Psychiatry & Psychotherapy Podcast - "Serotonin Toxicity", Otherwise known as Serotonin Syndrome

Episode Date: April 5, 2023

In today's episode of the podcast, we are joined by psychiatrist and neuropharmacologist Dr. Ken Gillman who is the founder and convener of the International MAOI (monoamine oxidase inhibitor) Expert Group and widely recognized as a world expert in serotonin toxicity.    Serotonin toxicity (syndrome) is a rare as well as potentially lethal form of toxicity that results from excess serotonin within neuronal synapses. There are numerous poorly written/controlled case reports that have perpetuated misinformation about drugs that can cause serotonin toxicity. While the word "syndrome" is often used, toxicity is a more accurate description given that toxicity represents a spectrum of severity rather than a defined set of symptoms. In today's podcast, we will discuss the pathophysiology, causes, clinical presentation, criteria, controversies, and medical management of serotonin toxicity.  By listening to this episode, you can earn 1.25 Psychiatry CME Credits. Link to blog. Link to YouTube video.

Welcome back to the podcast. I am joined today by Dr. Alexander Horwitz. He is a PGY3 at Community Memorial Health System in California. And he was so kind to connect me with Dr. Ken Gilman, who is out in Australia. He is the director of the Psychotropical Research Group and the presiding council chairman at the International M-A-O-I expert group. he is an expert in serotonin syndrome or what he will call serotonin toxicity so today we are going to be doing a deep dive on serotonin toxicity um let's see i have no conflicts of interest Alexander Horowitz says no conflicts of interest uh dr gilman was telling me he has a hundred dollar stake in neurowell therapeutics a company that has a patent for an MAOI um which which we're not, we'll be covering a little bit about MAOIs, but we won't be specifically talking about this.

So I think that's not a huge conflict for this episode. Yeah, why don't we start with, Alex, why don't you tell me a little bit about how you got connected with Ken Gilman and this topic and why you thought it was interesting to bring here? Yeah, sure, definitely. So during my intern year, I was on internal medicine, and I had a case of serotonin toxicity, and a professor actually recommended contacting Dr. Gilman because he's the world expert in serotonin toxicity.

And that's how I came to come in contact with him. I actually had a patient who was taking an MAOI and had overdosed. And this topic just comes up again over and over in my clinical experience. And I think that there's just a lot of misperceptions out there about certain medications that can cause serotonin toxicity? Yeah, so Dr. Gilman, do you want to give us like a brief introduction on what is serotonin toxicity? Yes, certainly. It's an intransynaptic concentration-dependent phenomena involving serotonin, of course, hence its name,

and it's caused by drugs that elevate serotonin levels way beyond. what is physiologically usual or normal. It has very characteristic symptoms, and when it occurs in its serious form, which is really only when two different sorts of drugs with different mechanisms of action, I mean by different sorts of drugs, when two different mechanisms are used at the same time,

that can elevate intra-synaptic serotonal. to a far greater degree than would ever occur with a single drug or under normal physiologic clinicians. So that's why we started to try to teach people to call it toxicity rather than serotonin syndrome going way, way back when I was involved with Professor White, who's a famous professor of clinical pharmacology and toxicology. And we thought there was such a muddle Because, well, first of all, if you want to use terminology precisely, it's not a syndrome. It's a form of drug toxicity. If somebody was intoxicated with lithium, you wouldn't call it lithium syndrome.

You'd call it lithium toxicity. And obviously, we used the word toxicity because that's usually meant to imply a condition of a severity. that's potentially fatal. So is it like on this more severe realm, is it fatal? Most certainly, yes. It's about the only, possibly the only, I think Alex, you're probably more up to date with this. I can't think of any other drug interaction that would occur in psychiatry,

possibly even in general medicine, that potentially kills people within 24 hours. There aren't many, are there? Okay, so I think that's a good introduction on why this is an important topic. Indeed. Can we cover the flip side of that very quickly, too? Because not only is it important, because if it occurs, it's potentially fatal, but as I've already said, severe potentially fatal degrees of elevation of interest in

apic serotonin that we would call serotonin toxicity only occur with combinations certain specific combinations of drugs that affect serotonin. And they cannot occur with many other combinations. So, for instance, an overdose of a serotonin re-uptake inhibitor cannot cause serotonin toxicity. Thousands of cases have been documented with overdoses, both small and large, and not ever has one of them required admission to an intensive care unit because of serotonin toxicity. Now, the reason that's really important to understand, David, is because the literature is full of people making statements like it's important not to miss mild

cases of serotonin toxicity. And that leads people to intervene with supposedly specific antidotes to the symptoms they think they're recognizing, often mistakenly, and other interventions, which are completely unnecessary and completely inappropriate. It leads to people getting into a panic about a clinical situation which requires no action other than simply observation and reduction or cessation temporarily of the medication in question. And it's immensely disruptive to sensible, logical patient care. One imagines that the cost of these inappropriate,

worries and interventions concerning so-called serotonin toxicity from drugs that can't cause serotonin toxicity must be costing healthcare systems huge amounts of money. And, you know, patients are being refused treatment because some misguided person thinks that drug X, Y or Z can cause serotonin toxicity, therefore the patient can't have it and so on and so on. So that's the other side to the coin. It's not just, but very rarely it can be fatal with certain particular drugs, but that in a great majority of instances, it's not serotonian toxicity and it's not going to lead to serious symptoms and it's not something to worry about. That's good. Yeah, we're going to get into all of that anticipation. Hi, here. Dr. Gilman. Take me through the kind of the mild to severe

serotonin syndrome, maybe in terms of the neuromuscular abnormalities. Wrist slap there, David. You mustn't say serotonin syndrome. The phrase, well, no, it is, terminology is very important. Words are crucial in this because people misunderstand them. I think the terminology I try to encourage and teach people to use is serotonin mediated effects. The word serotonergic is banded about, but of course that's not actually a very good word because a serotic serotonergic drug can be an antagonist, not an agnist, not something that

increases serotonin mediated actions or effects. So that's the first thing. Okay. What's the question again? Okay. So, you know, excess. So the thing to concentrate on is what are serotonin? mediated side effects. And of course, most doctors who use these drugs are, in fact, very familiar

with them because the much used, perhaps some would say overused SSRI-type drugs like Prozac, have a characteristic profile of side effects that's different to almost all of the other non-cerotonein affecting drugs. And there are things like tremulous. effectiveness affecting an orgasmia and GI upset. They tend to increase GI activity, so people might get a bit of indigestion or loose bowel motions or whatever. And then if the dose becomes higher, then those effects become more marked. And eventually, if you raise serotonin high enough, then you're getting along the spectrum,

so to speak. and we often use the term the spectrum concept, because of course it's progressive, depending on how much you elevate serotonin and which drugs are involved. So as you elevate serotonin more and more, then you get more and more effects. And the more specific and definite effects

of excessive elevation of serotonin beyond what you would normally get or expect in usual therapeutic circumstances are severe hyperreflexia and clonus. But it's important to understand that a little bit of hyperreflexia occurs in anxiety. Pathological hyperreflexia is substantially different. And likewise, clonus as part of serotonin toxicity is something that's really quite severe and repeated. It's not just two or three beats of clonis.

