Ergot: The Fungi & The Alkaloids
Ergot describes a group of fungi with powerful alkaloids. So powerful, that they have historical impact in history, medicine, and possibly religion. It's famous for the morbid poisoning in humans, for catalyzing the synthesis of LSD, and its potential role in ancient ceremony. Today we are honored to speak with Dr. Daniel Panaccione, who is one of few ergot alkaloid specialists. Having studied their biosynthesis and genetics, he is a true expert on their chemical matters.
Dr. Panaccione is a professor of plant and soil sciences at West Virginia University where he works on genetic manipulation and chemical analyses to understand underlying genes of ergot alkaloids and reconstruct its pathways.
- Defining Ergot species & their respective metabolites
- Life cycle of Claviceps purpurea and it's ecological roles
- How an ergot fungus may be behind the Salem Witch Trials and other historical events
- Synthesis of ergot alkaloid-based drugs and medicines
- Mechanisms of action with ergot alkaloids in the human body
- DEA regulation on ergot alkaloids and like compounds
- Evolution of ergot alkaloid producing fungi
- Potential and unlikely organisms that contain ergot alkaloids
- The inadvertent discovery of LSD
- Pharmacology of ergot alkaloids: challenges, history, methods and R&D
Dr. Panaccione's WVU profile: https://www.davis.wvu.edu/faculty-staff/directory/daniel-panaccione
Hamilton’s Pharmacopeia feat. Ergot and Dr. Panaccione: https://www.youtube.com/watch?v=7N4VoqeuK3s
Linnda Caporael's report on the Salem Witch Trials: https://www.pbs.org/wnet/secrets/witches-curse-interview/1502/
Growing Ergot: https://www.youtube.com/watch?v=BrKfF-G_Cug
Life Cycle of Ergot: https://www.apsnet.org/edcenter/disandpath/fungalasco/pdlessons/Pages/Ergot.aspx
Structure of Ergot Alkaloids: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480214/
Suggestive reports on Ergot in Sumerian Clay Tablets, Mesopotamian Temples, and Chinese literature: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1637017/
The Immortality Key — How ergot may be involved in religious influence: https://www.vox.com/vox-conversations-podcast/2021/3/4/21759683/christianity-psychedelics-brian-muraresku-the-immortality-key
Ergot as an ingredient in the Kykeon: http://www.psychedelic-library.org/paspali.htm
Downloadable literature: https://drive.google.com/drive/u/2/folders/1g64gVETsao2bC_cDK1QjBYbBW7Uu0iHQ
You're listening to the mushroom revival podcast.
Today's story is about a historical fungus. It's one of those species that radically impacted human life from possibly inciting which ones to influencing some of humanity's most legendary medicines
We're talking about ergot. And when we say Ergot, we especially mean the fungus claviceps purpurea. This fungus is considered to be a plant pathogen, although we will challenge that label later on that has a particular affinity for rye grasses, which is why Another common name is ergot of rye, but the word ergot can also refer to sister species or their respective metabolites known as ergot alkaloids,
And it's really the alkaloids of this fungus that made it so famous. So alkaloids are nitrogen containing compounds of botanical or fungal origin that have some physiological effect on humans to name a few are got contains lysergic acid, the main ingredient for synthesizing a surge ik acid, diethylamide, or LSD. And this is a big topic, so consider this episode a part one of two. Today we will highlight the fungus as a whole and next week we will dive deep into the LSD molecule.
Another notable compound with impressive action on the body includes er ghadimi, which in large quantities is a mycotoxin and was one of the compounds that cause the horrific side effects of ergot poisoning, but it's actually present in some pharmaceuticals to treat migraines. Other ergot alkaloids are used to make drugs like methyl ergometry, which primarily acts on the uterus and helps control postpartum bleeding and quickened childbirth.
We also find a more benign compound ergothioneine, which was discovered in 1909, and is a potent antioxidant Well, it was discovered in irga. The compound is found in many mushrooms with extra high concentrations in oyster mushrooms. Many of the alkaloids produced an earnout are found in opium and Bella Donna and other plant based poisons like strychnine. As frightening as these compounds are ergot alkaloids are amazing, their pharmacological power is vast and today we have the pleasure of speaking to an ergot alkaloid specialist.
