behavior in a way that is so altered

00:15:21.800 from reality that you put yourself in harm's way. Basically, is that the same with ketamine?

00:15:25.920 If you look at it from a purely pharmacology standpoint, there's no LD50, given that it

00:15:31.320 doesn't have respiratory depression and all these other things that we worry about? Or how do you

00:15:35.380 think about that? Yeah. I'm not aware of anyone getting to like a toxic dose of ketamine. And there

00:15:42.300 are problems with repeatedly taking high doses of ketamine, physiological problems. The ketamine has a

00:15:48.060 direct toxicity on the epithelial, so like the lining of your bladder, which is really interesting.

00:15:53.640 is something that only merge really with people using really high doses. There's no LD50, like you

00:15:58.540 say, and much more so probably even than LSD, where a lot more of your top-down higher cognitive functions

00:16:04.320 are preserved. With ketamine, they're not, and you are completely catatonic, people will be kind of

00:16:09.480 collapsed, anesthetized really, in a cataleptic state. So you're much more vulnerable to accidents.

00:16:16.500 The drowning in a bathtub example, that seems tragic. And to imagine how dissociated you would

00:16:23.860 have to be to slip into a bathtub, inhale water, and not respond.

00:16:30.540 Exactly. You are completely dissociated. And it's really sad if it's someone that I was working with,

00:16:36.060 and it's not the only example I know of people who that's happened to, various different accidents.

00:16:40.880 It's really tragic. While we're on the pharmacology, let's talk about the different

00:16:45.720 routes of administration. I assume that most of the time when it's used medically, it's intravenous?

00:16:53.160 Most of the studies, certainly in the depression field, and when it's used in anesthesia, I think

00:17:00.040 people would give it intravenously. It's the best via availability and the most well-characterized route,

00:17:05.500 or route, as you say in American. There are other ways of administering it, which I think have

00:17:11.140 been increasingly used. Intramuscular has got quite good availability in the blood. And then there's

00:17:16.980 people starting to use things like sublingual administration, so putting under the tongue.

00:17:22.400 Intranasal, obviously, is the route popularized by, first, the drug users themselves, but then

00:17:27.940 patented by the pharmaceutical company, Janssen, have now used that for their licensed form of ketamine

00:17:33.200 and depression. Those are the main ones. And oral dosing, that's not as great in terms of

00:17:38.220 bioavailability. It's obviously an easy way to get a drug over and across into the system.

00:17:43.580 There's no liver toxicity with, I know you're going to have a bad first pass effect, which is why you

00:17:48.660 prefer to put it under your tongue as opposed to swallow it. But there's no toxicity. It just means

00:17:52.720 you need a higher dose if you're going to take it orally, presumably.

00:17:55.840 I assume people are doing the toxicity studies at the moment, because I know there's some

00:17:59.140 pharmaceutical companies looking at oral dosing as a potential.

00:18:04.060 But I think for the purpose of our discussion, we're really thinking about what has been learned

00:18:08.020 through intravenous and intramuscular and perhaps most recently intranasal.

00:18:12.060 Yeah. And that's where the bulk of the research is, for sure.

00:18:15.100 In the 1970s, when this drug was being used pretty liberally as an anesthetic, was it

00:18:19.140 unscheduled in the United States? I know now it's a Schedule III. It's a much more regulated compound.

00:18:24.380 In the US, I think maybe 1996.

00:18:28.620 Yeah, I think it was the late 90s.

00:18:30.340 Late 90s, 2003, Putin banned it in Russia.

00:18:33.760 Just banned it altogether.

00:18:35.060 Yeah, even for use in humans. And quite an interesting story.

00:18:38.400 Brigitte Bardot, obviously the very attractive French actress, petitioned him to use it in

00:18:42.780 animals because it's obviously widely used in veterinary anesthesia. So he removed the ban for

00:18:48.820 animals, but kept the ban in place for humans, which is pretty horrendous considering what an

00:18:52.500 amazing anesthetic it is. In the UK, it became, it was 2006.

00:18:56.400 In the UK, it mirrors basically the US, our equivalent of C3.

00:19:01.180 Ours is class B. It's under the misuse of drugs scheduling, but it's obviously scheduled to

00:19:07.160 drugs, but medical use. Maybe it's something we'll get into whether you consider ketamine to

00:19:11.800 be a psychedelic drug, but there's not any other drugs with these kind of type of effects that can

00:19:16.280 be used medically that are legal.

00:19:18.220 That's right. So in the United States, the other psychedelics, LSD, psilocybin, and even MDMA,

00:19:24.160 which is not a psychedelic, are Schedule 1, which means they have no medical use at all.

00:19:29.600 I mean, it's interesting drug policy-wise, right? Because ketamine is the most

00:19:32.700 likely to be abused, I would say, of all of those compounds. But it's the one that's,

00:19:37.400 you know, legal for medical use. I mean, it has, as we've said, got an amazing

00:19:40.820 number of medical uses. But you don't consider MDMA psychedelic?

00:19:44.820 I don't think I'm an expert to say, but no, I don't consider MDMA a psychedelic personally.

00:19:49.360 I put it in the category of an empathogen. Because you don't really have any dissociation

00:19:53.280 with it. It's not altering perception in the way that LSD or psilocybin would. And your point is an

00:19:59.100 interesting one, right? Which is Schedule 1 typically implies no medical use, high potential

00:20:04.100 for addiction. Well, certainly there's medical use for psilocybin and MDMA, as you said, pretty low

00:20:10.080 potential for abuse. And interestingly, while ketamine clearly has a high medical use, I want

00:20:15.280 to talk to you about the potential for abuse as well. I've heard mixed things on this, but what

00:20:20.100 do the data say? How addictive is ketamine in terms of other things for which we have benchmarks,

00:20:25.760 like, for example, benzodiazepines and opioids? We really have a clear sense of the addictive

00:20:31.240 potential of those molecules. Where does ketamine stack up?

00:20:34.220 I don't know if we have really good data on that, but I would say in terms of physical

00:20:40.900 withdrawals, symptoms, I mean, it depends how you assess the addictive properties, right?

00:20:46.240 I struggle with things being addictive. People become addicted to things, but they're also,

00:20:50.420 you know, multifunctional tools that...

00:20:52.420 Sure. Coffee's addictive or whatever.

00:20:54.680 We did a study of people that use ketamine, so they're probably at higher potential for abuse.

00:21:00.040 So people who use ketamine non-medically, as in what you would say recreationally,

00:21:05.240 about 9% of them had symptoms of some sort of dependence or craving.

00:21:10.640 9%?

00:21:11.500 9% of a group of recreational users of drugs. So I'm finding that hard to benchmark that

00:21:17.440 against opioids and benzos.

00:21:20.420 The last time I looked at the opioid data, someone listening to this will probably say,

00:21:24.740 no, that's wrong because I'm going by memory. My memory was about 20% of opioid users

00:21:29.980 became addicted, but that was prescription-based opioid painkillers. That doesn't include heroin,

00:21:36.320 where that number might be higher. But of course, you're also pre-selecting a different

00:21:40.100 subgroup of the population. So it's not really an apples-to-apples comparison. In other words,

00:21:44.700 what I'm saying is of 20% of patients who would be prescribed opioids for medical use

00:21:50.660 could become addicted, which is a staggering number, right? One in five people who gets an

00:21:55.180 opioid prescription could go on to abuse them later. I don't know how much faith to put in

00:21:59.940 that number because it seems so absurdly high, but it's plausible. So the only way we would really

00:22:04.620 know this, I suppose, on an apples-to-apples basis is you took patients who were being treated with

00:22:11.120 ketamine for another indication, such as recalcitrant depression, and you asked the question,

00:22:15.980 how many of those patients would go on to experience dependency, pharmacologic, physiologic

00:22:22.440 dependency? So far, the data suggests it's pretty low. So we know that a little bit from the trials

00:22:28.760 that have gone on so far, but it's a really early stage. And I guess if you're doing apples-to-apples,

00:22:32.980 opioids, is that daily or benzos? I don't know, frequency. Obviously, how you're defining addiction

00:22:39.200 is quite hard because if it's physical withdrawal symptoms, or is it impacting on your everyday

00:22:44.020 functioning, or is it seeking beyond your prescription dose escalation? I mean, I know from having worked

00:22:51.080 with ketamine, people who are addicted to ketamine, that a small proportion of people do become

00:22:55.280 addicted. As we mentioned, it has these really serious physical consequences of having toxicity

00:23:00.920 on your bladder. You know, I was working with 16-year-old girls who've had their bladders had 1.00

00:23:04.720 to have a cystectomy. So you have your bladder removed, and then they're having to wear a colostomy

00:23:09.360 bag, really dire consequences. And I think that's quite rare. I was thinking about other drugs that

00:23:14.880 have got like a direct physiological...

00:23:17.080 So just to make sure I understand, so these are 16-year-old girls that were not using ketamine

00:23:22.140 for a medical indication, such as depression. They became addicted to it recreationally.

00:23:27.900 Yeah. And this was kind of an epidemic in the UK in the 90s, early 2000s, when we were

00:23:33.980 researching it, because people didn't really know anything about ketamine.

00:23:36.720 I was in medical school in the 90s. We learned about it as Special K. That's what it was referred

00:23:40.580 to. I don't know if that was the San Francisco name, because that's where I was going to school.

00:23:44.580 Was it called Special K in the UK also?

00:23:47.080 Yeah, I think people called it that. Some of them called it kiddie smack. It was basically

00:23:51.680 like heroin for kids.

