Ergotism: From Medieval Plague to Modern Medicine

One Health And Today’s Topic

SPEAKER_02 0:09

This is a podcast about OneHealt. The idea that the health of humans, animals, plants, and the environment that we all share are intrinsically linked. Coming to you from a team of scientists, physicians, and veterinarians, this is Infectious Science. Where enthusiasm for science is contagious. All right. Hello everyone. Welcome back to this episode of Infectious Science. I'm one of your co-hosts, Camille, and I'm joined by Christina today. Hello, hello. So we're going to dive into a pretty cool topic. We're going to be talking about ergoteism. And originally when we started this topic and I suggested it to the team, I was thinking about the salmon wish trials. But it turns out that there is some scholarship saying, like, oh, you know, the salmon witch trials might have been caused by an outbreak of ergoism. And that's not actually true, which I think is really interesting. So fun myth busting to start this. But there are some really fascinating aspects about this. And so I still wanted to dive into it. I still think it's a super worthy episode. And I still think it's pretty neat because there's always this sort of what's the difference between medicine and poison? And a lot of times it's the dose. And that really applies here. So we're gonna just set this up. There's when you have something like a really cold, wet winter followed by a really long spring, sometimes that gave rise to outbreaks, particularly in the Middle Ages in Europe. It was really common. And these really haunted the populace, right? Whole families would experience burning sensations followed by gangrene, or end up having convulsions, hallucinations. And the cause of this was basically having grains that were contaminated with a fungi. And it's a type of basically poisoning. It's caused by eating grains that are contaminated with the asymite fungus, Perfora. And the infection of the plants eventually leads to issues with the health of the human population. So it's a very one-healthy topic, very infectious science kind of focused. But what's also interesting, we're going to talk about too a bit, is that as much as there have been these kind of epidemics of ergot poisoning, there's also been a lot of instances where they might have been used by midwives medicinally. And there's records of that as early as the 1500s. And we also have records describing basically ergots dating way, way back further than that, which is pretty neat. That's my favorite topic. We're gonna talk about fungi. And we're gonna talk about how the difference between poison and medicine is always the dose. So if you're interested in any of that, keep listening. Okay.

How Ergot Infects Rye

SPEAKER_02 2:48

First off, I should say what really got me into this was this really cool article. It was for the American Society of Microbiology. It's by Dr. Ada Hagen writing about ergotism. And this is a direct quote because I think it's just so well said about the unique lifestyle of this. So just kind of to set up what this looks like. So, particularly in a lot of times, rye was the cause or the grain that people were consuming that they were then getting the poisoning from. And that's because it's a really robust grain. It can withstand colder temperatures, poorer soils a lot better than other grains. It's frequently planted in the fall and it grows slowly over the cold months. And once spring comes, that rye can grow pretty quickly, flower, ripen in the early fall. And then the airborne fungi spores infect the grain's flowers and they produce this sugary yellow slime. It contains additional spores and it attracts insects to it, and that sort of facilitates the transmission of the fungi to other nearby rye flowers. So it's like they're using the insects to spread it, which is interesting. Yeah. And then instead of turning to grain, that flower is actually replaced by hard ergot or spur. And that can fall to the ground. It's pretty sturdy exterior, it can protect the fungus throughout the winter. And then the spring, mushrooms will sprout from that and release spores to infect another round of crops. So this perfect little life cycle, right? If you have the right conditions for it, it springs up. And that's something we've talked about before with different fungi. But of course, once those plants are harvested, humans are at risk of injecting the air routes, which contain alkaloids. So you probably know more than I do about alkaloids or seeing that being in med school. So I'll talk a little bit about it and I'll throw it to you on this. Are you familiar with the concept of like terroir regarding wines? It's this idea that the climate and the soil and the agricultural practices will all affect like the taste of the wine that you're drinking. And what's interesting is that there's basically a terroir of gods and different strains that are grown in different soils will produce different alkaloids. So they've become these particular little alkaloid cocktails that are unique to that region, that soil type, that particular season, which I think is very interesting. Instead of alcohol, it's drugs. So yeah, but I thought that was pretty cool. And of course, alkaloids are really well known to us as having really powerful and unique effects on our bodies. And really common alkaloids, you include things like nicotine and morphine. And so a lot of times these are things that are naturally occurring in plants that we have then maybe taken out particular compounds that we use medicinally, or that in some cases people just use them to get high, right? And

Alkaloids And Regional Variation

SPEAKER_02 5:30

so that's kind of been what alkaloids are. And what's interesting is that until to date, researchers have actually isolated over 40 alkaloids from the fungi that cause ergotism, which I think is really unique. So yeah, I just thought that was super cool that there's this production.