My name is Dan Panaccione. I'm the Davis myco, professor of plant and Soil Sciences at West Virginia University. I guess one of the things that I always found interesting about fungi is the chemicals that make right because for the most part, the fungal world is invisible to us, until they do something that breaks through and crosses over into our realm and that might be producing mushrooms. And that's that's an exciting thing.
Who doesn't love to find mushrooms, but that chemical crossover of invisible action to our macroscopic world manifests in truly profound ways. And human beings specifically, are got fungi can cause intense effects like gangrene, where your appendages essentially die and fall off. It can influence the life or death of a fetus as it can both induce abortions or facilitate childbirth. And of course, ergo contains the compounds to create one of the most potent and life changing psychedelics.
So I got interested in trying to understand the genes involved in making different sorts of chemicals that fungi make. And when I came to West Virginia University, I became aware of a problem involving pasture grasses and symbiotic fungi in the genus abiquo that inhabit these pasture grasses can produce ergot alkaloids. So that was sort of the moment that I became interested in working in ergonomics, and I also had sort of a connection. Just looking at the structures of some of the organ alkaloids. I knew that some of the genes and enzymes I had studied previously, were likely to be involved in making that particular class of our good alkaloids and that, that I could use my the knowledge I had already gained on how to manipulate those genes to try and manipulate the ergot alkaloids.
So these alkaloids are dramatic, but the fungus itself looks like an unassuming little dark brown grain that grows from the stock of grasses and blends in with the berries, which partially explains the mass hysteria it caused in unlucky communities. The fungus is easily overlooked.
The fungus begins its life as a somewhat hopeless asko sport picked up into the wind successful spores will land on the ovary of a flowering plant, and hyphae initiate an infected, which results in masses of anamorphic spores. This then mixes with the syrupy fluid or honeydew from the host grass. At this stage, it attracts books which helps spread the fungus as it travels from flower to flower. And eventually, the fungus forms a sclerotia, known to some as the ergot body and is the overwintering stage where it patiently waits for springtime to produce stromata or the spore bearing body. These look like slimy burnt orange cap and stem mushrooms. And they are super tiny
and in this fungus his natural state the compounds we mentioned before are in unfavorable concentrations and can result in some severe side effects.
The ergot alkaloids can interact with several different neurotransmitter receptors, serotonin receptors, dopamine receptors, adrenaline receptors, and in some cases, they act as agonists meaning they enhance the activity of neurotransmitters. In other cases, they act as antagonists, meaning that block the regular narrow transmitters so they have a wide range of effects depending on the particular species or good alkaloid and the type of transmitters their neurotransmitter receptors are interacting with. We use ergot alkaloids for several purposes still up in list some drug names, most of these drug names are not things you will recognize I'm giving you like the generic names like cabergoline, nice circling pergolide bromocriptine hygain. Most of them are used for their vasoconstrictive properties or their visa relaxing properties. And a lot of them are used to treat dementia form that's caused by lack of blood flow. And so there are ways that relax it to allow more blood to flow to the brain. So certain forms of dementia, Lewy body dementia associated with Parkinson's disease. Other forms of seeing dementia are associated with lack of blood flow. And so the surrogate alkaloids, we wax blood vessels allow more blood to flow to the brain and Africans are quite effective that way. And also, migraines and cluster headaches sometimes can be relieved by either constricting or relaxing blood flow and allowing more blood to flow to the brain. So and then some of them are used because of their dopamine agonist affects the pituitary glands controls the amount of prolactin and so people sometimes suffer from hyperprolactinemia. Too much prolactin and they can't get pregnant, they can they can take some of these are good alkaloid dopamine agonists and temporarily reduce their prolactin output become pregnant and then go back off then they use for that purpose. And also there are some some pituitary tumors that can be treated with ergot alkaloids because they suppress the proactive production. So there have so many activities, but I think sometimes it's also a part of their curse as well as their their benefit is that people sometimes wish they were more targeted that instead of interacting with so many different receptors that they only interacted with one than then they might be more effective and have fewer side effects. And so those are some of the things we try to like modify them to see if we can change properties around 19 102. So Sandoz Corporation, and Switzerland began to really study the alkaloids and purify them. And that's where Albert Hoffman worked, who worked for Sandoz. And so he was, he was working on ergo ametrine, which is the the purified form of urban alkaloid that that's used in midwifery. But yeah, he was experimenting with various side groups when he when he synthesized LSD and accidentally dosed himself with it. And as we've all read the story about the bicycle ride, and then all the experiences he had based on that, and then he began looking at various other organoclay so
so that was a complete accident. He was not even looking to make anything like LSD. This was for midwifery, and totally had nothing to do with LSD. It's just stumbled upon it.