it's 10, 20, 50 beats of clonus, and patients with severe clonis will virtually bounce themselves off the bed because they're getting those repetitive contractions of both leg and arm muscles, and sometimes doctors mistakenly diagnosed them as having an epileptic fit, because it can be so spectacular. But that only occurs with severe serotonin toxicity. So just for those who are like newer to this, like hyper reflexy, how would you see that, how would that present? And Clonis, like, what does it actually look like? Oh, right.

Well, usually doctors, well, Alex would be a better person to describe this. He's more into clinical medicine. But obviously, it's usually elicited in the knee reflexes by tapping people's knee jerk. And you can list it in the arms, of course, too, and other places. But Alex, what would you say? Yeah, I mean, just think about. the classic knee reflex. And going back to the clonists, you have spontaneous, so it's just happening on its own versus inducible. If you took like a foot and jerked it up and it just kept

beating, that would be inducible clonis. And then there's also ocular clonis. Very important, yes. Describe ocular clonus first. Just picture rapid, almost like rapid movements of the eye. But one important caveat there, Alex, is of course they're symmetrical both ways. Nistagmus, which most doctors are much more familiar with, is quite different. The ocular clonus that you get with serotonin elevation is symmetrical both ways, and that's a key difference. What do you mean by symmetrical both ways? Like the eyeballs are going left to right? Yeah, the speed with which they deviate is the same. With Nisagmus, it's quick back, quick back. Okay, so with the, with a stagmus, this quick one way and then slow back, quick one way, slow back.

Whereas we'd agree with that, Alex? That's a correct description, I hope. Yeah, it's just, it's just good to listen to Stagmas for many, many years. That's good, no, it's a good clinical pearl. So that's why I think it's worth kind of zooming in on that, Because if... Yes, and also, David, whilst we're talking about that, the term myoclonus is often used, and sometimes, perhaps even often, it's used in perhaps a slightly loose and imprecise way.

Clonus is opposing muscles and a symmetrical movement backwards and forwards, usually gradually getting less and less over a period of 10 or 20 seconds, if it's definite. Whereas myoclonus is more of an uncoordinated movement involving a number of different muscles and groups of muscles so that a limb may appear to sort of flail about a bit, and that's quite different to the symmetrical movement of clonus. Now, you do see myoclonus in cases of moderate to severe serotonin toxicity, but it's not typical and it's not diagnostic, it's clonus, which is more or less symmetrical clonus progressing rapidly over time, is more or less

diagnostic of serotonin. It's the back and forth. Is that what you're saying? Opposing muscle groups back and forth. Well, it's not all that subtly different, but it's quite distinctly different from myoclonus and myoconus does not have the same diagnostic significance. Okay. Yeah, any other neuromuscular abnormalities that people should be aware of? Not really. We said before that tremor, exaggerated physiological tremor,

is a characteristic of milder cases, and some people get that with normal doses of serotonary uptake inhibitors, don't they, Alex? Yes, just like sweating sometimes. Exactly, yes. And a very small percentage of people will actually get a little bit of clonis. If you examine them carefully,

that you can elicit one or two beats of clonis in some people who are on serotonary uptake inhibitors. What about like acesia? Is that something? No. That's a different thing. Okay. Totally different. So that's not, it's not like someone would have aceshesia and serotonin syndrome.

No. Okay. So, okay, with autonomic hyperactivity, you have sweating, Tachycardia, breathing fast, high temperature. How often do you see that? Is it always there with the colonis? Or is it there sometimes? Autonomic symptoms tend to be fairly nonspecific,

and lots of cases of illness and toxicity will exhibit those sorts of changes. And it's difficult to define exactly what you mean by unstable blood pressure. But certainly you do see a little bit of autonomic instability, but it's not usually a very helpful diagnostic sign because it's very non-specific. Okay. What about altered mental status? Is that there, in every case of severe serotonin syndrome? Yes and no. The early signs as it progresses and gets more severe are usually more to do with being,

hyper alert or twitchy. Some people are even described as a bit excitable or even manic for a little while as the toxicity develops. But that's less diagnostic and less predictable. Do you have a thought on that, Alex? I would just point out that it could someone actually mimic acathesia, if that makes sense. Someone's moving around a lot. They're sweating. They feel restless. It really could look like acathia, but it's a different pathophysiological process. Yes. And would you agree, Alex, that if you question the patient properly, the usual typical features of acathia just aren't there. Right. But it's always the same in clinical medicine. You can describe a typical case. But every now and again,

of course, you'll find examples that are a little less than typical, whether it's a heart attack or a duodenal ulcer or this sort of thing. So I think we take it as read in medicine that there are always possibilities of atypical presentations. So I think it's helpful that you, you know, because often with serotonin syndrome, when you read it in a book, there's like a lot of, a lot of list of things, right? And I think what is most helpful that I'm taking away from this is clonis is really that giveaway, Because that's what you're going to visually see that's going to cue you in to like, oh, okay, this is actually happening. Well, it's a finding on examination as well, because as Alex quite correctly pointed out, in the developmental stages, you'll get clonus that's only elicited by examination like you described. But as it gets severe, then it's spontaneous.

So it's a gradation. So it's hyperreflexia, inducible clonus, and then spontaneous clonis, if you're. like in that order. And the other thing to emphasize is that so frequently people forget to recognize that you're talking about the development of something over time. And again, it doesn't matter whether it's a heart attack or a duodenal ulcer. From a point of view of making a clinical diagnosis, the key is the history and how the condition develops over time. Obviously, specifically with serotonin toxicity, you're going to almost certainly be able to. to discover that there's a history of ingestion of particular drugs, which is the giveaway.

I mean, it's the key thing. You can't get strychnine poisoning unless you've taken strychnine, and you can't get serotonin toxicity unless you've taken drugs which have a major effect on elevating serotonin levels. Simple as that. It doesn't occur spontaneously. There's nothing like it that occurs spontaneously. Yep. That's, yeah, I was going to say, if there's a physical exam thing, it's the clonis and the hyperreflexia.