00:23:53.200 I see. So it's kind of the JV or junior version of heroin, not quite as bad.

00:23:57.740 For those people, but there was zero information about it at the time. And they were not taking

00:24:02.220 the drug the way it's given for depression. They were taking grams and grams of it every day. So

00:24:09.000 these serious, something important to say.

00:24:11.260 So we'll come back and do the math on what that means. But if they're taking high doses

00:24:15.360 of this stuff daily, were they taking it and then basically passing out in their apartments

00:24:19.620 for hours and just dissociating on trips?

00:24:22.220 They would just tolerate it because it is the tachyphylaxis is like a rapidly developing

00:24:26.440 tolerance. And if you do administer ketamine repeatedly in a short time window, you do need

00:24:32.040 to give higher and higher doses. With these people, they were going, they were functioning,

00:24:35.880 you know, walking around on doses that, yeah, it would floor an elephant or certainly a horse.

00:24:42.180 But what was the drive? With opioids, the drive is that high. There's a really, really profound

00:24:48.040 high that comes from that mu receptor being hit. What was the high that they were getting

00:24:53.180 even once they were into that high state of tachyphylaxis?

00:24:57.280 We actually did some research on this. I think we spoke to about 120 Getzman users doing some

00:25:02.440 interviews of why they took it. So some of them said very pragmatic things, I think,

00:25:07.560 because it was very cheap. So things like it's cheap, it gets me really off my head.

00:25:11.080 I think at the escapism of it, there's some slight opioid actions of ketamine. Maybe we can come on to

00:25:16.140 that, talking about the different isomers of ketamine. But yeah, so some people are taking it

00:25:20.200 just for the escapism. Some people talk more as we'd see them kind of psychonauts, but almost addicted

00:25:25.700 to chasing the consciousness and the insights they felt they were getting. And they were just

00:25:30.760 taking more and more to try and get more insights. I mean, there's some really high profile examples

00:25:35.840 of that. I don't know if you've heard of John Lilly, who was the neuroscientist based in California.

00:25:42.240 The film Altered States is about him and he did quite a lot of unusual research, you know,

00:25:47.680 giving LSD to dolphins. He invented flotation tanks, I think. And he writes in his book,

00:25:53.540 The Scientist, clearly documents becoming completely addicted to ketamine to the extent that he was having

00:25:58.520 an intravenous drip of ketamine, you know, pretty much 24 hours a day. So he really heavily escalated

00:26:03.020 his dose and became kind of psychotic where he had these revelations and went to tell the president

00:26:10.160 of the USA about the world being taken over by computers. So, I mean, it's a really fascinating

00:26:16.800 book if you're interested in reading an account of ketamine addiction.

00:26:21.440 And how did that story end for him?

00:26:22.960 Did he manage to get off ketamine in the end? I'm trying to remember. That's a really good question.

00:26:27.400 I can't remember the end of it. I know there's some sad ends. There was another book called

00:26:31.540 Journeys to the Bright World by someone called Marsha Moore. Her husband was an anaesthetist and

00:26:36.220 she experimented with ketamine. It's actually quite interesting. They have very different

00:26:40.100 subjective experiences. So John Lilly's one's very machine state and he's experiencing hallucinations

00:26:46.920 very related to being in a computer and hers were very soft and round and going back to the earth.

00:26:51.800 She sadly, I think, froze to death. She took some ketamine outside. And again, that thing where you

00:26:59.200 are completely dissociated in your, yeah, from your body. And she'd gone outside one evening and

00:27:05.380 actually froze to death. That's really sad. There were people taking really high intravenous

00:27:10.020 doses of ketamine. It's got a rapidly developing tolerance.

00:27:14.020 And why is it different? So PCP, I'm trying to think, I don't really think I took care of any

00:27:18.660 patients that were strung out on PCP, but I certainly remember the lore of the drug. And

00:27:24.820 it struck me as a much more aggressive drug. People that were on PCP, as you alluded to earlier,

00:27:30.600 they seemed almost bulletproof, right? They'd punch their hand through a glass window,

00:27:35.320 be unfazed by the fact that they just broke every bone in their hand.

00:27:39.160 Given that these drugs have such a similarity, why did PCP seem to produce that phenotype? Or is that

00:27:44.280 just lore and that really wasn't what was happening?

00:27:46.400 Yeah, I think that's lore. I mean, I think it produced a protracted psychotic state. I think

00:27:51.960 they gave the police nets even to catch people on PCP. There was a lot of police brutality,

00:27:57.540 these special PCP nets, police brutality associated with PCP and maybe the people taking PCP. Some

00:28:03.880 people have suggested it's kind of a degree of racism or against kind of people in poverty. So

00:28:09.620 I've looked for examples of this kind of bulletproof phenomena, and I can't find any in the literature,

00:28:14.660 certainly. There's definitely examples of people having a protracted psychotic-like symptoms,

00:28:19.380 having hallucinations, having to be hospitalized. But this whole running at police and the kind of

00:28:25.600 violence aspect, I find hard to imagine.

00:28:29.340 And is PCP still being used? Is it still a street drug?

00:28:32.260 It's never really been a street drug in the UK. I'm not aware there's many reports in the US either.

00:28:37.660 But it's interesting. And it's interesting in the context of the new use of all these substances.

00:28:42.340 Nobody's really thinking about using PCP, but maybe that would be something to investigate.

00:28:47.020 So speaking of kind of the resurgence of these drugs, how would you contrast ketamine with

00:28:53.260 psilocybin and LSD? So psilocybin and LSD, of course, are much more similar to each other.

00:28:58.440 How does ketamine differ? I mean, obviously it differs in use case, but

00:29:01.820 do you have other senses of how it produces a different experience?

00:29:05.480 Obviously it has to come to a different action where they work on the 5-HT2A receptor

00:29:09.600 and ketamine, as we were talking about, works on these kind of glutamatergic receptors.

00:29:13.880 And there are some similarities in the acute experience, which is people talk about

00:29:19.000 eodissolution and ketamine causes that quite profoundly. So you lose your sense of self.

00:29:23.520 And that happens to a degree as well on psilocybin, mushrooms and LSD. I think you get much,

00:29:31.800 you can think more clearly on LSD and psilocybin. Ketamine impairs some of your higher cognitive

00:29:36.900 functions and causes that kind of analgesia, which is associated with ketamine's got an anxiolytic

00:29:43.640 effect. So even at higher doses, people don't report anxiety, whereas they can describe things.

00:29:51.120 So some of our patients describe things that sound scary, but they don't feel the kind of

00:29:55.340 physiological anxiety. Whereas drugs like LSD, psilocybin, people can report being absolutely

00:30:02.360 terrified by the experience. Maybe that's the dissociation that happens more on drugs like

00:30:08.500 ketamine, where you have the sense of being separate and everything's kind of emotionally numb,

00:30:14.200 as I guess you'd think with it being an analgesic or an anesthetic.

00:30:18.200 And that might be due to the greater inhibitory effect potentially of ketamine is probably why

00:30:24.040 you maybe can short circuit some of the anxiety that can definitely happen with LSD and psilocybin

00:30:29.940 if the setting isn't right or if the dose is too high.

00:30:32.640 Yeah. We were talking before about the abuse potential, maybe why it's got higher abuse

00:30:36.960 potential because- That's right. It has less of a negative feedback loop. I think anybody who's

00:30:41.120 tried the other psychedelics will say, look, if you go back to the well too many times,

00:30:45.800 you can get stung. It's unpredictable in that sense. If you're looking for a kind of escapism,

00:30:51.320 you don't want to escape into absolute terror.

00:30:56.340 Well said. Let's talk about depression because I think this is where people are really becoming

00:31:02.620 interested in ketamine. It's certainly how it came to my attention seven, eight, maybe nine years ago.

00:31:08.400 It was a physician friend of mine saying he's been prescribing intranasal ketamine to some of his

00:31:14.560 patients for depression. And I thought, none of this makes sense. Please say more. It's perfectly

00:31:19.620 legal. I have a compounding pharmacy and these are the instructions that we give the pharmacy and

00:31:23.760 they give the patient an intranasal spray and they use this spray. They were doing it once a week or

00:31:28.760 something was the use case. And at the time, again, this is maybe 10 years ago, I couldn't find a lot

00:31:34.480 of literature on it. You know, I found some and I found some interesting case reports. I remember

00:31:38.780 there's one study I found based in India that looked pretty interesting, but then I sort of forgot about

00:31:44.140 it until maybe four years ago. And I think what brought it back to my attention was frankly,

00:31:50.040 the epidemic, for lack of a better word, of ketamine clinics, which basically are almost as

00:31:55.400 ubiquitous as Starbucks now. Before we get into the business of ketamine clinics, I want to just kind

00:32:00.040 of understand where the idea came from. How was this something that people even thought was worth

00:32:05.320 pursuing clinically? And then how does it work? Who does it work in? Who does it not work in? Let's just

00:32:09.960 go down the depression rabbit hole. Sure. There was a really early study in Iran, I think. I mean,

00:32:15.560 it might even date back to some quite dodgy work by Salvador Roque. I'm not sure if you've heard of

00:32:20.440 him. He was a psychotherapist yet. I do want to compliment you on the use of dodgy. That word

00:32:25.340 cannot ever be overused. So anytime you want to just throw in that that's a dodgy scam or that's

00:32:30.920 dodgy work, please, please feel free to insert that. Thank you. It's not a very scientific word,

00:32:36.140 but thanks, Peter. No, no. It belongs here. It belongs here. Okay. Yeah. And he definitely

00:32:40.660 was a dodgy guy. So there we go. He was working for the Mexican government, actually, I think

00:32:45.100 interrogating people. And he took some of the techniques from that, I think, and tried to,

00:32:50.460 he's a psychoanalyst, kind of psychotherapeutic practice. And he was giving ketamine with other

00:32:55.020 psychedelics to try and produce changes in people's brain state. But I guess that's probably the first 0.61

00:33:00.740 documented cases of people using ketamine in a kind of psychiatric therapy sense.