SPEAKER_03 5:46

Yeah. And it's amazing how diverse these alkaloids are and the diversity that we can get from these this one family, the ergots. That's just so interesting. It always fascinates me how just efficient nature is.

SPEAKER_02 6:01

Yeah, but you can also see that if someone was trying to use them as medicine, what worked in one region might not work in another region, right? Because you might have like a totally different drug realistic.

SPEAKER_03 6:13

Exactly. And realistically, you really have you don't have that much control over what you're using because you back then I'm sure they thought, oh, this always leads to this. But if you can get such a diverse array of medications or derivative of medications from just one family, you probably don't really know what you're working with until you know how to look at that under the microscope and break that down.

SPEAKER_02 6:35

Yeah. And I think that one, that's really fascinating for us to look back on, but two, it also explains why it took us a while to really understand what was causing these basically poisonings, because they could present very differently depending on the composition of the alkaloids that was being produced that season or in that region. So, you know, sometimes outbreaks of ergotism, they were varying based on geographic location, right? So you could have places that were more western, they might have been like more gangrenous, and then outbreaks in the east that were more convulsive. And that's just looking at one region in France. If you look at these different outbreaks, they presented very differently. And what's interesting is that um ergotism is typically one or the other. So it either causes gangrene or it causes convulsions and hallucinations and that kind of thing. It's usually not both, though.

SPEAKER_03 7:22

That's so interesting. I can imagine that there's something in the difference between the two that allows these alkaloids, these derivatives to cross that blood-brain barrier. And that's

Two Faces Of Ergotism Symptoms

SPEAKER_03 7:35

probably what causes the difference in the presentation. Or at least one thing that might.

SPEAKER_02 7:39

Yeah. And I think what's really cool jumping off that, we do use some basically semi-synthetic compounds today in medicine that are derived from ergots, which I think is pretty neat. And the reason we do that is because they're serotonin agonists, right? And a pretty common one is dihydroergotamine, which is a semi-synthetic derivative of a naturally occurring alkaloid from ergots, and it's used to treat migraines. And that's because it binds to serotonin receptors in the spinal cord. And that could be a site where if you have too much of it, the poisoning aspect in actual ergotism could cause those kind of changes where you see convulsive ergotism. But if people nowadays are using that and they have too much of it, it can cause serotonin syndrome, which is when you just have way too much serotonin in your body, but it's super, super dangerous. And I honestly only really came across it when I was looking up this episode. You might know way more than I do about serotonin syndrome, or it might even be something you all watch for depending on what patients are receiving for medications.

SPEAKER_03 8:38

Yeah, definitely. It's definitely a major complication that we're taught, at least specifically in our psychiatric rotations, since a lot of medications that are used to treat anxiety and depression, OCD, and just anxieties in general are actually serotonin receptor inhibitors. So those lead to this large buildup essentially of serotonin in the body sometimes, and that can cause serotonin syndrome, which can be pretty scary. Absolutely.

SPEAKER_02 9:05

Yeah, yeah. I do want to note though, I would say that for listeners, when taken as directed, it's not a common complication by any means. It's when it's multiple things.

SPEAKER_03 9:16

Absolutely. And also that's why it's always so important to be taking medications under the supervision of a physician, because that's those act are actively things that we are monitoring for, looking out for. That's why we're always asking you if you have any side effects, any symptoms that you don't like, because we always have that running in the back of our mind. Yeah.

SPEAKER_02 9:36

Or that's why, like when the nurse asks you what medications you're on and the doctor confirms it, just go with it. Verify it to be super

Modern Medicine And Serotonin Risk

SPEAKER_02 9:45

sure that we're always looking for contraindications and stuff, or just what might we be potentially giving to someone when they're already on something that we don't want to mix those things. So yeah. Yeah, I agree. Yeah, but anyways, to kind of get back into poison, right? Our topic of the day. Um so I found this really interesting paper, and it's got such a cool title. It's so much cooler than any technical publication I've ever put out. The title was Ergot from Witchcraft to Biotechnology. And I just think that's such a cool title.

SPEAKER_03 10:18

We have to find a way to get you to publish a paper with the word witchcraft in it or something like that.