Unknown Speaker 9:08
Yeah, it's one of those things where Wow, yeah, I don't know. If you know, he is here to absorb that dose to his skin. So it must have he must have had a little bit sloppy with the chemicals to obtain that kind of dose just through absorption but uh, yeah, it's an interesting story for sure. And yeah, but then he had obviously the brilliant sensitive like, you know, go further and look for other things and, and, you know, develop LSD and then various other pharmaceuticals are developed.
Let's search like acid alone can cause mania and psychosis. Other alkaloids in the fungus can cause seizures, spasms, headaches, vomiting, and for medication, which is the sensation that you have insects crawling on your skin, morbid and ghastly symptoms like this maybe a play and the Salem witch trials. So there were a number of theories behind the Salem Witch Trials including sexual repression, or that it was fabricated as an excuse to compensate and redistribute land. But in 1970, a college student named Linda couple rail was assigned to write a term paper on American history. She chose the topic of the Salem witch trials, and not long after her eureka moment occurred.
During this era in Salem, Massachusetts, a staple food source was bread made out of rye grasses and victims of ergot poisoning experience many parallels with that of which behavior reports describe violent fits hallucinations, crawling skin, and doe eyed transas. The local doctor unable to pinpoint anything physically wrong, claimed witchcraft recall, the Salem Witch Trials happened in 1692. And if the parallels and symptoms weren't enough to convince you that ergot was to blame, Linda also wrote about the ecosystem that victims recited the accused mostly lived in West Salem, which is a marshy grassy area and a perfect breeding ground for her gut. She also noted that dry summers correlated with less witch hunts.
So could it be ergotism? And why did it seem like only part of the population was suffering from it,
I would first address the question of ergotism as a disease is really kind of a social nature driven disease because the people who suffered from ergotism had to rely almost exclusively on MRI as their source of calories. And those were people who had to live on marginal lands, right? People who had good good land, cultivated wheat and other crops and ate a variety of healthy foods, and didn't suffer from ergotism, the poor people who were confined to marginal lands, but the only thing that could grow on those lands was ride and ride is, is the most frequently affected of grasses, it, it's very good at living in poor soils, so people will have to grow it, but it's flowers staying open the longest. And that's it, we talked earlier about the spores of collapse purpurea being transmitted from that little, you know, radio source and just being blasted in all directions. So right plants get infected more. And people will rely on MRI for all their calories, even if only about 1% of the grain that's harvested is or God sclerotia 99% is grain, that's enough to make people sick, especially if that's the only source of food they have. So people would suffer all these terrible symptoms that he described, most of the natural ergot alkaloids are vasoconstrictive, so they constrict blood flow. So we have this happen to us physically, sometimes if you just like, fall asleep in a funny position, and you're cut off physically restrict blood flow to your hands or your flutter, you know, you get that fuzzy burning feeling and you wake up and then you shake it off, you know, because you can just stop. But if it was chemically induced, you could not shake it off, it would just be a burning sensation that would linger and linger and linger. And eventually, your limb could fall off because the amount of blood is so restricted, that appendage essentially just dies and drops off and you're not bleeding because you've constructed the blood vessels to that point where they're, they're essentially just sealed off. So yeah, it was a horrible disease and people suffer hallucinations and problems with sleep wake cycles, and problems with fertility and all these things for years. And it's really no longer a problem for a couple of reasons. One reason is, is the potato right Europeans explored America they came back with a potato, and that became the food of choice for the for the marginalized populations who had lived on crappy lands, and then they could grow potatoes easily. And so their diets became different and diversified. And the industrial revolution happened and people move to cities more and had more diversified diets.