But, of course, in the history, the history is paramount. Yes. And the progression over time. And that's why people's, I think, people's concentration on research diagnostic criteria is doubly flawed. Because, of course, research diagnostic criteria are for research, and they're talking about specific value of symptoms in making a research diagnosis. That's not the same as making a clinical diagnosis. So all these people that make reports and talk about the research diagnostic criteria that Professor White produced, it's jolly good to have a clear idea of what those are and what

the typical symptoms are. But as a clinician, what you're looking at is the history, the progression over time, and the drugs that have been ingested, which are at least as important. Very good. Yeah. Okay, let's jump to the pathophysiology. Alexander, do you want to summarize what you found in terms of what is the type of serotonin receptor specifically? Yes, definitely. So this is key in understanding serotonin toxicity is that it's mediated by stimulation or agonism of the serotonin 2A receptor subtype. Initially, was thought that the serotonin or five hydroxytryptamine is just another way of saying serotonin. So the 5HT1A receptor was initially thought to be involved, but now we know conclusively

that it's stimulation or agonism of the 5HT2A receptor. I agree with you, Alex, but it is important to note, I think, that there still are some people that don't agree with that. We had a little bit of a set to with a referee of one of our papers quite recently, who insisted that it was to do with 5HT1A receptors. And one of the reasons, David, that there's serious confusion about this. And Professor Isbister, who's a very smart fellow who started off working with Professor White, who I mentioned earlier. So he's a clinical pharmacologist and toxicologist. he wrote an excellent review of this whole subject of the animal and human pathophysiology

of serotonin elevation and its effects. And what he pointed out, quite rightly, and I had sort of touched on this before myself, but not reviewed it in anything like the degree of thoroughness that Jeff did. What he pointed out is that the 1A business is the manipulation of serotonin mechanisms that was taking place in experimental pharmacology, looking at new drugs and things like that, and that's actually quite a different syndrome to the human serotonin toxicity syndrome.

And people have totally inappropriately extrapolated information from those kinds of experiments in animals. So you've got a double problem. First of all, experimenting from rats, so extrapolating from rats to humans, which is not always a very good idea. says he is his whiskers twitch. But also the fact that you're looking at the wrong syndrome.

The animal syndrome is quite different to the human syndrome. So it is true that in the animal syndrome, manipulations of 5HT1A receptors have an effect on the symptoms, but those animals are not getting severe hypothermia and they're not dying. They're just getting a few behavioral effects. that the chaps who play with those sorts of drugs like to measure as an estimation of what their new drugs are or aren't doing.

So I think that's a really important point, don't you, Alex? Definitely. So that's why so many of the reviews about serotonin toxicity are seriously mistaken. Because unfortunately, David, there seems to be quite a big disconnect between basic science research and clinical medicine. This has been so throughout the whole of my career. And so many people who write reviews of these things don't know the history and the knowledge that we've got in terms of basic pharmacology and electrophysiology and all those sorts of things. And therefore, their interpretations of what are happening clinically are severely compromised. I checked only this

morning. I checked it before and I wanted to make sure that I was going to mention something about this. I was correct in what I said, since one's memory can trick one sometimes. The best early papers on this in 1983 and 84 by a pharmacologist at the Maudsley Hospital in London were excellent papers that revealed the basic interactions to do with serotonin toxicity, which, of course, inevitably involve MAAI drugs. It's almost impossible to have severe serotonin toxicity if you haven't taken an MAOI, certainly in any clinical scenario,

and even if you include illicit drugs, that statement is almost true. So it's really important to understand the history of the basic pharmacology experiments on this. And these papers, a whole series of about five papers, produced by this fellow Marley back in the early 80s, have hardly ever been cited. In fact, most of his papers have only been cited either by me

or his own team citing something that was done later. Almost nobody else has cited those papers. And I thought, isn't that an extraordinary illustration of how people just aren't taking account of the basic science research? So you combine that with what Alex has already said. said about this business of 5HT1A receptors, and you can see that helps you to understand why so much of what people are talking about is seriously misinformed. So, okay, so in summary, to repeat what we're talking about, there's 5H2A agonism, which contributes to serotonin toxicity. That seems to be absolutely the main determinant of the potentially fatal effects.

Let's just get one thing clear quickly. When serotonian toxicity becomes severe with mixtures of these drugs, then chest wall rigidity, this process of clonis and hyperreflexia, when the clonis becomes really severe, you essentially get rigidity of the muscles. And if that happens to the chest muscles, of course, you can't. can't breathe, and that's a bit of a problem. And secondly, hyperthermia. So 5HT2A receptors have a direct effect on the mechanisms in the brain that control body temperature, and you interfere with those in a serious way and over-stimulate them, and your body temperature goes up, and people die of

hypothermia, because once your body temperature gets much over 40, you know, your chances of dying are extremely high because your blood goes haywire and heaven knows what else happens. It's an extremely serious condition. It's a medical emergency of the same degree of urgency as an acute heart attack. The first thing that I thought when I was looking at this, the 5HT2A, when I think of an agonist to that, I think of LSD. Very interesting question. Do you want to speak to that, Alex, a bit?

So, yes, LSD is an agonist of 5HT2A, just like psilocybin and other classic psychedelics. But my understanding is that LSD is not a potent enough stimulator of 5H2A to precipitate serotonin toxicity, and there aren't any good case reports demonstrating that LSD actually has caused serotonin toxicity. But Dr. Gilman can comment more on that. I think you're quite correct there. I think the underlying reason is utterly fascinating, David. One of the first papers, after I stopped doing clinical work some years ago, and basically I was retired from clinical work,

so I kept myself occupied by continuing my theoretical research in all these things. And one of the first things I did was to do something I'd been wanted to do for a long time, which was to use the occurrence and severity of serotonin toxicity as an index of what drugs given to humans were actually doing to the serotonin syndrome. Because, of course, if somebody claims the drugs a serotonin re-uptake inhibitor, and you give it to somebody who's already on an MAOI, we can state very, very confidently that if it's a potent serotonary uptake inhibitor, it will precipitate serotonin toxicity.