SPEAKER_02 10:25

Just something that just has a Halloween kind of tone.

SPEAKER_03 10:28

Yes, I feel like you deserve that.

SPEAKER_02 10:31

And I thought that was just the perfect title for a paper. But they also talked about how the first really well-documented epidemic was AD 944 to 945, and about 20,000 people living in Paris and in that region of France died of erbot poisoning, which doesn't sound much. 20,000 today does not sound like a lot of people, sadly. I think we're kind of numbed out to numbers and casualties. But this was at the time about one half of the population there. So you can just imagine how devastating this was to a region where maybe you had these really cold, ugly, wet winters, and then you had this long damp spring, things weren't growing well. You have a harvest, you bring it in, and then people start getting really sick and people start dying. And you could see how this also definitely ended up with this wrathful overtone because it was just sweeping. All of these people would get really sick. And also at the time, even nowadays, those are scary symptoms, right? To have gangrene without cause or to have convulsions seemingly with no cause. But then when there wasn't a treatment, it suddenly just if you can imagine everyone in a town getting really ill. Yeah. Yeah, yeah. And so you can see why those theories were popular. So yeah, so I think that's just something to kind of keep in mind. And also, I think it's really interesting that the reason it it affected people the way it did, a lot of times with these hallucinations or like these really wide-ranging effects, was because of how it was interacting with our hormone receptors. But also, if you're wondering like how it was causing gangrene, which I was kind of like, how is this occurring? It actually causes something called dry gangrene. And that's because it would basically result in the contraction of smooth muscles that are lining your internal organs. And though that includes things like your arteries, and that resulted in arterial constriction, it slowed the blood flow and then deprived of blood and the oxygen it brings, that tissue dies. And so it becomes as a dry gangrene, is what it's called.

SPEAKER_03 12:36

Yeah. And the reason you typically see dry gangrene and things that are similar to that in your distal, your extremities, so your fingers, your toes, and stuff like that is because when you get that far away from the central area of your circulatory system, so the heart, that's where your arterioles and your capillaries and everything get really small. And so any little change in the radius or the diameter of those pipes essentially makes a really big difference and really decreases the blood flow to those areas. And when you decrease blood flow, you have death, unfortunately, of a lot of tissues.

SPEAKER_02 13:09

Yeah, I think that's a great addition to that and a good visual of exactly what's happening, right? You can't just keep constricting the hoses that are running down your body, right? Exactly. And that's really it's what it comes down to. And so it's just interesting because I feel like it's worth explaining because it's not what we typically think of when we think of gangrene, right?

Medieval Epidemics And Mass Fear

SPEAKER_02 13:30

I think most people think of gangrene as someone had frostbite or they had the wound, and then it gets really infected, and there's the death of tissue and things like that, and this is quite different.

SPEAKER_04 13:38

Yeah.

SPEAKER_02 13:39

So to kind of shift from this, it's also been used as a medicine, right? And I thought that was really interesting. We've talked a lot about like the poisoning aspect of it, but I also want to get into the fact that while that was certainly something that frightened people, it also seems that as early as the 1500s, people at least sort of knew that ergoths could cause certain effects. And I think that's really interesting. So it's it was used as a medicine, albeit a very imperfect one, because as we talked about, the region and the season could basically change what kind of alkaloid cocktail was going to be present. But also the aspect of how are we knowing how much is in an ergot, right? We don't know exactly what's in it, and we also don't know how much of a certain compound that causes an effect that we're interested in might be in that. So because it's a natural substance, right? And so, but what's interesting is that apparently in the 1500s, an observation was made that pregnant pigs that were fed ergots went to premature labor. And I think this is really fascinating, uh, again, from a one health perspective, that someone was making an observation of animals that they were around, and enough to link it to what they saw happening, and then think about how different am I from what would happen if a human had this or whatever. Yeah. And so in people, we have records that following this observation, ergot was used by midwives to aid in birth. There's a 1582 prescription to ingest three intact ergots that were collected directly from the field. And so that