The Salem Witch Trials often get all the attention when it comes to looking at or got social impact. But Ergo epidemics have occurred in many other communities also likely a social disease, where the less wealthy people tend to eat more contaminated flowers. documented outbreaks have been recorded as early as 944 ad or some 20,000 people died of ergotism in France, and as late as the early 20th century with cases in Russia, England and France
Before it was identified as a fungus in 1764. Ergo It was called Super ripe because it possessed a large kernel and for the more mindful harvesters, it was actually used as medicine. The earliest authenticated report we found on Oregon and its effects appear to be in Chinese writings written in approximately 1100 BC, where the substance was used to aid in childbirth. There are also records in Mesopotamia and temples dating around 1800 bc that refer to an infected grain known as Meru Sumerian clay tablets in the same period described Simona which is a grain that reddens when dampened, or God is also postulated as part of the endogenic theories in the alessian mysteries, there are even more examples of Aragon showing up in early history. As we said, or gods history is a massive topic, so be sure to check our show notes if you'd like to know more
Nowadays, cases of ergotism and humans is super rare, but remains a concern in animal agriculture.
So in terms of agriculture, the major concerns are pasture grasses with EPA, colonias. And that's a case where it's really all about understanding things well, and managing things well, because you don't want to remove the fungus people that people try that years ago, and that the grasses don't thrive. They don't do well without their fungal partner. But you also don't want that fungal partner to be cranking up ergot alkaloids and affecting farm animals deleteriously. And so people are finding ways to either modify the fungi or looking for natural variants that that have reduced alkaloid contents and finding success. and managing that sort of agricultural ecosystem that way.
People still farm or got on purpose. Because it's a key part of medicine making and contemporary pharmacology, it is much more practical to grow the sclerotia and harvest the alkaloids as a natural starter chemical than it would be to synthesize them from scratch. Most of these farms are in Eastern Europe, most likely Czech Republic and Hungary. But back in the 40s, it was also farmed in Minnesota, where there remains an Oregon Museum in the small town of dassel.
I would love to go
Yeah, if any of you make it out there,
tag us on Instagram, please, per sclerotia, you can derive about one milligram of lysergic acid. So if you were efficient with your chemistry, you can make one milligram of lysergic acid derived medicine, this equates to roughly a single dose, depending on the target drug and effect.
I feel like that makes each sclerotia I'm so precious. It's as if one sclerotia was one pill.
Yeah, we've been working at various natural sources of ergot alkaloids and seeing if any of them might be better starting material for medicine or fungi that we can modify the pathway to make interesting scaffolds on which pharmaceutical companies might build new things. Also, in terms of medicine, we haven't mentioned Aspergillus faema goddess, which is a human path is probably one of the more common human pathogens. Typically, Aspergillus fumigatus, affects immunocompromised individuals. So it's an issue in hospitals because that fungus is very ubiquitous. Its spores are abundant and buoyant. And it's hard to keep them out of, you know, h vac systems and so that in hospitals where people you know, many people are immunocompromised, that that fungus causes severe issues and fatalities, that that fungus produces its own unusual branch of ergot alkaloids and we're just beginning to look at that a little bit. And we've only worked with insect models so far, but an insect models those are good alkaloids help Aspergillus fumigatus be a pathogen and Sophie translate the insect models to other animal models and other animal models to humans, there may be a connection there that we want to look at further.
So like most drugs, you need a permit. But these alkaloids are especially regulated, since they are precursors to schedule one drug. But Daniel has special permission to do that.
