So nice to have a Res Obscura post in my inbox this morning! Welcome back from doing something more important and harder than delighting readers interested doing history.
I have some skepticism about those results. Specifically, there are a number of Tropane alkaloids which are very close to cocaine and are present in other plants - especially nightshades (e.g., belladonna) - which were known to and used for various purposes by Europeans for a long time. Look at the resemblance with Atropine, Scopolamine, Hyoscyamine, all of which are found in belladonna which also contains Hygrine, indeed, Atropine is named after "Atropa belladonna". Does the hospital's pharmacopeia mention any nightshade plants or derivatives?
Consider, from "Exploring the History, Uses, and Dangers of Belladonna: Unveiling the Mysteries of the Deadly Nightshade" (Nikandish, 2024): " ... the Greeks valued the plant’s extracts for their analgesic and anesthetic properties that could be used in medical treatments (Javed et al., 2023). The plant was used in a similar capacity in ancient Rome and was later used for different purposes during the Italian Renaissance."
Previous similar studies (some mentioned in the article) claimed to find cocaine in Egyptian mummies, and these were dismissed as probably being due to 'environmental contamination' in the laboratory, somehow, maybe. But another possibility is that those researchers ran a tight ship and did indeed pick up tropanes, but slightly different ones, from different plants.
That being said, I believe the ecgonine methyl ester, if actually present, is much more indicative of coca than tropanes from other plants. However, my hunch is that the fragmentation and retention time profiles of those other tropanes looks very similar because of the extra carbons and hydroxy group, not to mention the kind of reactions and rearrangements that can happen to those cyclic chemicals during whatever process mummified those tissues and during subsequent conditions over such a long period of time.
The fact that the article does not even mention nightshade tropanes or try to demonstrate why this possibility can be excluded also raises my level of suspicion.
Very interesting and well-informed comment, thank you! I am by no means an expert in the chemistry or toxicology side of this, but what would your response be to this in the article? This seemed convincing to me when I read it: "The 3rd molecule detected in the brain tissues of our subjects, hygrine (an alkaloid present in the leaves of Erythroxylum spp. only), was essential to determine that the molecules detected in these human remains derived from the chewing of coca leaves or from leaves brewed as a tea, consistent with the historical period. Therefore, the detection of hygrine excludes that the molecules were derivatives of some external and more recent contamination from anthropic influence." Based on my reading on this, I could find reports of belladonna containing cuscohygrine but not hygrine per se, which this article is treating as a telltale marker of coca use.
Heh, I knew that "chemistry of cocaine and substituted tropanes" knowledge would come in handy again one day.
The presence of Hygrine is not a telltale marker of -coca- use, it is a telltale marker of ingesting relatively unrefined material or extracts from one of the several plants with tropane alkaloids.
The authors use the presence of Hygrine to dispose of the possibility of what was suspected from those earlier Egyptian results, which is that they were just cases of contamination from the environment, perhaps in the laboratory voted "funnest place to work" by institute researchers three years in a row.
If a sample gets contaminated with cocaine but far away from where coca leaves grow, it is almost certain that it was contaminated by the contraband of commerce, refined cocaine hydrochloride salt or the freebase (i.e., 'crack'), with almost all the rest of the plant alkaloids removed (though occasionally 'cut' with fillers, like what used to be the case with Levasimole.) Since these sources of contamination don't contain Hygrine, if you find it, you know someone was ingesting crude matter from plants which make tropane alkaloids. But you DONT know that it was from COCA leaves, since Hygrine is going to be found in ALL tropane-producing plants, yes, belladonna as well.
The reason is that Hygrine is formed by the decarboxylation of the last step precursor (itself derived from amino acid ornithine) which is turned into Tropinone by the aptly named Tropinone Synthase. See "Redirecting tropane alkaloid metabolism reveals pyrrolidine alkaloid diversity in Atropa belladonna", New Phytologist, Parks et all, 2022.