So if you start examining the databases that people like Professor White have, and you look at people who've taken different combinations of drugs, and they do or don't get serotonin toxicity when they take bigger or smaller overdoses of things, then you can make some very interesting deductions about whether those drugs really are acting as serotonin re-uptake inhibitors. Now, of course, that's pretty important, because ever since the introduction of Prozac all those years ago, that's been the bees and ease everybody's been going on about serotonin because the marketing people for the drug companies, you know, that was the thing they wanted to persuade everybody

that you needed to do and you needed to have a serotonin re-uptake inhibitor and blah, blah, blah. And so they were all claiming drugs were serotonin re-uptake inhibitors or jewelry uptake inhibitors or whatever. And of course, what the toxicity data shows is, in some instances, that simply isn't true. You can, you know, metazapines, the classic example of this, isn't it, Alex? You know, that was marketed as a combined, you know, serotonin and noradrenaline elevating drug by some, you know, clever mechanism, which was close to imagination rather

than reality, in my opinion. And they said, of course, that you can't combine it with MAIs because it'll cause serotonin toxicity. That is manifestly not true. Not only is it not true. If you go back to the animal experiments that we spoke about earlier and make sure you're grounded in reality and experimentation, what you actually find is if you take the rat model where you kill people by giving them these combinations of M.A.I. and serotonin reuptake inhibitors, which kills them very efficiently quite quickly. And you give them metazepine before you give them the serotonin reuptake inhibitor. They don't die. They don't get serotonin toxicity. So the irony is that, Metazepine is actually lessening serotonin toxicity, not making it worse. Therefore, you can deduce pretty reliably it can't be acting as a serotonary uptake in here with that.

Because if it was, the rats would be dying even quicker, not dying. Yeah. Yeah, that was, that's a helpful little pearl as well, that it's not going to worsen or cause serotonin syndrome. Or, sorry. I'm going to say. Slat, slap, slap. Oh, man. And for me, as a resident, this is where the rubber meets the road, really.

It's with the medications. And this is why I'm so interested in the topic is because again and again with my instructors, I've gotten into multiple arguments about certain medications causing serotonin toxicity. And certain people will say attending physicians, you can't combine these medications, but a lot of the time you can. And Mertazepine is a really good example of that. Yeah. This goes back to what I said before, David, which is this is not a trivial issue because

it's causing tremendous disruption of the clinical care of patients. I mean, let Alex speak to that, because I've been out of clinical practice for a long time now. But it's obvious from all the reports and documentation I see that many, many patients have their management completely disrupted for no good reason. Alex. Yeah, I think we can definitely get into some specific medications. And I was kicked off the Internet earlier. I'm in a hotel, actually.

I'm on in a way rotation in Cleveland. But did you talk about the Hunter Area toxicology service? Yes, I mentioned Professor White and his toxicology database, yes. Okay. I would like to actually talk about the criteria, the two different criteria. I think it's worth going into a little bit more. Alex, since you summarized this so well in this document that you made, why don't you talk about Professor Ian White, what he initially did?

May I just quickly intercede on this with a caveat, if you like. What Professor White and his colleagues now say is that trying to diagnose the specific form of toxicity is generally not really the issue, because the toxicologists who treat these people, if they finish up in an intensive care unit, actually strive not to use supposedly specific antidotes. Like, for instance, some of my early work suggested that cypraheptidine and chlorpromazine, because they're 5HT2A antagonists, do help suppress the serious, manifestations of serotonin toxicity. But these guys who actually treat the people say it's much safer

to use conservative measures. So first of all, you stop all the drugs. Second, you use conservative measures if necessary to reduce people's temperature or treat whatever symptomatic things are severe enough to require some sort of treatment. Usually, it's all they do is give people benzodiazepines just quieten down a bit and passive cooling and such like general medical care. So, They stress that giving specific anecdotes is not the issue in a great majority of instances. And therefore, striving to make a specific diagnosis of what form of toxicity it is is often actually not really as important an issue as many people seem to think it is. But with that caveat in mind, Alex, over to you. Sure. So there are two major criteria for the diagnosis of serotonin toxicity.

the first criteria, the Sternback criteria, created by Dr. Harvey Sternbach in the early 1990s, and he based his criteria off of basically 29 different cases, and he came up with his own sets. And then much later, as Dr. Gilman alluded to Ian White in New South Wales and Australia, when colleagues came up with the Hunter Area toxicology service, well, through their service, they came up with the Hunter criteria for serotonin toxicity. And their criteria are based off of 16 years of data, I believe, with over 2,000 patients who are admitted to the... It's more than 20 years of data now, Alex.

Because it started in 1997 or 8. I went down to meet with them to help them decide, because they asked for my input on helping to decide exactly what things they ought to be observing. because, David, the important thing for everyone to understand is they decided that to deal with toxicology properly, they needed to have a proper database where particular sets of symptoms were accurately recorded on a prospective basis so that it could go back later and look at all the data in the computer and see which patients got what sort of symptoms with what sort of drugs and build up a much more systematic and logical analysis of the whole thing. So that's what they started doing.

I'm pretty sure they started that. I mean, it was in the days of Palm Pilots. I remember I had a Palm Pilot. How long ago is that? Yeah, I see from the data here, it was a 1987. Yeah. That sounds exactly right. I seem to remember I just got a Palm Pilot, and it was the end of 87 or 97 or 98 that he started

the database. Anyway, sorry. And then that collection went, I think, to 2003, and then they published. and it's still ongoing. And I believe that Dr. White has retired, but Hats is still ongoing. Yep. Yeah.

So I think, and what did they find that was different or unique than the prior way of sort of characterizing it? I think what it did, David, was to add a great deal of certainty and confidence because, of course, case reports, which are usually a single. case, at most two or three, four or five cases. They're atypical, they're unrepresentative, et cetera, et cetera, et cetera. They wouldn't get published if they weren't atypical, because otherwise

the journal would say it's not very interesting, we're not going to publish it. So when you're looking at case reports, you're looking at an extremely skewed sample of data, which for things like this is, in fact, not only is it useless, in many instances, it's worse than useless for the kinds of reasons we've already talked about because it generates all of these false positives of you can't give this drug and that drug. And almost all of that stuff is based on case reports. So their systematic collection of data in hundreds and hundreds, and in case of SSRIs, of course, because they're used so widely, I think their database contains over 5,000 overdoses of SSRIs where they've monitored their symptoms systematically and carefully. So that enables me to say,

to people, if you've taken an overdose of an SSRI, you will not need to be admitted to an intensive care unit because of serotonin toxicity. If you take acetylopram, you might need to be admitted because you've got a cardiac arrhythmia abnormality, and they have to monitor that in intensive care, but not because of serotonin toxicity. And not one single case in that huge series did people have significant hyperthermia, excess body temperature, when they had only taken an SSRI. But if they'd taken an MAI in combination with it, they were in big trouble extremely quickly. Yeah. And one thing I'm curious about is like what level of increase of serotonin are we really talking about here in someone's that has serotonin toxicity?