So I would say most of the ergonomical, but you know, certainly LSD. And then most of the drugs I've listed as affecting dementia and cluster headaches, that sort of thing. The way those are made is that people will start with all of the ergot alkaloids and a fungus, you know, the complex mixture, for the most part, you know, if you look at the, the way, the path they built from the ground up, evolves, the amino acid trip the fan and some other precursors, and they're put together and built in progressively bigger and bigger, bigger structures. Maybe two thirds of the way through that pathway is lysergic acid. And then lysergic acid is built on two different ways to make regarding me and other amides of lysergic acid, and those are the compounds that mainly build up in ergot alkaloid producing fungi. So with pharmaceutical companies collect either the sclerotia or they grow the fungus in a bioreactor and get a complex mixture of lysergic acid amides or the lysergic acid peptides. They then treat that with usually a strong base and just cut all those side chains off to go back to lysergic acid and then semi synthetically built back on whatever structure they want to make. And LSD does not exist naturally people have to collect the organ to avoid stripped everything off and then build back to make LSD or they built back to make cabergoline or nice ergoline or hydro gain or any of these other structures whether or not lysergic acid is regulated as a scheduled compounds. I have to have permits to work with it to the DEA and follow a lot of rules which we do a lot of other chemicals. Maybe They aren't specifically regulated. There's one DEA regulation that says, even if we haven't specifically named it, if it's a lot like one of the schedule compounds that were regulating it also right, I forget the name of that rule.
As with most fungal alkaloids, they evolved independent of homosapiens. Which begs the question, What are these highly impressionable compounds doing in the wild? This is actually the question that psychedelic chemists and journalists Hamilton Morris asked Dr. P. and how we found out about him.
The best evidence we have and this is not my evidence, this is work by Jim white and Joey spattered for and some other researchers are that the ergot alkaloid producing fungi probably began as insect pathogens, and like virtue of parasitizing insects that were associated with plants eventually broke through that next level and started colonizing plants as well. And then, since the production of alkaloids helped the plants, that sort of level symbiosis evolved, where the either EPA Chloe's or quadriceps is, would colonize plants and protect the plants gain nutrient gain nutrition from the plant, so the plant gives nutrition the fungus gives protection. Yeah, and whether you consider these fungi to be pathogens, or mutualistic symbiosis really is it's not semantics is true, there's real biology there, but it's a tough one, in terms of the individual grass head that's infected by a claddagh seps. It is, you know, it is infected and it's losing some of its reproductive potential because the fungus is occupying, or, you know, taking over what would have been a flower and then a seed producing its own structure in place. But by doing that it on a field scale, it might be helping, you know, the species of right to thrive. on a small scale. Yeah, it's a pathogen, but a larger scale, it might actually be helpful to the grass plant. We as humans, who wanted to make bread from that right and not be poisoned by it, consider it to be a pathogen, but ecologically, you could make the argument and people have that it's, it's actually pitch yahwistic. The fungus obtains nutrients from plants and plants are obviously very good at fixing carbon and providing like sugars. And it's so it's really not much of a donation at the plant to make that little bit of sugar to keep these fungi going. And the fungi provide protection by virtue of the chemicals they produce.
I'm curious if you know anything about the first common taxonomic tier, that are about alkaline alkaloids are found within the kingdom of fungi. Is there any kind of pattern that you've seen through your studies?