Why Ergot Causes Dry Gangrene

SPEAKER_02 15:12

likely contains enough acolytes to cause symptoms of ergotism. But individuals were only receiving the dose around active labor. It wasn't a prolonged, this is what you're eating because this is all you have to eat. So it would potentially have the effect that they were looking for, like if someone was really struggling in labor. And what I think is interesting about that is that this ASM article that I keep mentioning, that particular dose was shown to probably contain about 0.5 milligrams of the active alkaloid ergometrine, which was actually later used by OBGYNs up until the 1970s that was actually used around labor and delivery, which I think is really interesting. Of course, I'm assuming we're not getting that straight from our gut because then we're making a synthetic of it. But it's something that I just I always think is something that's very interesting. That we often had a very imperfect version of it, and it continued to be an imperfect version of it. And now, of course, we have a lot safer drugs to use on labor and delivery, but ergometrine is actually still used to prevent bleeding after delivery. And why is that? As you said earlier, it's basically constricting the blood vessels. And so that can really prevent maternal mortality, right? If someone has extensive bleeding after giving birth, they're at risk of potentially losing a mass amount of blood, going into shock, having major complications. But if you can stop that bleeding, they're much more likely to survive and thrive later on.

SPEAKER_03 16:39

Yeah, absolutely. That's so interesting. It's definitely

Midwives And Labor Uses

SPEAKER_03 16:43

not one of the main medications that we're taught about. But if there's a plan A for things in medicine, there is always also a plan B, C, D, E, F. And so it's like, I would not doubt that it is one of those plans. Yeah. Um and that's just so interesting to me that something from A D whatever is still around to this day. So that's incredible.

SPEAKER_02 17:03

Yeah. And speaking of AD, so there's definitely even earlier references to um ergots in human history. So one paper in molecular plant pathology, which just sounds like the coolest journal, states that there's actually a really early reference to Ergotten history, a description of an Assyrian tablet in 600 BC, referred to it as a noxious muscule in the ear of grain. So clearly, someone was mad that this was in the grain that they had taken all this time to sow and then to then harvest. So obviously, somebody was not impressed. Some farmer was like, this is a noxious muscule. So I just thought that was that was great language. But in around 350 BC, descriptions of noxious grasses that cause pregnant women to drop the womb and die in childbed existed. And that was likely referring to ergots, right? And so you can imagine that if something is being used around labor, if someone had basically stalled in delivery and they were not able to actually deliver and give birth, you could see how something that would help them along with contractions. But you could also see where if someone had taken this and they were much earlier on, it could also kind of act as an abertifacing, right? So it's interesting that that knowledge also existed as early as something like 350 BC. I just find it all really fascinating to think about. But I also do kind of want to bring us to a close with a really interesting alkaloid that is probably the most famous one as a semi-synthetic ergot alkaloid. It was accidentally first synthesized by Albert Hoffman in 1938. And today it's the most potent hallucinogenic known. I feel like I set you up with a jeopardy question there. What do you think the most potent hallucinogenic known is that is a semi-synthetic ergot alkaloid? What do we think?

SPEAKER_03 18:51

Some kind of opioid. Are you familiar with the needles? Lucy in the sky with diamonds. I don't know what drug that was, though.

SPEAKER_02 18:57

LSD. LSD. Oh, okay. Oh yeah.

unknown 19:02

Yeah.

SPEAKER_02 19:03

And an opioid. Yeah, which I just think is fascinating. That's also from ergots, right? Plants produce all of these alkaloids, and in so many cases, humans either use them medically or use them recreationally or whatever that looks like. But there's just so much to it, and I think that's really interesting. And I I always love to return to this idea that a lot of things can be medicine until there's too much, and then it becomes poison. And I think, you know, to me, that just speaks to how delicate the balance is in our body and in this kind of ecology of the self.

SPEAKER_03 19:37

Yeah, no, it's so true though. And it's really amazing when you think about it. And I think that is also a reason why medical training in itself, and I'm sure pharmaceutical training in itself for pharmacists

Ancient Records And Early Warnings

SPEAKER_03 19:50

and obviously for researchers and scientists, like why our training is so long, is because it really does boil down to those tiny little details. And when something is off by just the smallest little increment, that can really mean life or death. It can mean right or wrong scientific outcomes. It can mean the right medication or something that's potentially lethal. And I think that's something that's beautiful about nature, and it's something that's beautiful about us when we are a part of nature.