00:33:07.440 This is in the eighties or nineties?

00:33:09.160 No, that was back in the sixties. Yeah. So way back, maybe the seventies, there was this study out

00:33:14.960 of Iran, but really the work that's caused this whole explosion in ketamine depressant research,

00:33:21.260 because I don't think anyone was really watching those areas of research came out of a group at Yale

00:33:27.140 and a guy called Robert Berman, who did an early study in 2000, giving a single ketamine infusion

00:33:34.360 to patients with treatment resistant depression. And they showed this thing, which was kind of

00:33:39.340 groundbreaking in that you could get this rapid reduction in depressive symptoms, not as our

00:33:46.880 traditional SSRIs, the Prozacs and your traditional antidepressant drugs have got a delayed onset of

00:33:53.020 action. And it was just kind of accepted that they take two weeks to work. And, you know,

00:33:57.140 there's various ideas of why, but ketamine works immediately and people with treatment resistant

00:34:01.540 depression. So this isn't mild depression.

00:34:04.200 Tell me how it was administered in those early studies. Was this?

00:34:06.960 So that was intravenously.

00:34:08.460 Intravenous. Okay. And what kind of doses were they using?

00:34:10.880 0.5 milligrams per kilogram.

00:34:12.720 So an 80 kilogram person is getting 40 milligrams.

00:34:16.600 Yeah.

00:34:17.380 Intravenous.

00:34:17.940 Over 40 minutes.

00:34:19.140 Over 40 minutes. So not an IV push, but a pretty quick drip.

00:34:22.280 Pretty quick, like mild dissociation, I would say from my experience of using different doses

00:34:26.720 and some kind of peripheral subjective changes. Yeah. We've used that dose in acute studies.

00:34:33.740 And then just for reference, what would a recreational drug user who's not completely

00:34:39.120 habituated, so they're not way up the tachyflaxis curve, but if a recreational person went to their

00:34:44.920 drug dealer and said, I want some ketamine because I want to blast off, what dose would they be given?

00:34:51.560 That's really variable, I'd say, but maybe more on like at least 100, if not 200 milligrams,

00:34:59.440 I would say.

00:35:00.560 So they're going to be given two and a half to five times the dose and they would blast off

00:35:07.220 with that. They would probably take that intramuscularly.

00:35:09.960 Intranasally, I think, is the typical route for ketamine users.

00:35:13.320 And is the bioavailability similar? I'm sure the onset is different with intranasal versus

00:35:19.480 intravenous versus intramuscular, but does the same amount of drug basically get to you with each

00:35:24.140 of those routes?

00:35:24.940 Slightly less than intravenous is obviously the optimal route for that, but yeah, it's a pretty

00:35:29.520 good way to get it across, which is why it's now been taken forward as a treatment in depression,

00:35:33.720 I guess.

00:35:34.060 So going back to this patient that's getting 40 milligrams, that's a dose that they know

00:35:39.280 something is happening. They're not getting a placebo. They're not being blown out of the water.

00:35:44.540 It's really variable. Through all my work, I guess I must have given hundreds of people

00:35:48.160 ketamine in research studies and it is, response is really variable and not necessarily predicted.

00:35:54.180 So we wait, adjust all of our doses.

00:35:56.200 So give me the range. What's the sort of interquartile range?

00:35:58.740 Are there some people that literally feel nothing at 0.5 migs per gig?

00:36:02.940 I don't know that anyone would feel nothing, but maybe feel more like slightly drunk and feel a

00:36:07.280 bit disoriented. You know, that kind of feeling like intoxicated basically and slightly dissociated.

00:36:12.700 And at the other end of the spectrum, are there people that are just tripping?

00:36:16.400 People have gone down a canoe in their mother's eardrum, like doing really weird stuff,

00:36:20.840 like having frank hallucinations, basically. We can talk about that in a bit. We've found out a

00:36:25.060 little bit about what predicts that I think now.

00:36:27.020 Tell me, I'm very curious because I just know myself with any single agent that I've ever

00:36:33.840 ingested in my life, anything that ranges from alcohol to acetaminophen to a psychedelic agent,

00:36:41.440 I need like three times what anybody else needs to feel it. And I've always been curious as to why.

00:36:47.720 The things that we found out from our research is that people with a family history of alcohol

00:36:51.240 problems, they have a greater acute response to ketamine.

00:36:55.360 They're more sensitive to it?

00:36:56.480 They're greater response to the therapeutic effects. They've actually got less of the

00:36:59.860 response to the acute. Sorry, I said that completely wrong. And what are the other

00:37:03.600 things? BMI, which is kind of obvious, I suppose, is so higher BMI, body mass index is

00:37:10.160 predictive of a higher acute effect.

00:37:14.420 But that's because they're getting a higher dose.

00:37:16.140 Well, in a way, but then the BMI is slightly different. And I suppose maybe that's something

00:37:20.480 similar to consider. It's similar with alcohol, right? Like your lean muscle versus your fat.

00:37:25.100 That's not surprising, right? Because BMI really speaks to how much lean mass and non-lean mass you

00:37:31.180 have. It doesn't really speak to your organs, and it certainly doesn't speak to your brain.

00:37:34.740 No, no, it doesn't speak to your brain. So no, these are really obvious things. I mean,

00:37:38.200 and this is why we haven't got very far in predicting how people respond. And therapeutically,

00:37:43.380 we know with depression, the more suicide attempts, people have a better response.

00:37:47.060 So they're more likely to respond, which probably maybe means they're more severe, I guess.

00:37:52.420 We know not very much at all, really. There's some kind of...

00:37:55.360 So let me ask another question. Does the acute response that you are watching

00:37:58.780 during the, call it two or three hours that they're in your chair being administered the

00:38:04.860 drug, right? Because it's a 40-minute infusion. Presumably, it's another couple of hours while

00:38:09.080 they're under the effect of the drug. We call that the acute response. Is that predictive of

00:38:15.580 what you're really after, which is the abatement of depression?

00:38:19.700 Yeah, that's a really good question. I think the field is pretty divided. So the way that the

00:38:24.700 acute effects have typically been measured is with a scale called the Clinician-Administered

00:38:30.260 Dissociative State Scale, which basically looks at dissociation. But it was designed to look at

00:38:35.600 dissociation from people having flashbacks from traumatic experiences. So it are some questions

00:38:40.740 that are relevant for ketamine, but some that are not. So it's like, are things moving in

00:38:44.940 slow motion? Have colors changed? Do you have a sense of forgetting chunks of what have happened?

00:38:51.160 A lot of it is relevant, but people have looked at other aspects of the acute experience. So

00:38:55.360 with these dissociative effects, some studies, I'd say about 25% find they predict the therapeutic

00:39:00.940 effects. We've actually done a systematic review on this, but the others don't. I think in general

00:39:06.500 psychiatry, there's a feeling that these acute effects are a nuisance. And as a whole research

00:39:12.940 effort has been devoted to finding drugs that don't have these acute effects with kind of limited

00:39:18.400 success. And actually, when you look into the data, people who use a bit more nuanced ways of looking

00:39:24.440 at the acute effects. So there's some scales that look at some of the a bit more, I guess you'd say

00:39:28.060 trippy effects and things like mystical experiences in the sense that you can't explain the experience

00:39:33.300 that's gone on. And those do seem to predict. So it's quite interesting.

00:39:37.560 Wow. First of all, just try to unpack that. It's not crystal clear that the person who's sitting there

00:39:43.240 feeling slightly drunk is going to have a lesser outcome or a greater outcome than the person who's

00:39:50.940 on the canoe in their mom's eustachian tube. So the second point I would extract from what you said is

00:39:58.200 we're probably using too crude an instrument to try to tease out exactly what effects in the acute phase

00:40:06.280 matter. And it's either because we don't know what questions to ask them in that window, or we're not

00:40:14.500 doing our analyses on a fine enough gradation of symptoms. Is that a fair assessment?

00:40:21.000 Yeah, that's what I'm saying. Basically, I think we need a finer, more nuanced understanding of the

00:40:27.440 effects. So we're doing some stuff now, just recording what people say and getting them to

00:40:31.780 describe it and then using artificial intelligence, machine learning algorithms to find patterns in

00:40:37.880 that to see if that might predict it. Because I mean, that seems like a bit of a no brainer now

00:40:41.360 that we've got quite a long way with just using natural language to predict outcomes.

00:40:46.780 By the way, does ketamine produce amnesia?

00:40:49.080 Yeah, it's got some amnesia, but people can't remember the experience.

00:40:51.800 You might forget aspects of what's happened. And it certainly impairs your

00:40:56.020 episodic memory, but people do remember the experience. So we do interviews with people about

00:41:00.600 the salient points of the experience they'll remember. But I guess it's through a bit more

00:41:05.420 of a fuzzy haze than maybe your classic psychedelics. It's a bit less accessible, I would say.

00:41:12.020 After you've done this, the patient wakes up and it's three hours later, wakes up is the wrong word,

00:41:15.660 but the patient sort of returns back to their baseline state. Do they immediately feel the

00:41:21.300 alleviation of the depression? Is that how quickly it can onset?