That's quite a complex question for the first reason that experiments in rats can't necessarily be extrapolated to humans. And of course, we can't measure serotonin levels in humans suffering from these kinds of things. But nevertheless, we've got a whole host of data from all sorts of different kinds of experiments in test tube experiments and animal experiments and whatever else. And the ballpark answer to your question is to get serotonin toxicity, you need to increase serotonin by at least 50 to 100. times the usual physiological level. And in fact, for severe serotonin toxicity with combinations of M-A-O-I's and S-R-I's,

then you're talking about a thousand times higher, huge elevations. Whereas with the serotonin re-uptake inhibitor alone, you're elevating serotonin by threefold, something like that. So nowhere near the levels that you get with severe serotonin toxicity, not within a country mile. Interesting. That's good. I actually answered your question.

I've forgotten what the question was. I think so. I think so, yeah. I'm all out of questions. No, we can keep going. This is like, someone out there is listening to this, and they're like, this is exactly the deep dive that I wanted to know

on this topic. Everyone else is gone. No, I'm joking. Maybe we could talk about specific medications that are commonly associated with serotonin toxicity. that actually don't cause serotonin toxicity. So before we mentioned mertazepine, so that's classified typically as a noradronergic and specific

serotonin antagonist. But like Dr. Gilman was saying that that's really negligible, and it's primarily a histamine antagonist, and it also antagonizes 5HT2A. And we discussed the different reasons why it doesn't cause serotonin toxicity. But some other examples could be tryptan medication. which are used for migraines. They're agonists of 5HT, 1B, and D. So that doesn't stimulate 2A.

Another example would be Trazodone. It's classified as a serotonin antagonist and reuptake inhibitor. So it's antagonizing 2A. Yeah, you know what antagonizes me is when I get the serotonin warning. Whenever I prescribe that with another SSRI, it's like, warning. I remember even a pharmacist wouldn't prescribe it one time. I had to speak to this pharmacist. I'm like, I've given this to so many people I've never had any issues.

So now I have some data to support it. And I thank you. Yes, indeed, David. And that is one of the reasons we've started the MAOI, international MAI expert group because we wanted to have the authority to be able to make statements about these kinds of things rather than just me. because of course people say, well, there's just this fellow in tropical North Queensland who says everybody else is wrong and he's right and that sort of thing.

So we want to sort of put it on a better academic foundation supported by famous professors whose names people recognize because otherwise you're not going to be able to persuade these pharmacists and GPs who refuse to issue a script because their stupid little computer flashes read at them and they can't think for themselves. Sorry. Yeah. Yeah.

So awesome. Well, no, I mean, I mean, like, there are some GPs that listen to it. And we love when GPs are digging into the knowledge and not to rag on GPs. But, no, I get it. It's like we want more nuance than just listening to some computer algorithm or we want the computer algorithms to change to support what actually makes sense. That's what we're trying to achieve. Yep.

Yeah. I have some coaching clients who are influencing these algorithms. So hopefully we'll be able to make some changes. So, okay, Trazidone, I think the point is, it's a 5H2A antagonist, and you have to have an agonist, right? So that one would, you know, just like... It is a weak serotonin re-uptake inhibitor. This is exactly where these toxicology databases

and the animal experimentation of in vitro assays of cert affinity and everything else come in. Let me give you a quick example. Of course, before the Prozac-like serotonin re-uptate inhibitors came into use, we had chlomipramine. It was in use in Europe for a long time before the Americans got it, but a lot of people didn't realize that chlamipramine is, in fact, a very potent serotonin re-uptake inhibitor. But like many of the other drugs with a self-a-rethor, similar structure that are called tricyclics, but actually have very different neuropharmacological profiles.

Many of those drugs are potent 5HT2A antagonists. And what Professor White's database showed very early on was utterly fascinating, that although chlomipramine was actually a more potent inhibitor of cert than most of the new specific serotonary uptake inhibitors, it caused serotonin toxicity type symptoms less frequently. was it about a tenth or a fifth of the frequency? And of course, that's because it's got built-in 5HT-2A antagonism. So even though it's a very potent serotonin reuptych inhibitor, the built-in 2A antagonism makes it cause serotonin mediated side effects

to a lesser extent, even in overdoses. And that extends to combined overdoses of different drugs. So one of the latest updates from their database, they looked at, amongst other things, the chance of having serotonin toxicity type symptoms with the size of the overdose of an SSRI. And what they demonstrated was once you'd got up to an overdose of two or three times the defined daily dose, that the chance of getting serotonin toxicity didn't get higher as you increase the dose, the size of the overdose.

But what they did show as part of that was that the patients who'd taken either risperidone or chlorpromazine in combination with their SSRI were five or ten times less likely to get serotonin toxicity symptoms, again, because they're two-a-antagonists. So the neuroleptics that were potent two-A antagonists drastically reduced the chance of exhibiting serotonin toxicity type symptoms and the ones that didn't, didn't, that weren't two-A antagonist, didn't have any effect. So that's yet another confirmation of that notion, but it's a balance between SRI and 2A.

So going back to Alex's excellent point about Trazadone, it's 100 times weaker than the typical SSRI's insert potency. Something like that, isn't it? Right, and it doesn't have sexual side effects. It doesn't treat OCD or catalypsy or cataplexia, excuse me. Yes, really important point that Alex has just introduced there. Do you want to enlarge on that, Alex? Yeah, definitely.

So another way of identifying medications that can contribute to serotonin toxicity is thinking about certain conditions that you need serotonin to treat. So one example would be OCD. Another example would be cataplexy and narcolepsy. Yeah, that's good. Well, let's jump into the trip. Trichotillot. Gotcha.

Yeah. Let's talk about the triptons. What did you learn about that? So those are agonists of 5HT, 1B, and D, so they don't really have an effect on 5HT2A. Dr. Gilman actually wrote a paper in, I believe, headache in the mid-2000s about this. And the American Headache Society actually put out

a paper. There was an FDA warning in the mid-2000s about triptan medications causing serotonin toxicity, but those cases have been analyzed and it's no longer thought that triptans can cause serotonin toxicity.

Yeah, there was one article you cited 19,000 patients were concurrently taking triptans and S-S-R-I or S-N-R-I's and they only identified 17 patients with possible serotonin syndrome. So very, very non-existent, right? So we can not worry too much about tryptans.

Definitely, yeah. And I believe that there were two that they had definite serotonin toxicity, but, you know, correlation and causation, two totally different things. The other thing to add about that, Alex, is that when definite serotonin toxicity occurs in those kind of circumstances, it enables you to say with quite a high degree of confidence that the patient must have taken some other drug that the doctors don't know about. And indeed, just very quickly, that is what led me to propose that methylene blue was a monoaminoxidase inhibitor. And likewise, What's the other?