The biosynthesis of Tropane is one of the most famously difficult problems in biochemistry, and the complete picture was only worked out quite recently and is still the subject of some lingering controversy. See "Tropane alkaloids biosynthesis involves an unusual type III polyketide synthase and non-enzymatic condensation" in Nature, Huang et al, 2019. Sir Robert Robinson's double-Mannich approach to Tropinone is a famous early triumph of modern organic synthesis and was one of the things that got him his Nobel.
I'm willing to bet that if one can get a hold of that pharmacopeia one is going to find belladonna or some other nightshade on there. We have a lot of corroborating evidence for contemporary use of belladonna in that time and place, and almost none for coca leaves, and, given the chemical similarity and the failure of these researchers to -even mention- the possibility, I strongly suspect that's what actually happened here. Maybe the excitement of going to press with headline result of finding coca leaf use in a very surprising time and place is not quite "too good to check", but plausibly, "too good to check at the requisite level of rigor."
There's another point that weighs against this being a case of coca usage that is more Historical than Chemical, which is to consider the typical history of what happened anytime any new very pleasurable culinary or psychoactive compound was introduced as a novel substance.
Which in my impression is pretty much always an explosively rapid rise in adoption, spread, popularity, conspicuous consumption, commercial activity to include global trade networks, focal points for socialization, literary records, major personal and cultural impacts, and then reactions to some of those more seriously negative impacts by the authorities. Consider what happened - and how fast they happened - when things like coffee, tobacco, pepper, and chocolate hit the scene. Mocha is named after the city in Yemen that was once a major coffee hub and exporter, and so many people were spending so much time in coffee bars that various Muslim leaders tried to ban either the bars or the drink itself, with Murad IV raising the penalty to death! Consider how quickly newly available drugs spread, especially addictive ones, for example opium.
Now, the idea that these two Italians are chewing addictive coca leaves and having some kind of medical or other psychoactive benefit and that this kind of thing wouldn't be seed, imitated, tried, and spread like wildfire, well, I suppose anything's possible, but in my judgment it seems awfully inconsistent with the typical pattern of human affairs.
This is all quite fascinating. Thank you, I am delighted by these comments. I think I will write a followup post about precisely this, actually. My takeaway from going fairly deep into the history of how drugs globalized is that it is surprising how *infrequent* it was for a drug to truly take off as a global commodity. For instance, cannabis was being experimented with and used outside its historical growing regions by various people in the 17th century (including, apparently, Robert Hooke) and yet it failed to become an item of widespread use in early modern Europe [1]. I still find that odd, but it isn't a one off. So coca might've been like that.
The use of psychoactive cannabinoids from the Eastern Mediterranean to South and East Asia ('ganja" is from the Sanskrit for 'hemp', 'hashish' is Persian, from which 'assassin' is derived) goes back thousands of years and was even recorded back in classical antiquity (Herodotus describes the Scythian hemp-seed-smoke sauna, but we know from other sources they ingested the stuff too - http://classics.mit.edu/Herodotus/history.4.iv.html). "Cannabis" is from the Scythian language, and likely originated near Tibet (https://en.wikipedia.org/wiki/Cannabis#Phylogeny). For a long time the only way to get really buzzed was to make and east hashish, because the concentration of THC-family cannabinoids in hemp was fairly low (almost nothing in fiber-hemp itself), and horticultural techniques of the time took a long time to make any progress on the challenge of identifying and cultivating varieties for higher concentrations that they could only assess subjectively and couldn't really measure. You can't just look at the plants to know the slight differences to seed another iteration of selective breeding, and there are many genes involved, so there was a lot of luck involved overcoming multiple hard-steps, and that was a slow process. (Compare, for example, the problem of trying to breed oaks which produce the highly-prized non-bitter acorns.) Smoking cannabis apparently did not become really popular as the preferred route of administration until tobacco smoking became popular and cannabis came along for the ride.