00:41:25.260 People can feel just, yeah, quite considerably better. A colleague of mine,

00:41:29.160 Rupert McShane, he set up the first NHS treatment resistant depression clinic here in the UK. And he

00:41:35.140 likened it, you know, the film Awakenings, which is actually about Parkinson's. These people are really

00:41:39.400 severely depressed. They often can't get out of bed and that they suddenly come alive. Some people,

00:41:44.140 you know, not everyone responds to it, but that it's pretty rapid. And people just feel a kind of

00:41:49.840 sense of clarity, a bit more interest in the world, I would say. Almost like you're able to detect

00:41:55.920 novelty where you weren't before, you know. It's quite a great thing to see.

00:41:59.900 What is the mean and median duration of how long that lasts?

00:42:05.820 It's really variable. And obviously some people don't respond at all. So it's important to say that.

00:42:10.340 What fraction do not respond at all?

00:42:12.280 I don't think we have a good handle on it, basically. We need more real world data. Because

00:42:16.280 if you look at people in trials, it's often very different. I think it's around 50, 50, 60%.

00:42:23.420 Oh my God. I had no clue it was that high. So you're saying half the people that show up

00:42:28.340 with completely treatment resistant depression and go through this experience under the well-controlled

00:42:34.220 setting of the lab in a clinical trial have no benefit from it.

00:42:38.300 Yeah. I think that's what's happened over time. So the early studies, it's like Carlos

00:42:42.560 Ratti's study. It was 75%. And this typically happens with any new treatment. As more and more studies

00:42:48.120 come out, the rates of response reduce. Maybe I'm being overly conservative. So I should probably have

00:42:53.460 that figure to hand. But I will say, I think the duration is probably about two days to a week often.

00:43:00.360 And some people will have longer. We'll have two weeks. But that's the bit where my research comes

00:43:05.300 in really, because we've been looking at how you might extend that response. And that's something

00:43:09.440 that does seem to be coming out now. If you give it alongside psychological therapy of some kind,

00:43:15.800 you can really extend the response to ketamine and the antidepressant effects as well. So my

00:43:21.360 trials have been looking at ketamine and the treatment of alcohol, but we found still reductions in

00:43:26.440 drinking six months following just three infusions. How far did you space those three infusions?

00:43:31.020 Either a week or two weeks, probably on average, with seven sessions of psychological therapy.

00:43:37.220 So quite a limited treatment program, really. Let's define treatment-resistant depression for

00:43:41.640 somebody. It's not defined by duration, is it? No. I mean, that's a tricky one because it's defined

00:43:47.360 differently depending on different trials. Often people define it as not responding to two

00:43:51.600 conventional antidepressants in the current depressive episode or having had multiple

00:43:57.540 different treatments. Some people take a more conservative definition of that to have maybe

00:44:03.540 three failed responses. So it is pretty variable in the trials.

00:44:08.340 And depression requires at least two weeks of the set of symptoms that we typically associate with

00:44:13.740 depression. Would it be classified as depression if there is an obvious externality? So loss of a child,

00:44:19.940 you know, if your child died and a month later, you can't get out of bed, is that considered

00:44:25.000 depression? No, that's natural sadness. What I mean by that is like, how does that get classified

00:44:29.800 given that there's such a clear explanation for the why? If that continued for a really prolonged

00:44:34.760 period of time, but then even that in itself is maybe contentious. There's a clear boundary between

00:44:41.400 grief, what we would anticipate from grief and natural sadness, and then depression. Let's keep this one

00:44:47.520 sort of simple and say that this is not something that's clearly associated to a trigger such as

00:44:52.100 grief. But instead, the less obvious to explain form of depression. It's been going on for at least

00:44:57.920 a couple of weeks. Let's make it interesting and say it's been going on for months so that this person has

00:45:03.320 gone through one SSRI. They've taken it to a therapeutic dose. They've had no benefit. They've then progressed

00:45:11.160 and moved to a different SSRI or a different class of drug and SNRI or something like that.

00:45:15.800 And similarly, we're just not getting the benefit. Do we assess how much psychotherapy they've been

00:45:20.260 doing at the same time? I'm just thinking about the clinical trials or the reasons we give for

00:45:24.640 prescribing off-label ketamine here in the UK. Typically, it would be the antidepressants,

00:45:30.000 like not responding to two antidepressants. You could say failed response to CBT. In a lot of the

00:45:35.300 trials, they would have non-responders to CBT. I know it's particularly some of the psilocybin studies,

00:45:40.360 but that's cognitive behavioral therapy. So now the person comes in, and again,

00:45:45.200 we've just said 50% of those people are not going to respond. That's pretty sad. So what are we saying

00:45:49.560 to those 50% of people? We're going to go back to trying more and more conventional therapies,

00:45:54.180 or do we say we should try this again and maybe the second time we use a higher dose or something

00:45:58.920 like that? There's some evidence that people take maybe three. This is in depression. It might not

00:46:04.680 respond to actually three ketamine doses, but maybe the fourth one. There's some evidence that having

00:46:11.520 an extra beyond three doses might increase the response. I mean, certainly unlabeled ketamine,

00:46:17.940 which is this bravato, this is the Johnson version of ketamine, which is intranasal. That's indicated

00:46:24.840 for repeated dosing. So you start out twice-weekly, I think it's for a month, and then move to weekly.

00:46:31.580 And what they're finding with the long-term studies is that people are staying on the dose.

00:46:36.520 I think there was an idea that people might progress off or drop down to, I think they

00:46:40.240 dropped down to fortnightly, but they're staying on it for a number of years now, I think,

00:46:47.520 is the kind of long-term data. So it is a maintenance.

00:46:51.260 So the plan is to keep people on ketamine, or let's go back to somebody who responded. So let's go back to

00:46:56.460 a patient whose depression is profound, and they've been through all the treatments and nothing's work.

00:47:01.580 They do their first ketamine infusion, and they feel remarkably better. And it lasts four days.

00:47:09.740 And then all of a sudden, the depression sets back in. Is the thinking that we're going to repeat this

00:47:15.140 treatment and get longer and longer periods of benefit, during which time we can work more on

00:47:23.000 psychotherapy to try to wean off the need for ketamine?

00:47:27.920 That would be my thinking, and that's some people's thinking, is that targeting the therapy

00:47:32.200 during that time is really important if you don't want to keep someone on ketamine as a maintenance

00:47:38.520 dose.

00:47:39.500 By the way, do patients need to stop their traditional antidepressants when they are coming to these

00:47:45.100 trials? Because most of them are probably on SSRIs and not doing well. Do you at least get to keep

00:47:50.780 them on that?

00:47:52.000 In our trial, our funding body, which is the UK state, didn't want us to include people on SSRIs,

00:47:57.820 but actually most of the studies, the depression studies, people are still on them, and there's

00:48:01.420 no interaction. It's not like some of the other novel substances like psilocybin, where it's working

00:48:07.320 in a completely different way in the brain. There's no sense. I mean, we probably wouldn't be

00:48:10.720 responding to them, I guess.

00:48:12.380 Why do we think this works? What do you think is the mechanism of action?

00:48:15.200 That's where I think potentially the therapy and targeting the therapy is really important.

00:48:21.040 People have talked about ketamine and indeed the other psychedelics, the psychoplastogens.

00:48:26.620 I'm not sure about the term, but maybe the idea that they provoke this kind of cascade and

00:48:32.640 the study showing they increase synaptic plasticity in the prefrontal cortex, which certainly ketamine

00:48:37.880 does. So it increases the growth of new synapses and dendrites and basically the ability of the

00:48:43.680 brain to form new connections. And that that is correlated with the antidepressant effect.

00:48:49.340 We're doing some work at the moment to chart the time course of that in humans by looking at

00:48:53.720 EEG. So that's kind of electrical signals from the brain and trying to target the window of this

00:48:59.960 synaptic plasticity. Because we know from animal studies, this might be kind of starting four hours

00:49:04.580 following the ketamine dose, peaking about 24 hours. So we just sort of track the antidepressant

00:49:09.920 effects, which is quite interesting. I think the idea, you know, for me as a psychologist,

00:49:13.680 is that you could time your psychological therapy when your brain is most plastic, most able

00:49:20.260 to learn new things. And we know actually this kind of plasticity is impaired across a whole

00:49:24.440 range of psychiatric disorders. So not just depression, but also in alcohol and addiction

00:49:30.160 and trauma. So actually being able to stimulate the brain to learn new things, while it's really

00:49:36.020 plastic, then actually giving some psychological therapy that uses that process. Because we know

00:49:41.880 that's what we're asking people to do really in psychological therapy is to think definitely

00:49:47.160 about things, learn new ways of thinking about old problems. That to me, it seems like an

00:49:52.000 intuitively appealing mechanism. I mean, there's some problems with it in that neuroplasticity

00:49:55.560 happens from all sorts of things. Some might argue, you know, is this specific enough as a process?

00:50:01.000 Other drugs produce neuroplasticity that we wouldn't say were necessarily potential treatments for

00:50:06.240 mental health problems and psychiatric disorders. So such as well, like cocaine. So people say the

00:50:11.480 neuroplasticity produced from cocaine is why it becomes addictive. There's a stimulation of that

00:50:16.320 from an acute cocaine dose. I do think we need to find out a bit more about it. And maybe it's down

00:50:21.160 to something really specific and neurobiological. I'll leave that to my preclinical researchers.