Metaxalone. You probably know about metaxalone. It's used as a sort of, I don't know, what do people use metaxalone for in North America, back pain or something? I don't quite understand why. It's supposed to be some kind of muscle relaxant or something. But it's actually a very weak MAOI.

And what some of the other toxicologists who are actually in our group, but based in America, what they showed was if somebody takes an overdose of metaxone and they're on a serotonary uptake inhibitor, they do get significant serotonin-mediated symptoms that can sometimes reach the level that you would define as toxicity,

but not with normal therapeutic doses. So there's another jolly interesting example of how you can make quite accurate predictions about drugs from simply observing cases like that. Interesting. Is that clear, or have I confused you? I hope I haven't confused the issue. no makes makes sense to me although i've been reading up on this so let's let's go to boostaron

boost prone is a 5 h t1 a partial agonist right so would we expect boostbarone to cause or you know worsen serotonin toxicity with an m aoi and now the answer is no uh remember that 5HT1A agonism causes hypothermia, not hypothermia. I think that's a very nice a very nice

pearl there. There's some good clinical pearls here. I feel like some, I love the nuance. I love the level of nuance. Okay. What about Zophran on dosterone? So, yeah,

Zophran is a 5HT antagonists, different from 2A, so it really has nothing to do with 2A. You can combine it with an MAOI, totally safe, does not contribute to serotonin toxicity in any major way. Okay. Let me, have we touched on this already? But I think what these things that Alex is correctly emphasizing reminders of is the extreme unreliability of case reports. So people, I imagine, are aware of the fact that the medicines agencies, whether in Europe or the FDA in America, have issued warnings saying doctors should either not give these together or whatever for triptans, centrons, and a few other things too. I can't even remember.

And these are completely misinformed. And back to what we were saying earlier about, you know, upsetting proper clinical. care of patients because doctors become frightened of giving these drugs for no good reason. And all of that warning stuff, it's all based on case reports. In fact, actually, it's even worse than that, because of course, what's that system in America, F-A-E-R-S or something? These are self-generated reports or something. I mean, they're so unreliable. It's utterly ridiculous. But even case reports and reports submitted to the agencies by doctors in these situations, I've looked through many, many of them when I was writing about serotonin toxicity long ago. And the data in them simply isn't amenable to that kind of interpretation.

Drawing any conclusions, you can't make a silk purse out of a sals ear. If you haven't got proper data, you can't draw reliable conclusions. And of course, again, that's what Professor White's well-done, systematic database proved absolutely conclusively. So case reports are as proven by these things like cetrons and triptans. There are innumerable case reports in the literature of supposed serotonin toxicity with these drugs. And they're all misinformed. They're all misrecognized, mistaken, incorrect. Let's jump to a differential diagnosis of NMS.

And it's inevitably brought up the similarities. And so how can we differentiate the two rather quickly? Alec, would you like to start on that? Yeah, sure. So one thing that initially comes to my mind is taking a good thorough medical history and seeing which medications the patient is taking. So for serotonin toxicity, we would expect them to be taking medications, which increase introsanaptic serotonin.

and then for NMS, they would be on dopamine blockers. Another major difference would be the time course. Serotonin toxicity is much more rapid. So we're talking about hours opposed to NMS, which is much more insidious and developed slowly over days. Yep, I think that sums it up pretty well. I guess one of the other, I think, really important things from perhaps a slightly more theoretical point of view, David,

is that the features, supposed features of NMS, and they're not really very well defined, the supposed features are not features associated with the normal use of the drug, and secondly, they're not dose-dependent, and thirdly, they don't bear a time relationship between the initiation or increase of the drug and the development of symptoms. Now, all of those things make you wonder, well, what on earth's going on there? If those criteria aren't met, what exactly is the cause-effect relationship between the administration of the drug and the appearance of this rather ill-defined syndrome? And that contrast quite dramatically with serotonin toxicity, where the symptoms come on highly predictably within an hour or two of taking particular combinations of drugs. And that's what led Professor White and I to say many, many years ago, chalk and cheese.

I believe I'm correct in saying that Ian once said to me that if his resident couldn't make the differential diagnosis standing in the door at the end of the ward, then he probably wouldn't get a job on his service. That's good. Yeah. So neuroleptic malignant syndrome, one other thing I think is that, It's not hyperkinesia. It's Bradykinesia. Indeed.

That is exactly a fundamental difference. NMS is to do with bradiphrinia and bradykinesia, whereas serotonin toxicity is the opposite. Yeah. diametrically opposed. Okay, Alex. Tell us about Libby Zion and our beautiful work hours. Okay, yeah, definitely.

So this Libby Zion, very famous medical case malpractice. So in the 1980s, there was this 18, 19-year-old female named Libby Zion. And she presented to New York Hospital. It's kind of unclear why she presented. But there was a major fallout from this and involved serotonin toxicity, and this is why we have the resident work hours that we do now. So basically, she presented to the hospital with some unknown flu-like. illness. And the doctors really weren't sure what was going on. There was an intern, a second year, and an attending, I believe. So they ended up giving her Maparidine, which is an opioid

medication. And at the time, they weren't aware that myperidine is actually a serotonin re-uptake inhibitor. And she was on an MAOI at the time, phenylene. And that precipitated serotonin toxicity. So she ended up getting a temperature, I think, of 107 and going up into cardiac arrest and dying. And because of her death, her parents were obviously distraught. Her father, Sydney, was a famous lawyer and a journalist for the New York Times, so all hell was raised. And these residents were basically dragged through the mud. They were sued, I believe. And through that, there was a commission that was created.

and now we have the 80-hour work week as well as 24-hour shifts instead of 36 hours. Can I add a subtle twist to that story, which was never recognized? I actually spoke to the doctor in charge of that inquiry. I won't make any comment about what I thought of him, but he obviously didn't know much about pharmacology. Because the other drug that had been given to that lady, Do you realize what the other drug was, Alex, that was in fact serotonomy uptake inhibitor, but nobody even realized? No, I've never heard about that.

Oh, right. Well, this is back to the history of psychopharmacology. What was the first SSRI on the market? Your starter for 10. Not Prozac is the answer. The first one was developed in Europe. It was called Zimeladine. It was developed years before. Prozac, and it was taken off the market after a couple of years because it precipitated Guillain-Barre syndrome.