One interesting question is why wasn't there a thriving international trade in long-distance shipments of hashish like there was in a bunch of other spices and substances. When the colonial-era Europeans were eventually exposed to it they apparently liked it, at least, when they couldn't get alcohol. My wild guess is that the hashish of the time didn't keep well and couldn't be transported profitably in long journeys, combined with it being probably that THC-concentrations were still very low back then and so the stuff probably wasn't all -that- good if one was looking to get intoxicated, indeed, it is only in the post-WWII era that modern techniques have pushed THC levels from "stinks, takes a lot, and is barely worth it," to levels that now, ahem, sky high.
Fascinating! I'm reminded also of the Black Death research of recent years, in which documentary historical research and lab science have come together in exciting ways. And I'm remembering Beth Macy's DOPESICK, which opens with a shocking narrative of how industrial chemists both purified a different addictive compound and sounded the alarm decades ago - to no avail: this is the story of opioids.
So nice to have a Res Obscura post in my inbox this morning! Welcome back from doing something more important and harder than delighting readers interested doing history.
I have some skepticism about those results. Specifically, there are a number of Tropane alkaloids which are very close to cocaine and are present in other plants - especially nightshades (e.g., belladonna) - which were known to and used for various purposes by Europeans for a long time. Look at the resemblance with Atropine, Scopolamine, Hyoscyamine, all of which are found in belladonna which also contains Hygrine, indeed, Atropine is named after "Atropa belladonna". Does the hospital's pharmacopeia mention any nightshade plants or derivatives?
Consider, from "Exploring the History, Uses, and Dangers of Belladonna: Unveiling the Mysteries of the Deadly Nightshade" (Nikandish, 2024): " ... the Greeks valued the plant’s extracts for their analgesic and anesthetic properties that could be used in medical treatments (Javed et al., 2023). The plant was used in a similar capacity in ancient Rome and was later used for different purposes during the Italian Renaissance."
Previous similar studies (some mentioned in the article) claimed to find cocaine in Egyptian mummies, and these were dismissed as probably being due to 'environmental contamination' in the laboratory, somehow, maybe. But another possibility is that those researchers ran a tight ship and did indeed pick up tropanes, but slightly different ones, from different plants.
That being said, I believe the ecgonine methyl ester, if actually present, is much more indicative of coca than tropanes from other plants. However, my hunch is that the fragmentation and retention time profiles of those other tropanes looks very similar because of the extra carbons and hydroxy group, not to mention the kind of reactions and rearrangements that can happen to those cyclic chemicals during whatever process mummified those tissues and during subsequent conditions over such a long period of time.
The fact that the article does not even mention nightshade tropanes or try to demonstrate why this possibility can be excluded also raises my level of suspicion.
Very interesting and well-informed comment, thank you! I am by no means an expert in the chemistry or toxicology side of this, but what would your response be to this in the article? This seemed convincing to me when I read it: "The 3rd molecule detected in the brain tissues of our subjects, hygrine (an alkaloid present in the leaves of Erythroxylum spp. only), was essential to determine that the molecules detected in these human remains derived from the chewing of coca leaves or from leaves brewed as a tea, consistent with the historical period. Therefore, the detection of hygrine excludes that the molecules were derivatives of some external and more recent contamination from anthropic influence." Based on my reading on this, I could find reports of belladonna containing cuscohygrine but not hygrine per se, which this article is treating as a telltale marker of coca use.
Heh, I knew that "chemistry of cocaine and substituted tropanes" knowledge would come in handy again one day.
The presence of Hygrine is not a telltale marker of -coca- use, it is a telltale marker of ingesting relatively unrefined material or extracts from one of the several plants with tropane alkaloids.
The authors use the presence of Hygrine to dispose of the possibility of what was suspected from those earlier Egyptian results, which is that they were just cases of contamination from the environment, perhaps in the laboratory voted "funnest place to work" by institute researchers three years in a row.