00:50:26.160 When you think about things like MDMA and psilocybin, a lot of the therapy takes place while under the

00:50:31.780 influence of the drug, whether it be for PTSD or depression. Is that happening also with ketamine

00:50:37.380 when that patient is in the aftermath of the infusion? Or are they basically just left alone

00:50:42.080 during that period of time? And the psychotherapy takes place immediately following the next day and

00:50:47.780 the next day and the next day, trying to take advantage of them being less dysthymic? 0.87

00:50:51.980 In our work, certainly, we wouldn't be trying to do any therapy under the influence of ketamine.

00:50:58.740 I think people are too dissociated, their memories impaired. There are some ketamine therapists who

00:51:06.540 do use this what's called kind of psycholitic approach, which is where you use mild doses to

00:51:11.440 be able to do some therapeutic process. There's a really interesting study actually from a guy,

00:51:17.160 where is he? In Texas, I think. I would have had some correspondence with him. He's actually looking

00:51:21.600 at complex PTSD, really severe multiple traumas. And he was treating complex regional pain syndrome

00:51:28.140 on top of that. So these are really traumatized people who've got really severe pain. And he was

00:51:33.840 giving continuous, quite low dose, over 96 hours, so continuous infusion. And he was doing very basic

00:51:40.460 psychological therapy during that time and found massive reductions in CAP score, which is our

00:51:46.560 measure of PTSD symptoms. It was a really small study, but I thought that was quite interesting

00:51:50.780 approach. To answer your question, we do the therapy outside of that. And I think most people with

00:51:55.140 ketamine do do that. I think really with psilocybin as well, even people would argue

00:51:59.060 what you're doing and when they're having the acute experience is really just supporting them

00:52:03.640 and the work happens. And then it's the integration afterwards, where with psilocybin?

00:52:08.780 Well, there's very little research on what integration is or what the key fundaments are.

00:52:13.560 It's kind of accepted that it's this thing that you have to do, but I don't know. We're kind of

00:52:18.000 lacking in research from that side. What do we know about the brain under the influence of

00:52:23.120 ketamine? Have people done fMRI or FDG PET and looked at either the metabolic state of the brain

00:52:30.640 or the activity of the brain? You've obviously mentioned the prefrontal cortex, but can we get

00:52:34.860 even more granular than that? Are there certain sections of the PFC that are more active than

00:52:38.700 others? There's quite a lot of really interesting work. I guess, as you'd imagine, the default mode

00:52:43.940 network. Tell folks what the default mode network is. It's very important in this space.

00:52:48.380 It's basically what happens in your brain when you're not doing anything active. So when you're

00:52:53.060 in a scanner and we don't give anyone anything to do, then that's a resting state scan. And you look

00:52:58.920 at how the brain networks connect. So people say it's kind of the kind of background activity of

00:53:04.060 the brain and have likened it to things like rumination, which we know are important in

00:53:08.340 depression, which is like where you repetitively think about something. You can have positive

00:53:12.040 rumination as well. Repetitively think about something good, but repetitively thinking about

00:53:17.060 something bad or mind wandering. So that's where the default mode network has been shown to be

00:53:22.380 disrupted following psychedelics. So there's kind of background, normal kind of chatter of your brain

00:53:28.520 and also similarly with things like mindfulness. So there's been studies looking at that.

00:53:32.640 We mentioned the prefrontal cortex. There's some really interesting studies

00:53:35.140 looking at prediction error signalings. The idea that your brain is basically making predictions all

00:53:40.620 the time about the world. And that's how we understand everything perceptually. We know that there's

00:53:46.060 whatever behind your computer screen, there's a world behind that. I would predict that.

00:53:49.720 If I put my laptop screen down and found there was a gap in reality, then I'd have like a massive shock

00:53:56.300 of surprise because that would signal to my brain that I had to learn something new. So every time a

00:54:00.660 prediction that we make based on our learning is violated, then you get this increase in learning

00:54:06.120 and attention and activity in your brain. And there's some work doing that ketamine basically

00:54:10.080 disrupts. There's a bit of the torsolateral prefrontal cortex, there's sort of in your prefrontal

00:54:15.560 cortex, but a bit back and a bit to the side. Really associated with this prediction error processing

00:54:20.260 and that's disrupted with ketamine. So things that aren't surprising become surprising. The things

00:54:25.820 that shouldn't be surprising and are completely predictable and things that aren't predictable

00:54:29.360 are no longer surprising. So basically kind of noisy signal. Just quite an interesting way of

00:54:33.700 understanding maybe the subjective experiences from a lot of these drugs that you turn off some of that

00:54:38.880 forward prediction from the brain and make noisier signals. I think that's quite interesting way to

00:54:45.020 think about the subjective experiences. And is the brain hypermetabolic under the influence of ketamine?

00:54:50.420 The idea is that it's more hypo in some ways. Get an increase in prefrontal glutamate. And we know

00:54:56.560 that as well because you get attenuated and an increase in prefrontal function. So I don't know that

00:55:03.000 that's particularly clear, I guess. And the neuroimaging, as I've done it as a method in the past,

00:55:08.680 it's not my area of expertise. How many patients do you think when relieved of their depression

00:55:14.140 during these ketamine trips will need to stay on ketamine as a long-term treatment? And if so,

00:55:20.460 at what frequency? That's what's really frustrating in a way is that there's all of these ketamine

00:55:25.880 clinics, as you mentioned, that sprung up all across the US. We don't really have that in the UK

00:55:31.100 because we have a state healthcare system. So in the UK, any patient who is receiving ketamine for

00:55:36.600 depression is doing it through the NHS? It's paid for by the NHS?

00:55:41.820 There's a couple of private clinics now that have sprung up giving ketamine. I'm involved with one

00:55:47.200 actually. Mainly there's five centers prescribing on the NHS, but it's all off-label because our state

00:55:54.180 healthcare regulator have not recommended yet Spravato, which is the intranasal ketamine for use.

00:56:01.500 And so there's no licensed ketamine for depression. So it's all prescribed for treatment-resistant

00:56:07.160 depression.

00:56:08.200 But if the physician prescribes it off-label, is it paid for still by NHS?

00:56:12.700 Some of these clinics, yeah, that have sprung up, maybe five of those at the moment. Potentially,

00:56:17.340 there's a lot of data out there that we could be looking at, but we don't have a good registry of

00:56:21.600 all the patients. In answer to your question, there would be a number of people that probably might

00:56:25.280 respond. In all of these clinics, my sense is that not everyone has treatment-resistant

00:56:29.320 depression. I think, particularly in the US, it's being given for a wide range of indications.

00:56:33.820 My guess in looking at the way it's being done in the US is there is no indication.

00:56:37.580 The only indication is, do you want to pay for it?

00:56:39.740 Yeah. That's why I think it would be amazing if we could have an international registry where

00:56:43.460 then we could look up this data. We'd have the data to be able to say, with this presentation,

00:56:49.720 how long someone would likely be on ketamine. Because speaking from the trials data is one thing,

00:56:55.280 but actually it's already being given out there for all manner of things. It's a shame because I

00:57:01.300 think those data would be really helpful. And also it would add a level of safety potentially

00:57:06.220 for the patients and for the clinicians. I know there's a couple of case reports of people

00:57:12.300 going across state lines, ketamine seeking. I don't think it's a huge problem, but we don't know.

00:57:17.900 We must be mindful of the potential of these things.

00:57:20.640 I've seen some slightly worrying trends recently. I've organized a ketamine conference with some

00:57:26.500 colleagues, some of them from the US. We had a few pharmaceutical companies coming in and developing

00:57:30.860 ketamine for all daily dosing. To me, that's a bit of a worry having worked for 10 years researching

00:57:37.960 ketamine users, because even if you're using very low or daily dosing, you're going to have to dose

00:57:43.500 escalate. So where's the end point? If you aren't giving it in a supportive therapy,

00:57:47.940 is the idea that people are just on ketamine all the time. I don't know. To me, it seems a bit

00:57:52.440 worrying. Maybe there's something I'm missing about the drug development pathway there.

00:57:57.380 I mean, I'm going to just take the skeptic's point of view on that. I don't think you're

00:58:00.320 missing anything. I think it's a land grab for a greater profit motive without enormous

00:58:05.660 consideration for the downside. I don't know what it is about ketamine that has me sort of cautious.

00:58:11.060 And maybe it's just the anecdotes and that's a bad frame, but this is going to sound really 0.69

00:58:16.420 silly. But have you ever seen people with these sort of ketamine eyes, sunken, distant? This person

00:58:21.320 has taken too much ketamine in their life and their brain doesn't work as well anymore. I'm sure there

00:58:26.480 are lots of different drugs that can produce that phenotype. I'm sure somebody that's taken far too

00:58:31.020 much cocaine can experience something. But it's something that you see more commonly, I would

00:58:35.600 assume, with ketamine than you would with LSD or psilocybin. Because as you said, the frequency of use

00:58:41.180 is much harder with those other drugs. It's far less likely that a person is going to take heroic

00:58:49.460 doses of LSD or psilocybin over and over and over again. Whereas you could get down that path with

00:58:56.720 ketamine. And again, it's just anecdotal, but you see some of these people where you get the concern,

00:59:03.740 it's not just the bladder. I mean, the cystitis is a very obvious and tangible objective side effect

00:59:09.100 that can be devastating. This is much more subtle. It's just something's changed in that person's

00:59:14.300 brain and it's not for the better. Am I just sort of making this up? And it's possible I am,

00:59:19.120 and that I'm just over extrapolating from something else. But you've been around this

00:59:23.580 more than almost anyone. Do you have a concern around that? Yeah, no, we've done a lot of studies

00:59:28.460 on that as well. And we haven't studied that sunken eyes, but we have looked at the brains.