I remember using it when I was in my early career in London, and that was developed from the nucleus of chlorfeneramine, sometimes called chlorfenamine now, which is, of course, the supposedly anti-histamine that's in the over-the-counter medicine that goes by various names, I'm sure, but Avil is one of them, I believe. And it's actually quite a potent serotonal optic inhibitor, which is why Arvid Carlson, who got the Nobel Prize for Medicine in 2000, used it as the skeleton for developing Zimelodyn. So there you are. History comes full circle. and she had taken Avil. I can't remember how much, and nobody even realized that that, in fact, that was actually

more likely to have caused, if it was serotonian toxicity, which it probably was. I analysed the case years ago, and I can't remember what I said about it, but I think it probably was serotonin toxicity. But that's much more potent as a serotonary uptake inhibitor than myperidine, which is actually quite weak. I mean, you know, to be honest, you could give, you know, 20 patients a standard dose of myperidine if they were on an MAI, and you probably wouldn't get into trouble. It would only be one in 10 or one in 20 times that somebody developed a high enough blood level to cause, you know, a major problem, or if you gave repeated high doses or something.

So it really is a pretty weak serotonary uptake inhibitor. Best to avoid it, but it is pretty weak. Hmm. That's good. That's like, uh, uh, uh, yeah. Well, you know, as I hear this story, you know, I can understand why the father was so upset. And, um, you know, I think we can critique the potential cause of the death, but the death is horrible. I mean, who, like, who, it's just absolutely, indeed. Absolutely horrible. And you know, it is probably also not healthy to have people work too much. I remember... Oh, for sure. I remember the work hour change happened, I think after I went through my intern year sometime. And I remember just days where I was, it was brutal. I was actually invited to be part of a study. There was a military group. that was doing like a study on sleep deprivation. And they did cognitive tests before and after a 30-hour shift. And I remember going in there, and I was trying my hardest, and I knew that I was not doing this very well.

And so, yeah, I think there's a, I remember they used to say, well, but it's so good when you admit that patient in the middle of the night to be able to follow them, you know, for extended period of time because you know their case so well, you know? And it was kind of the justification for making us work these super long shifts. And we were, yeah, willing subjects. So, or unwilling subjects that had to get through to get to the next step, right? So, I don't know, maybe there's meaning beyond, you know, maybe an incorrect reason.

for the hour issue. I don't know. Is that what you were thinking? Oh, yeah. I mean, definitely. I kind of glossed over how much the residents were working. I mean, they, you know, they basically lived at the hospital. And the word resident comes from, you know, residents actually residing at the hospital back in the day. Yeah. Yeah. So, okay, let's talk about management of serotonin syndrome. I know we talked briefly about it. Now, in the paper that you have put together, you mentioned that there's a couple 5H2A antagonists that may be useful, but then I'm hearing Dr. Gilman earlier saying that they're kind of leaning away from doing that.

So Dr. Gilman, help me out here. I think you've summarized it. What I said earlier was that the toxicologists, who specialize in treating these people, if they have to be transferred to intensive care, strive to avoid giving specific anecdotes because it just complicates the issue. If people are already poisoned with drugs,

you don't want to give them more drugs unless there's some very, very specific reason. I think Professor White said to me a year or two ago before he retired that they hadn't given a specific antidote I was going to say anecdote, specific anecdote, an anecdote about an antidote, to somebody with ST-type symptoms for a long time. Okay. But maybe some Ativan to calm them down.

Yeah, large cases of benzodiazepines. I'm not sure what their favorite one is. Is it Medeza Lam or Loraisopam or one or the other or both? I don't know. Yeah, so going back to that case when I was an intern, they ended up calling poison control and I inherited this patient and yeah fluids and lorazepam okay that's good is there um like a 24 hour phone call you can call if you feel like you have a serotonin syndrome or like how did you know just general poison control uh yes i believe yeah in the united states you can call um poison

control and speak to a medical toxicologist yeah so if you're listening to this trying to figure out what to do. You can phone an expert, I guess. Yeah, so any other sort of big points that we haven't talked about that you wanted to talk about, Dr. Gilman? I think you've covered a lot of stuff. I mean, one could make all sorts of general points about the factors that influence medical practice

and the administration of drugs and things like that, but I think that's another discussion really, isn't it? No, I think we've covered a lot of very important things. Well, I suppose we could mention NMDA just very briefly because, of course, that's starting to come into therapeutic use. And early in this talk, I mentioned that in usual therapeutic practice, but of course usual therapeutic practice is changing. And MDMA and psilocybin, I think they're just about to be approved in Australia.

So let's mention very briefly the serotonin toxicity triangle, which I dreamed up some years ago, to illustrate the point that the combination of an MAOI and a serotonin reuptake inhibitor, whether it's specific or non-specific, is they're going to have a pharmacodynamic interaction and much multiply the end result of increase in introsynaptic serotonin. But if you give a serotonin re-uptake inhibitor in combination with MDMA, you will actually attenuate its effect. Because, of course, just like tyramine precipitating the blood pressure reaction with MAOIs, MDMA has to get into the presynaptic neuron first before it can release serotonin. And if you take a serotonin reuptych inhibitor, it utilizes the cert to do that.

So you block that. So you reduce or completely stop the MDMA getting into the presynaptic neuron. But if you combine it with an MAOI, then that's a serious. potentially fatal, what there are definite fatalities with that combination. Because you don't see it as often because most doctors don't use the old MMOIs. The newer MAAIs like the reversible maclobamide, which has been fairly widely used in Europe, will precipitate fatal serotonin toxicity if you combine it with MDMA. And likewise, what's the other thing I was going to say? Cilocybin, LSD.

No, no, no, not psilocybin, because that's not a releaser. So that reaction is a releaser and an MAOI is fatal. You guys don't really have in North America maclobomide, except the Canadians and the Mexicans do. But some people in America do get a hold of maclobamide, so it's important for people in North America to know that maclobamide and ecstasy is a fatal mixture, potentially fatal.

I've certainly seen several cases where people have died as a result of taking that. Anything about psilocybin or LSD? No, I think Alex has already said something about that. And obviously, we're waiting on more data, so you wouldn't want to be too dogmatic about it. But, you know, our basic knowledge of pharmacology and the mechanisms and all the other basic research that we have heard to earlier in our talk

would strongly suggest that it's highly unlikely. going to have any effect because it doesn't cause any of those things in normal usage. And after 50 years of however relatively infrequent, the co-administration of M-AIs and LSD has been, there isn't a single case report or report of any sort in the last 50 years of serotonin toxicity with that combination. I suppose as a last interesting twist, we could mention that this perhaps relates to this phenomenon agonist directed signaling? Do people talk about that much? It's a very interesting phenomenon which seems to me not to perhaps have achieved quite as much prominence in

clinical space as it might have done. But of course, it's now evident that agonists that stimulate a particular receptor like the 2A receptor can elicit different downstream effects, even though they appear to be acting via the same receptor. Now, that presumably must be the explanation for why psilocybin LSD don't appear to precipitate hypothermia if you give them with an MAI. So that's another aspect of how knowledge of serotonian toxicity in its mechanisms can tell us something about how these drugs are working and what they're doing. And the fact that LSD doesn't seem to precipitate, and that's a fairly reliable statement,

I think, with the data we've got. You know, when I was looking at this, I was looking up articles earlier on LSD and serotonin syndrome, and I found this one, and I'm wondering if you guys have seen this, prolonged LSD induced serotonin syndrome. It's an article from 2019. And it said, introduction, serotonin syndrome is a life-threatening condition that may be often be, Difficult to diagnose. La la la. And then there's severe cases often require. Okay, so then it goes through case presentation.