SPEAKER_02 20:17

So yeah, it's amazing. I think it is really cool. It makes me think of this book I read last year called The Light Eaters. I think I've I might have brought it up before on a previous episode. I think we talked about it. Yeah, but this idea that plants existed way before we did on an evolutionary timescale. And so if you think about it, a lot of the compounds that plants produce are meant to basically induce certain behaviors in other creatures, whether that's an insect or the mammal, and maybe even in us. We don't really know. Yeah, honestly. And we've got no way to really tease that out. And I'm sure it's probably a contentious thing in the plant science field, but I think it's a really interesting question that kind of deserves more of an answer because a lot of times, like I don't think things are just produced in nature always for the sake of it, right? Like they have a purpose. Like caffeine, for those of you who don't know, is a pesticide, right? It's meant to keep the bugs off the plant. And then humans came along and we're way bigger than bugs. And so we're like, wow, this is nice awake. This is a good alert feeling. This is great. And so now we cultivate them specifically for caffeine. So think of that next time you have a cup of coffee. It's your daily cup of pesticide. Yeah. It's a natural pesticide, but it's still a pesticide.

SPEAKER_03 21:26

A mug that has that on it. This is my daily cup of pesticides. Yeah. Yeah.

SPEAKER_02 21:31

Just I just I want you to bring that to your next rounds or whatever.

SPEAKER_03 21:34

Just send me your address. I'm gonna make us some mugs that say that.

SPEAKER_02 21:42

We'll have our special little podcast mugs.

LSD And The Poison-Medicine Line

SPEAKER_02 21:45

Exactly.

SPEAKER_03 21:46

Let us know, guys, listeners, if you guys want us to make that as merch. Yeah. That'll be our first merch item.

SPEAKER_02 21:52

First official merch item. Your daily basic pesticide right here in this mug. Yeah. Yeah. I think it's just so fascinating to think about that broader context and the the organizing aspect of that. So yeah, absolutely.

SPEAKER_03 22:08

I love to think of us on a systems level and how we interact with the rest of the world. Yeah.

SPEAKER_04 22:12

Yeah.

SPEAKER_03 22:13

I agree. It's really fascinating. And I know a lot of people will say we want to return to a more natural way of life or doing things more naturally. But realistically, so much of medicine comes from nature in itself. So much of the medications that we use and what we know is nature derived. And it's totally fascinating. And I just wish more people knew about the origins of medicine and the things that we do now.

SPEAKER_02 22:40

And I think too, like a lot of times, again, going back to using something in its natural form that has not been purified or that it might have other cocktails of chemicals that you don't want is a lot more dangerous, right? And I think that's something that I think about a lot of times that in many ways, the reason something is now packaged in a pill bottle instead of, you know, go pick this or go forage this is because we can control for the toxicity of it, right? And have more of that kind of management, right? And it's not to say that you can't drink your coffee and have your daily dose of pesticide or whatever. But it's just to say that I think there is this kind of idea that's been lost that, oh, like you've grounded up and put it in a pill and now we're charging so much for it. And well, there's issues with that, right? It's not a perfect system that everyone can access. I do think the reason in many ways that it started was as a way to keep people safe, right? And to protect from the detrimental aspect when you don't always know what you're getting, right? So you could take way back in the 1500s three ergots from a field, or in the 1970s, if someone was really bleeding, they could get a perfectly tailored dose, yeah. Yeah, um of this particular medicine to prevent that. And I think that that is something that also really matters to keep out the contaminants and toxicity of it, too.

SPEAKER_03 24:04

So this is really fascinating. This is really cool. I know we love talking about fungus on

Nature-Derived Drugs And Coffee Pesticide

SPEAKER_03 24:10

this show. And it's a great example of how interesting fungus is. The fungus among us. The fungus among us. Something I was thinking about while we were talking about this was other things that have been incredibly detrimental or are just like historic landmarks in our history that are caused by funguses and stuff like that. And one of the ones that I was thinking of while we were talking was the potato famine. So I'm pretty sure that was due to some kind of fungal infection within the potatoes. That might be something to talk about as well in the future.

SPEAKER_02 24:42

Oh, yeah, that's a really good point. I think there's so much to it of, again, one health, right? Like you can't tease out plant health without talking about human health, and you can't look at human health without thinking about the environment. And I think this was a really good case study on that, right? The seasons affected what was happening on the infection cycle with plants, which affected people. And so I think that there's so many examples of this, right? This is not just a kind of a category that was just made up, it's a very, very real phenomenon. So yeah, I agree. Cool. Well, that's all I had for today. Thanks. Great getting to talk with you again. Yes. All right. Thanks everyone for joining us on this episode of Infectious Science. As always, let us know what you want to hear. We do take requests on topics. Let us know what your favorite fungus is. If you think there's any. Yeah. Let us know you want our pesticide mugs.

SPEAKER_03 25:39

That's awesome.

SPEAKER_01 25:41

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