00:59:33.420 I mean, that sounds silly to say it. It's not physically sunken like you would with hypothyroidism.

00:59:37.880 It's a vacancy is more what I'm describing. A kind of dullness. I mean, I guess like any

00:59:43.680 addiction, one thing I noticed, and again, anecdotally, it was just like a lack of,

00:59:48.000 you know, when people lose their sense of humor and that seems to be like a thing in addiction,

00:59:51.460 it's the spark has gone out of life, which is odd, right? Because what we're giving ketamine for

00:59:56.460 is quite a paradoxical drug in depression is to like put the spark back, but then it makes sense.

01:00:01.880 You do it too much and maybe that spark is gone. And we found that cognitively,

01:00:05.620 we found cognitive impairments and with planning, and we found actually reductions in, you know,

01:00:10.740 your hippocampus, which is involved in processing novelty and encoding memories. And that's the

01:00:16.940 function of that is reduced in some of our brain imaging studies with people who, these are people

01:00:21.340 who take daily heavy doses of ketamine. So I'm not saying even your non-medical recreational user

01:00:26.760 would show this kind of symptoms to people who take it occasionally, but yeah, really, really,

01:00:31.180 really heavy doses. I think that's possible. I don't know because seeing the way that it's

01:00:36.700 administered in clinics, the idea of it as a rapid acting antidepressant. And I think the promise

01:00:42.100 is that it's not a maintenance medication and how empowering that is for patients to not be on a

01:00:47.800 daily medication. And that's why I feel a bit sad that there's not more research effort going into

01:00:53.460 looking at enhancing the antidepressant effect with therapy. So we don't have to give people hundreds

01:00:58.040 of doses of ketamine. Or maybe some people will just need that. And that's a cost benefit analysis,

01:01:02.500 I guess, you make when you're prescribing any drug. Some of these people, this is life threatening,

01:01:07.500 right? Like people who are really heavily suicidal. So has anyone done that study where you,

01:01:12.580 because that's the closest way to get to a quality adjusted life year analysis, which is going to be

01:01:17.600 that cost benefit analysis. Has anyone taken that group of patients who are the most treatment

01:01:22.680 resistant and randomize them to continuing to try to treat, even though it's resistant versus ketamine

01:01:28.680 and looking at really hard outcomes like differences in suicide rate?

01:01:32.600 Because people have definitely done work with patients with suicidal ideation. Yeah. And you get

01:01:37.240 reduced mortality with ketamine. I mean, these are tough studies to do, right?

01:01:41.640 Yeah, of course. They're ethically difficult as well when you know that you have a treatment.

01:01:44.940 So what does your intuition say is probably the sweet spot for what the intermittent,

01:01:52.060 call it transient, but fixed use of ketamine is as a bridge to go from completely treatment

01:01:59.300 resistant to depression to treatable depression? Just from our data, but there we used three doses

01:02:06.180 and seven sessions of therapy. Three doses separated by seven days each? Seven days to two weeks. And then

01:02:12.980 that was a 0.8 milligrams per kilograms, a slightly higher dose than in depression because you get

01:02:17.800 a sort of cross tolerance with alcohol because alcohol also works on the same receptors as ketamine

01:02:24.080 at higher doses. So that's when people get really intoxicated and feel like they're spinning out,

01:02:29.100 that's kind of your alcohol working on your NMDA receptors. So yeah, we use that three doses.

01:02:34.720 And these people with alcohol problems have depression as well and can be quite severely treatment

01:02:39.100 resistant. What we found, I think is interesting, is we were still seeing,

01:02:42.980 impacts on like reductions in rumination, which are meant that repetitive negative thinking

01:02:48.200 and reductions in anhedonia, which is a hallmark of depression, but also across multiple

01:02:53.580 disorders. And that's an inability to experience pleasure in the world. So we saw reductions in

01:02:59.180 that at three months, but they were back to baseline at six months, whereas they were still showing

01:03:04.540 reductions in drinking, which I thought was really interesting. So they might suggest certainly in

01:03:09.140 depression that maybe that would be the time, maybe weekly or fortnightly dosing.

01:03:14.360 That model makes a bit more sense. If you could say, look, this is a treatment that you need to do

01:03:19.660 once a quarter, every three months. So you have a loading phase where you do the infusion weekly for

01:03:26.160 three or four weeks, and then you're onto kind of a quarterly schedule. That to me is very interesting.

01:03:32.000 What's less interesting to me and what I'm seeing certain people do is twice a week ketamine infusion

01:03:38.540 for life. A, I worry about the toxicity of the drug and B, it would have to really have an enormous

01:03:45.280 efficacy to justify it seems. And I look at the short-term studies where they're comparing ketamine

01:03:50.860 to Versed. It's not that much better. Not that Versed is a good option, by the way, but when you're using

01:03:56.600 Versed as a control and you're seeing, well, basically that's telling you there's a pretty

01:04:01.080 big placebo effect from doing this as well. No, exactly. I mean, that's my intuition as well.

01:04:06.760 This is a positive thing if we're maintaining people on this twice weekly for life.

01:04:12.060 So tell me why you think it's working in addiction and do you primarily work in alcohol addiction or do

01:04:17.120 you also look at opioid addiction? We want to look at opioid addiction as well. And actually there's

01:04:21.260 some other work going on in the US looking at opioid addiction. And this work dates back to some work

01:04:27.660 by a Russian psychiatrist, Jenny Kropitsky, who did work with heroin addicts and found a similar

01:04:34.240 dosing regime, which was just three infusions with this psychological therapy around it,

01:04:40.880 produced reductions in heroin use at 12 months, you know, quite significant.

01:04:45.200 Do you know how much, how much of a reduction?

01:04:47.640 I know in alcohols, there was a 40% reduction in relapse, right?

01:04:50.340 At 12 months?

01:04:51.480 At 12 months, yeah.

01:04:52.640 Is the control doing pharmacotherapy or behavioral therapy, such as 12-step programs?

01:04:57.500 For context, this is in the 80s in Russia, they were inpatient alcoholics in locked words. So I

01:05:02.780 remember saying to Evgeny, did anyone drop out? It's like, they can't drop out. They're locked in.

01:05:07.180 So I think it wasn't in the normal consent and ethics processes we have now, but still a really

01:05:12.240 important study. And both groups had a hundred people in, but it wasn't a randomized control trial.

01:05:16.740 So he asked people if they wanted to be in this ketamine and psychotherapy group or just have

01:05:21.600 stand.

01:05:22.220 So I'm sorry, I don't understand the trial. You have an inpatient trial where all the patients

01:05:26.360 are given a trial, in quotes. This would constitute a dodgy trial.

01:05:30.420 Yeah, this is dodgy.

01:05:31.540 There you go.

01:05:32.560 It's inpatient and they're all given unlimited access to alcohol.

01:05:36.280 No, no, no, no, no, no, they're not. They don't have any access to alcohol.

01:05:40.020 So how do we know what the relapse rate is?

01:05:42.080 So they do their detox. They get given their ketamine treatment. They're discharged.

01:05:46.960 And then when followed up at 12 months.

01:05:50.120 Oh, I see. So they behave as outpatients, but they're not allowed to drop out. In other words,

01:05:53.800 if you drop out, the KGB bring you back in.

01:05:56.140 They couldn't drop out of the treatment. What I was asking him about was,

01:05:59.180 do people tolerate the treatment well? But they just did the treatment.

01:06:02.100 So I guess they didn't get shot by the KGB. They were really important studies.

01:06:07.040 Donnie asked people if they wanted to have this group psychodynamic psychotherapy with

01:06:11.920 just three infusions of ketamine. He was using higher doses and intramuscular to one to two

01:06:18.420 milligrams per kilogram. Quite strong.

01:06:21.140 But we haven't done the head to head of ketamine plus behavioral therapy versus

01:06:26.560 pharmacologic plus behavioral therapy for alcohol.

01:06:31.120 No, we haven't. I've done ketamine plus therapy plus compared to ketamine with therapy control

01:06:38.780 compared to placebo and therapy compared to placebo. So I did a four arm trial.

01:06:44.080 Tell us about that trial.

01:06:45.300 What we found, I mean, which was great because that's what we hypothesized. And that's quite rare.

01:06:49.740 I wasn't expecting to get what we hoped for was that we saw the strongest,

01:06:53.680 greatest reductions in drinking and greatest abstinence in ketamine and therapy group,

01:07:00.280 86% abstinent at breaks at six months. And then the second best effect was in our ketamine and

01:07:06.660 education controls. We wanted to look at the effects of therapy, ketamine within and without

01:07:11.500 therapy, but there's really non-specific effects of just spending hours with a therapist who's quite

01:07:15.860 nice. A bit like medication management, which is used in a lot of the US trials.

01:07:19.460 That's a very elegant trial design because you get away from what's called the performance bias

01:07:25.920 of the therapy. The therapy itself, you have to make sure you're controlling for just the fact

01:07:31.540 that an hour, three times a week, they have to go talk to somebody. So tell me what they do in the

01:07:36.260 education arm of that.

01:07:37.940 People were doing calculations about alcohol, talking about how alcohol affects the body.

01:07:42.360 And we did some relaxation, but just as we thought as a bare minimum of what we wanted to do

01:07:46.980 with people going into ketamine session, you know, a ketamine infusion was to have a bit of a

01:07:51.740 relaxation. Maybe the relaxation helps with the blinding.

01:07:55.380 And then for the non-ketamine group, did they get Versed or what type of a control do they get?