Yeah, that's it's a very good question. There have been some reports of ergot alkaloids produced outside of the kingdom fungi, and I have not studied sea squirts or sponges, or some you know, some animals. I have not studied those organisms directly. My hypothesis is that if people are finding ergot alkaloids, there's a fungus associated with those animals. That's the real source of your good appetite. But I don't I don't want to say anything. I can't back up because I cannot back that up. But that's just the offices. So I the best of my knowledge, ergot alkaloids are restricted to fungi. People often thought that morning glories could produce ergot alkaloids. They certainly do contain large amounts of organ coins, but we now know that there are symbiotic fungi that grow those morning glories that are producing the Oregon alkaloids. And in terms of the taxonomic regs, the ones all the ergonomical is am aware of excluding those couple of animal reports are in the phylum ascomycota. And mostly in the order, hip hop, well, no, it's not true. There's a couple of different orders that you could find them in a couple of major groups the the clavis Epson related organisms in the apoc release, and then Penicillium, Aspergillus species in the Roshi Italy's, so a couple different orders of fungi that make you happy here, right? We have found him in Penicillium, some Penicillium species, including very close relatives of Penicillium canonbury. penicillin, Kim and Verity itself only makes a very early pathway precursor, and it does not make it when it's grown in milk or in cheese. Right. So it's Penicillium Kim and Betty has the capacity to make or its recent ancestors have the capacity to to make certain ergot alkaloids but I want to be clear that you are doubly protected in Cayman bear and breach cheese's but for two reasons. One is, even those recent ancestors that do make ergonomic Woods do not make them when they're growing. Add milk or during the cheese ripening process. So that's one level of protection. The second level of protection is that penicillin, Cameron barity. That domesticated form contains a mutation that prevents it from going very far down the pathway. So even when it's growing under ideal or get overweight conditions in culture, where it will make them, it only makes a very simple precursor to ergot alkaloids. But Penicillium by for me, penicillin commune close relatives do make her again, alkaloids we have domesticated the fungus, and its own nutritional pattern is such that it only makes them under certain conditions, which are not found when making cheese.
Yeah, this seems to be just how fungi live, right? They have all these genes to express all these different compounds, but only do so if the environment really calls for it. If there's some sort of competitor they need to ward off or maybe like push through a cuticle or whatever the situation may be. So given that they're so impressionable by their environment, do you in your lab ever subject fungi to novel environments or stressors to try and discover new compounds in the inner gut?
That's, that's an excellent question. Yeah, I mean, I'll try to come back to that. But just as a good example of what you described is memorizing species. A lot of people I know are familiar with metarhizium in ossipee, a or memorizing Burnham memorizing aquadome as entomopathogenic fungi, they are very common fungi, one of the more common causes of diseases and insects, but their primary purpose really is to grow in soil as plant roots symbiotic, so that a lot of plants will have met arising species on their root systems in a symbiotic sort of way that beneficial to the plants. And then the sun rising species can infect insects and parasitize insects and protect plants in that way and also obtain a lot of nitrogen from insects that way, but memorizing species and we several of them have all the genes required to make very interesting lysergic acid derived ergot alkaloids and same sort of things that people would use for precursors for drugs. When when memorizing was growing in a plant, no trace whatsoever of any ergot alkaloid. When you grow metarhizium and culture, you have to really work to give it conditions where it'll make a little bit of ergot alkaloids. If you put in that arising in an insect, then the concentrations just go through the roof, they produce so much work it operates in a little inset so we we know we started here, we'll just inject a little wax for him, right Galleria mellonella. And that's worth like liters of material to us is there's so much alchemy that comes out of that one little larva that compared to and so, yeah, so they, you. And so we have tried to wake up some other fungi that way. We said, Well, maybe if this works for memorizing maybe we can put other fungi into into insects to try to wake them up that way. We haven't really had success with that. Yeah, it's exactly, you know, the obviously flight back. And so if the organism hasn't evolved to some way of colonizing the insect that doesn't work, but yeah, otherwise, you can try, you know, there are little cultural dishes, you can get to have various nutrient sources and you can, you know, flood your fungus over all those various nutrient sources, and then try to pick things out that way that if you find a particular nutrient that triggers production of chemicals you're interested in. But you're right, that we can look at genomes, and make a pretty good guess, what an organism might make. But then sometimes, you know, we've we found some things that we think are quite interesting in terms of genome sequence, but then never got the fungus to respond. And so, you know, the genes look fine. They look like they would still work, but we just don't know the conditions where they might work. tricky. Dharma is another good trick a different people are familiar with that fungus as if I control it has the genes but I've never gotten triggered Jeremy to make anything arising. Yes, it certainly will. And some other things we've found, we'll wake up when you put them in the right environment.
This show could have been hours long. So for those of you itching to learn more, this is one of the few myco topics that have been covered extensively on other platforms. And we've got some hefty show notes for you to indulge in. And make sure to tune into next week's podcast where we will go deep into the world of LSD or God's most famous analog
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