So let's see here. It's a 28-year-old male visiting Europe with unknown medical history brought to the hospital after sudden onset, diaphoresis agitation confusion at a restaurant. he presented with status epileptus, with combative behavior leading to intubation, sedation, and paralysis, seizure control required multiple agents. Initial objective data revealed no electrolyte or metabolic abnormalities, negative toxicology, imaging a brain, an infectious workup was unremarkable within hours. The patient became hyperthermic and hypertensive.

Pernan exam findings include clonis and hyperreflexia, based on the find in serotonin syndrome versus sympathenomatic toxicity were the highest in the differential diagnosis. Treatment with Cyproheptidine was initiated. The hospital course was prolonged and complicated with aspiration pneumonia. Deep vein thrombosis, prolonged delirium, high amounts of fentanyl propofal were required to maintain adequate sedation. The patient remained hypertensive, febrile, signs of hyperreflexia and colonis for seven days. Fencell was discontinued due to the potential serotonergic additive effects. Rapid clinical signs of improvement were observed. It was ultimately discovered the patient was using

LSD. So there's a couple things going on here. One is the use of the LSD. We don't really know if this was LSD and there are often many things which mimic it. And another, thing that I would point out is that this lasted for seven days. I mean, this is obviously a very severe reaction, but it does not sound like serotonin toxicity to me. And I feel like something else is going on, especially with the seizures in seven days of clonis. If you withdrew the drug within a couple of days, the symptoms should go away. So that tells you that this probably is not. Or even quicker than that. Look, my comment would be, it'd be jolly interesting for a sort of journal club

presentation discussion to discuss this paper. But the bottom line is, one swallow does not a summer make. You know, you can't draw any reliable conclusion from one case report, especially when, as Alex has pointed out, it really is very atypical. And the way it presented doesn't look like serotonin toxicity, which takes us back to what we were discussing before, which is that it's not research diagnostic criteria that make the diagnosis. It's the overall presentation and the agents that have been used, which makes the diagnosis. So what were the other medications he was supposed to be on when he came into hospital? Is it just LSD? Just LSD or something, yeah. And then the other thing that was interesting was they gave him fentanyl and propofal. But I think my question is,

Like how long would, and I think you make a good point, like how long would LSD even exist in your body at a level that would cause the issues? So LSD, you can give, you know, typically a dose of LSD is in the micrograms, I believe, about 100 micrograms. And, you know, they've given elephants massive doses of LSD and, you know, tried to kill them. And I think that they ended up killing an elephant, but it's because of the, the medical. that they gave it to save it, ironically enough. So you can't overdose from LSD is what I'm saying. Oh, right. So this is not LSD.

You know, there's something else is going on. This is a different drug. Whoever was synthesizing it, you know, this, they messed up. I don't know. Exactly. Have you read Poisoner-in-Chief by Stephen Kisner. He talks about how L. LSD was used by the CIA.

Because it sounds like they were giving some pretty heavy doses to some people, and some people ended up not doing well. Yeah, Project MK Ultra. Yeah, for mind control. Yeah. You know, so I think your point is, that's probably the strongest, is like, look, this went on for seven days, something else was going on because it doesn't make sense that LSD would stay in a system that long

or cause such an issue. like so i think that's a good point and and i think your your point dr gilman is that one case report doesn't lead to how you're going to practice medicine or you know how you're going to fear you know are we going to fear something from just one case report no but it can spike our curiosity right indeed yeah and providing it's intense with the proper knowledge of the basic pharmacology, etc., etc., it can be very instructive. I mean, there have been instances in the past when I've been consulted about a case of somebody who's taken an overdose, and I've said to the doctor, well, the symptoms you're describing couldn't

possibly have occurred with a serotonary uptake inhibitor. So you need to go back to the patient's medicine cupboard or question them and find out whether, in fact, they also had a monoaminoxidase inhibitor. And people have come back to me and said, yep, the patient had maclobamide in their bedroom cupboard, and they admitted on questioning that they had taken it. And of course, the toxicology tests, I mean, they just say toxicology was negative,

but we don't know what methodology was used, how sensitive it was, what it was capable of picking up. So as a statement without qualification, I don't think that's very reliable, is it, Alex? Right. Yep. Very good. Well, any final thoughts, Alex, that you want to say before we wrap this thing up? No, I mean, I just think that there's a lot of stuff here. And if your listeners have made it this far, congratulations. It's a dense topic, but I think it's super important. And I just want to say thank you so much for having me on the podcast. This is awesome. I'm a big fan. Well, I appreciate it, and this handout is truly excellent. I've got into chat GPT, and I ask it to summarize articles for me. And it's pretty lousy at it compared to this. It can do like a very sort of cursory. And sometimes it creates citations and sometimes it creates quotations and sometimes it creates quotes that the person never said.

It's really interesting, but I imagine 20 iterations from now, it'll be up to your level, Alex. But until then, your summary is fantastic. And Dr. Gilman, I appreciate your years of expertise, your curiosity. And, you know, we want to keep, part of my goal of the podcast is to keep people like yourself who have decades and decades of both clinical knowledge and, research, expertise, and keep their information for the next generations so that we don't lose all of the knowledge, you know, and we keep moving forward. So I appreciate you coming on. Thank you. And I hope we've generated some understanding of this complex but not complicated topic in our listeners. And I agreed to participate in this because, as you said, David,

The summary that Alex sent me when he asked me if I'd be interested in participating was so excellent. I thought, yes, I'd be very pleased to participate with somebody who obviously had such a fine ability to critically analyze the data and come to a sensible view of it, which not everybody is able to do, as all of these spurious publications illustrate. And also, of course, further information that our listeners might like to know. know, is available on Psychotropical, where there's quite a large section on serotonin toxicity, which analyzes some of the less satisfactory reports that have been published. Okay, we will put that in the show notes and or in the article that we summarize. And we'll ask you to read over that article, Dr. Gilman to be a part of that.

Alex would be the first author, of course. And yeah, thank you guys for coming on. I really appreciate it.