01:08:00.180 What's the placebo?

01:08:01.340 Just got saline, basically.

01:08:03.240 Oh, so no dissociative effects.

01:08:04.980 No, I know, which is a bit of a shame in retrospect. We should have used something,

01:08:09.580 yeah, like midazolam or we just used the saline placebo.

01:08:14.040 But it's still a very elegant two-by-two study, perhaps only limited by the fact that the control

01:08:18.460 didn't get some sort of active substance. But nevertheless, at 12 months, or sorry, at six

01:08:24.500 months, you said that the double positive group, double positive meaning ketamine plus actual

01:08:29.580 psychotherapy dedicated towards alcohol reduction. Did you say 86% were still alcohol-free at six

01:08:37.080 months?

01:08:37.760 Abstinence rates, which is good, really.

01:08:40.100 What about in the other three groups?

01:08:41.620 The response were quite good in all of the groups, but it was statistically significantly

01:08:45.520 different. Well, it was 96 patients. It didn't feel like a small trial because only 24 patients

01:08:50.720 per arm. So we weren't powered for the full interaction, but actually we're taking it forward

01:08:56.160 now into a phase three with 280 patients, again, funded by the UK state, which is great.

01:09:01.240 So we get to run it in NHS settings and hopefully see it as a medicine in those contexts. Because

01:09:07.720 I don't know what you think of the psychedelics world. And I think some of the therapies are amazing,

01:09:13.020 but for our state healthcare system, those things are not ever going to happen. You're

01:09:18.220 never going to have two therapists for 40 hours. So I wanted to come up with a therapy

01:09:22.480 that was deliverable in our state healthcare system. It's a great idea that you could do

01:09:26.880 have that kind of system, but we've got some of these kind of slightly lower level trained

01:09:31.220 therapists, and there's a lot of them in the NHS here. And so we designed our therapy to

01:09:35.620 be quite manualized so that they could deliver it. And it takes a short amount of time.

01:09:40.440 How much therapy were they getting in the active therapy group?

01:09:43.620 In total, about 11 hours.

01:09:45.360 In six months?

01:09:46.540 Yeah. So they just get for the treatment part. They check in.

01:09:50.540 Oh, so just in those first three weeks or two weeks when they're getting,

01:09:53.720 it's three doses separated by seven days a year.

01:09:55.940 Yeah, for a total. So they have a therapy session before their infusion, immediately before.

01:10:02.140 And so if they were in a therapy group, they would be doing kind of mindfulness practice.

01:10:05.520 And then in the education group, there's some relaxation, and then they have the ketamine

01:10:10.120 session. And then they just recover, you know, as you work from an anesthetic, and they go home,

01:10:15.860 come back the next day, where we think the peak of their synaptic plasticity effects are,

01:10:19.900 and they have another not. So these are longer sessions of an hour and a half therapy. So it's

01:10:24.560 kind of a ketamine infusion sandwich between two therapy sessions. And they repeat that three times.

01:10:29.660 What is the therapist talking about? I don't really know much about alcohol addiction. In

01:10:34.520 particular, when that patient comes in the day after their first ketamine infusion, when they're,

01:10:39.600 as you said, at their maximum neuroplasticity, I assume the therapist has a very clear playbook

01:10:45.440 for how they want to work with that patient in that 90-minute block. What's in that playbook?

01:10:51.940 Some of it's very pragmatic. Things like, what are your most risky situations for drinking,

01:10:56.480 like trying to preempt situations where they might relapse, but some of it's more about how

01:11:01.660 you want to live your life and the values you want to embody. So trying to think about,

01:11:06.160 think about your life without alcohol, how would you structure that? Things about thinking about

01:11:10.420 your thinking around drinking, which is more cognitive behavioral therapy based. What are your

01:11:14.900 thinking biases? Let's identify those and then planning. So they have quite a lot of activities to do

01:11:20.380 in the week or weeks in between the sessions, I guess like standard homeworks, but planning their days,

01:11:26.660 journaling, keeping track of those things. We teach mindfulness techniques to enable people to

01:11:31.660 deal with cravings, to get a bit more of a space between them and their kind of addictive impulses.

01:11:38.000 So yeah, there's a whole range of stuff really. We threw the book of the evidence-based therapies out

01:11:42.680 them. Tell me about the inclusion criteria. I mean, obviously you're dealing with a patient

01:11:46.500 who's motivated, who says, I want to stop drinking. They actually come and do a pre-infusion

01:11:52.680 therapy session. Is there anything that in that session, the therapist says,

01:11:57.880 we're not going to include this patient? Is there another decision that's made of a go,

01:12:02.720 no-go based on that pre-infusion session?

01:12:05.580 Well, the go, no-go is normally made before that. So they had to go through like a number

01:12:10.800 of screenings basically to get, as is with a clinical trial, which is kind of a problem with

01:12:15.640 clinical trials that we end up with quite pure populations. But we needed people to be abstinent

01:12:19.380 when they started. As we were talking about right at the beginning, with a lot of people who are

01:12:23.240 drinking, they can't stop straight away. So they either need to go through a medical detox in most

01:12:29.600 cases. Most of those are in the community now. So you can work with people's healthcare providers

01:12:34.340 to support them as they're doing that. So we keep checking in with them until they're ready to start.

01:12:39.940 So normally maybe two weeks after if they've done a full detox. If someone's drinking really heavily,

01:12:44.540 but they're at levels that we think we can help them put them cut down over a four-week period,

01:12:49.320 we would do that. So there'd normally be a kind of pre-screening where we check all the medical

01:12:53.400 contraindications for people and psychiatric ones. So we don't include people with psychosis

01:12:58.660 or psychosis in a first-degree relative, people with uncontrolled blood pressure because of ketamine

01:13:03.640 increasing. So uncontrolled hypertension because ketamine increases your blood pressure and a variety

01:13:08.560 of other things. We would exclude people from the study and then we have to access their medical notes.

01:13:14.320 Yeah, it's quite a process. But the main bit is getting people abstinent. The therapy is all

01:13:19.160 around supporting people with their new life and using the ketamine experience really to get that

01:13:24.900 perspective, a perspective they might not have had for a while, a kind of new perspective to think

01:13:31.000 about their life in a new way and try and focus on how they want to go forward really. So it's really

01:13:37.220 using the ketamine as a catalyst for the therapy rather than purely focusing on the pharmacological

01:13:41.780 properties of it. Remind me, how much does blood pressure go up in that type of a therapy when

01:13:46.520 you're at 0.8 mg per kg? What's the increase in systolic and diastolic blood pressure?

01:13:51.560 It really varies. So some people are really minimal. Some of it goes up about 10, I'm trying

01:13:56.180 to think. A psychologist, I guess. We have anesthetists there for the whole thing, so they're

01:14:00.960 probably checking that. And there was someone we had to stop the infusion because it went above,

01:14:05.020 I think it went over 180. That's pretty rare. And that's, you know, why we exclude people.

01:14:11.120 But then my anesthetist colleagues say, if we're people in theatre, we just give them ketamine

01:14:15.280 perspective of this. So I guess because of the way, anesthetists are the people that kill you,

01:14:20.840 ultimately, of all the medical professionals. They're quite desensitized, I guess, to risk,

01:14:25.620 whereas we're like, oh.

01:14:26.640 So again, tell me what the response rate was in the double negative group. So the group that didn't get

01:14:31.940 the ketamine and only got the education, but without therapy. What was their six-month?

01:14:36.680 Still really high, so about 68%, I think.

01:14:41.100 What do you attribute that to? So that means there's a 20% difference between the two extremes,

01:14:46.000 which is still great. But how do you attribute a 68% abstinence rate in people that didn't get ketamine

01:14:54.800 and didn't really even get therapy? They just sat down and talked with somebody about alcohol

01:15:00.260 biochemistry.

01:15:01.800 I think that was pretty extraordinary for any clinical trial. And we did have a really lovely

01:15:06.460 team. So I partly put it down to that. Something you see in clinical trials, people just do better.

01:15:11.280 They've gone through this whole rigmarole process with this really strong intention

01:15:14.660 to stop. So they've been through quite a lot of hurdles. The trial was pretty demanding.

01:15:20.000 So, you know, if you start with it, we also had things which I hadn't mentioned, like we had

01:15:23.640 a scram. I don't know if you've ever seen them. They're using criminal justice more. Lindsay Lohan

01:15:28.340 had to wear one when she had some DUIs. It's basically like a tag that you put around your

01:15:32.920 ankle that measures your alcohol through transderminy because you're screed about 1% of 0.98

01:15:38.820 alcohol in sweat. So there were things that we were using to measure alcohol that might

01:15:42.780 have actually acted as an intervention on their own. Now we're using a much more discreet

01:15:46.760 wearable, but then really clunky thing. You know, you have to say, you're not going to

01:15:51.160 do swimming for six months. You know, all these things, I think that in itself was an

01:15:54.780 intervention. A lot of these people don't have a lot of social connections. Some of

01:15:59.300 them did, but the fact of having people looking after them, checking in on them all the time,

01:16:03.980 people just showing you general human kindness, I think can have obviously a really positive

01:16:07.980 effect in a group that might be quite isolated.

01:16:10.720 That's amazing. I think these are really staggering insights because you have everything from the

01:16:15.180 monitoring of compliance to just the interaction. I don't say any of this to diminish the fascination

01:16:22.780 I have in both two components of this. One being the effect of the ketamine and therapy producing

01:16:27.940 88% abstinence at six months, but also just looking at the control group and realizing it didn't take

01:16:34.840 much to move the needle. And what can we learn from that sort of more big picture? It's a bit of a sad

01:16:39.760 statement.

01:16:40.180 It really is. Our alcohol services here in the UK are just so dysfunctional at the moment. People,

01:16:46.580 by the time they get to any sort of treatment, people that are really seriously, complexly with

01:16:52.420 multiple health problems, well, people have been through multiple treatments and they've not worked

01:16:56.760 and it's really hard to access therapists. So it's multiple things just like, oh yeah,

01:17:00.840 it's really sad. It doesn't actually take that much to shift something that's pretty entrenched.

01:17:05.480 Well, the other thing too, is it makes me wonder about less responsive cohorts down the line where you

01:17:10.740 would expect the response rate to be lower. But let's say you took an individual who's

01:17:14.020 less interested in not drinking. I don't think you could treat someone who says,

01:17:19.220 I'm going to keep drinking, but someone who maybe hasn't fully hit rock bottom, but says,

01:17:23.820 you know, yeah, maybe I'm drinking too much. And yeah, I probably meet the criteria for being

01:17:28.600 an alcoholic. I haven't destroyed my life yet. I just sort of wonder if you have these places for

01:17:34.460 earlier intervention as someone is on the path towards really destructive alcoholism.

01:17:40.200 Lots here. So in the phase three, obviously you said 200 plus patients. So that's going to be

01:17:45.260 great. You're still going to do the same four arms?

01:17:47.520 It's funded by the NHS Department for Health here. So we've gone down to take the two most extreme

01:17:52.900 arms. In an ideal world of infinite resource, I would definitely have the four arms because I

01:17:57.760 really like that design. And I think something that's really missing from the broader psychedelics

01:18:02.120 world is teasing apart the impact of the therapy and the drug.

01:18:04.600 But speaking to clinicians, so we've got like a patient advocacy group involved from the start

01:18:10.420 that actually given, you know, some of the risks with ketamine that we wouldn't really want to give

01:18:14.840 it without a therapeutic container. So having found these promising effects for this efficacy study,

01:18:21.840 which is more of a definitive study, then we would just take the most extreme arms.

01:18:25.300 We're looking just with the therapy and then the various other more discreet wearables

01:18:30.180 compared to our placebo, but we're using a low dose ketamine this time instead to manage expectancy

01:18:36.760 and the same education protocol.

01:18:40.160 What will that low dose be? Will the high dose still be 0.8 mg per kilogram?

01:18:43.380 Yeah. And the low dose is low, like 0.05. We're sort of working out with some piloting.

01:18:48.540 And why is that? Because at 0.5, they will, or 0.05 actually, they'll experience nothing. I mean,

01:18:56.360 they shouldn't feel anything.

01:18:57.400 Yeah. We've done some other studies and we've done some studies with morphine and

01:19:00.700 childhood traumas. They're looking at people's, I mean, it's a completely different area of

01:19:04.100 research, looking at how childhood trauma seems to sensitize the brain to respond to opiates.

01:19:08.880 And there we found actually using a very low dose, morphine was kind of a better control than

01:19:13.900 another drug. I think it is actually helpful in expectancy. So you tell people-

01:19:17.820 You're getting the drug no matter what.

01:19:19.100 You're getting one of two doses of ketamine. Also because we had patients actually drop out,

01:19:23.460 well, two-page, they knew that they hadn't got the ketamine. They hadn't got the active.

01:19:27.440 So we're saying you're getting one of two doses of ketamine. It's kind of easier

01:19:30.580 to maintain people in that, I feel.

01:19:32.940 The other thing is you might be able to recruit some KGB officers to help with that dropout, right?

01:19:36.840 Exactly. No one drops out. We're not doing any dodgy stuff.

01:19:40.520 This is a non-dodgy trial.

01:19:42.100 Non-dodgy.

01:19:42.940 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

01:19:46.620 ketamine story. What would you say to people here in the US where ketamine clinics are ubiquitous?

01:19:52.740 And as far as I can tell, I think you can just walk into them. I don't think you need a referral.

01:19:57.760 I don't think you need a medical referral to go to a ketamine clinic. Although I think there are

01:20:02.000 therapists who do make referrals and say, look, this is a reputable clinic. And I'm sure that there

01:20:06.780 are many reputable clinics and your depression is recalcitrant or you're having this problem in

01:20:13.620 your life. And I think it could get better here. So I suspect that there's a really good conduit

01:20:18.140 of therapists sending patients appropriately to good ketamine clinics. But let's also posit that

01:20:23.780 anybody can walk into a ketamine clinic, which I really do believe is true and sort of tell the

01:20:28.600 persons there, hey, I'm having this issue. I want to do it. But there's a bit of a conflict in that

01:20:33.900 model because when you walk into the clinic, they're incentivized to do what they do, right?

01:20:38.280 When you're a hammer, everything's a nail. When you're a ketamine clinic, you're incentivized to give

01:20:41.640 ketamine. How would you caution people around ketamine use liberally in that context?

01:20:48.780 I suppose I'd say that the evidence that we've gathered and not just us, another group at Yale,

01:20:54.240 Sam Wilkinson has looked at therapy and ketamine and there's another trial starting in depression.

01:21:00.800 It's a bit of a waste. If you just do the ketamine, you should certainly try it embedded within therapy.

01:21:05.960 And you probably don't need all of those doses. I think interrogating what you're trying to get out

01:21:10.520 of that experience. I think it's great to hear that therapists refer people to ketamine clinics,

01:21:15.860 like we've got so far with therapy, then we're going to use this as a boost so we can continue

01:21:20.580 the therapy. To me, that just seems much more appealing model. I don't think people want to be

01:21:26.020 kind of stuck on a drug, even if you're not addicted, but you're going in twice a week or

01:21:30.120 even once a week. That's so disempowering for patients. We know that, right? And speaking to

01:21:36.300 patients, one of the things they said was great about our treatment approaches, you know, rather

01:21:40.620 than being on daily meds, things like other treatments and alcohol, like the campus that

01:21:44.440 you have to take three times a day, they feel pretty liberated, you know, and they know they're

01:21:48.140 doing the healing themselves, which I think is a really important part of the process. So I'd say,

01:21:53.640 yeah, get a therapist. Think about using a really minimal number of doses. It's worrying. There's

01:21:59.660 some really worrying practices that you hear about. Some male order ketamine clinics.

01:22:03.960 I don't really worry about them from the abuse side. Maybe I'm wrong not to, but just because

01:22:08.340 it's so expensive, you have to have a lot of money to be able to afford that ketamine.

01:22:13.640 But I just think it's unsafe because certainly don't take ketamine at home when you're not

01:22:18.720 supervised. This drug makes you completely dissociated from your environment. If something

01:22:23.060 happens, there's a fire or all sorts of things could happen. You can't take it unsupervised,

01:22:28.300 but I think a lack of clinical care and supervision in some of these models that I find that really

01:22:34.700 worrying. You sort of answered what my next question was going to be, which was not at all to

01:22:38.860 say, do you condone the use of non-medical or recreational ketamine, but more to say,

01:22:44.120 if someone is going to use ketamine recreationally, what is the instruction set you provide them to make

01:22:49.860 sure that they don't harm themselves psychologically and physically? So one of them is, if people are

01:22:55.120 going to do ketamine recreationally, there really needs to be somebody around watching them. You

01:22:59.500 can't trust yourself to be under the influence of this drug, at least at a high dose, which I'm

01:23:03.960 guessing based on what we've said is depending on your size, 100 to 200 milligrams would be considered

01:23:08.640 a high dose. Yeah, really high. Start really small doses. I guess it's the advice that you'd always give

01:23:14.480 to people with any non-medical use of a drug in a safe place with someone who's not under the

01:23:20.480 influence of any substances and start with a small dose. I don't know so much in the US.

01:23:27.300 You rarely get ketamine particularly cut with other things, but it can happen. So there's something to

01:23:33.420 be careful of as well. Wow. That's interesting. What would it typically be cut with? I mean,

01:23:37.100 there are ketamine analogs, which people have shown. So there's a drug methylcetamine. So they're the kind

01:23:43.380 of research chemicals that have come out of labs in China, Israel. So it's an analog of ketamine,

01:23:48.420 but studies have shown more toxicity of the bladder and slightly maybe higher abuse potential.

01:23:53.960 I don't think it's normally particularly cut with things, but it's something to be mindful of and

01:23:58.900 why it's really important to take a small dose. Oh, that's super helpful advice. I've sort of been

01:24:04.100 deliberately ignorant of ketamine. I don't know why I've gone down the rabbit hole and trying to

01:24:08.880 understand as much as possible about these other agents, which ironically tend to be the one that are

01:24:13.560 schedule one and therefore not really readily available for clinical use outside of trials.

01:24:18.100 We do have many clinical trials here in the United States looking at, in particular,

01:24:21.980 the use of psilocybin and MDMA. But ketamine has been a bit of a black box to me. And yet it's the

01:24:26.500 one that I probably have seen the most people use because of course it can be used legally.

01:24:31.660 I found this discussion very helpful. I found this discussion really insightful.

01:24:35.320 It clarified for me a lot of the use case, the neurobiology, the risks, and perhaps most importantly,

01:24:41.100 what the promise of this agent is. I want to thank you for your time. And again,

01:24:45.680 I know it's late there in the UK at the moment. And more importantly, I think, thank you for the

01:24:49.320 work you're doing. This is really fascinating. And I kind of love the model.

01:24:53.380 Oh, thanks for having me, Peter.

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The Peter Attia Drive - August 29, 2022

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

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