If a sample gets contaminated with cocaine but far away from where coca leaves grow, it is almost certain that it was contaminated by the contraband of commerce, refined cocaine hydrochloride salt or the freebase (i.e., 'crack'), with almost all the rest of the plant alkaloids removed (though occasionally 'cut' with fillers, like what used to be the case with Levasimole.) Since these sources of contamination don't contain Hygrine, if you find it, you know someone was ingesting crude matter from plants which make tropane alkaloids. But you DONT know that it was from COCA leaves, since Hygrine is going to be found in ALL tropane-producing plants, yes, belladonna as well.
The reason is that Hygrine is formed by the decarboxylation of the last step precursor (itself derived from amino acid ornithine) which is turned into Tropinone by the aptly named Tropinone Synthase. See "Redirecting tropane alkaloid metabolism reveals pyrrolidine alkaloid diversity in Atropa belladonna", New Phytologist, Parks et all, 2022.
The biosynthesis of Tropane is one of the most famously difficult problems in biochemistry, and the complete picture was only worked out quite recently and is still the subject of some lingering controversy. See "Tropane alkaloids biosynthesis involves an unusual type III polyketide synthase and non-enzymatic condensation" in Nature, Huang et al, 2019. Sir Robert Robinson's double-Mannich approach to Tropinone is a famous early triumph of modern organic synthesis and was one of the things that got him his Nobel.
I'm willing to bet that if one can get a hold of that pharmacopeia one is going to find belladonna or some other nightshade on there. We have a lot of corroborating evidence for contemporary use of belladonna in that time and place, and almost none for coca leaves, and, given the chemical similarity and the failure of these researchers to -even mention- the possibility, I strongly suspect that's what actually happened here. Maybe the excitement of going to press with headline result of finding coca leaf use in a very surprising time and place is not quite "too good to check", but plausibly, "too good to check at the requisite level of rigor."
Such an well informed comment restored my hope on the internet.
There's another point that weighs against this being a case of coca usage that is more Historical than Chemical, which is to consider the typical history of what happened anytime any new very pleasurable culinary or psychoactive compound was introduced as a novel substance.
Which in my impression is pretty much always an explosively rapid rise in adoption, spread, popularity, conspicuous consumption, commercial activity to include global trade networks, focal points for socialization, literary records, major personal and cultural impacts, and then reactions to some of those more seriously negative impacts by the authorities. Consider what happened - and how fast they happened - when things like coffee, tobacco, pepper, and chocolate hit the scene. Mocha is named after the city in Yemen that was once a major coffee hub and exporter, and so many people were spending so much time in coffee bars that various Muslim leaders tried to ban either the bars or the drink itself, with Murad IV raising the penalty to death! Consider how quickly newly available drugs spread, especially addictive ones, for example opium.
Now, the idea that these two Italians are chewing addictive coca leaves and having some kind of medical or other psychoactive benefit and that this kind of thing wouldn't be seed, imitated, tried, and spread like wildfire, well, I suppose anything's possible, but in my judgment it seems awfully inconsistent with the typical pattern of human affairs.
This is all quite fascinating. Thank you, I am delighted by these comments. I think I will write a followup post about precisely this, actually. My takeaway from going fairly deep into the history of how drugs globalized is that it is surprising how *infrequent* it was for a drug to truly take off as a global commodity. For instance, cannabis was being experimented with and used outside its historical growing regions by various people in the 17th century (including, apparently, Robert Hooke) and yet it failed to become an item of widespread use in early modern Europe [1]. I still find that odd, but it isn't a one off. So coca might've been like that.
[1] https://publicdomainreview.org/essay/how-the-english-found-cannabis/
The use of psychoactive cannabinoids from the Eastern Mediterranean to South and East Asia ('ganja" is from the Sanskrit for 'hemp', 'hashish' is Persian, from which 'assassin' is derived) goes back thousands of years and was even recorded back in classical antiquity (Herodotus describes the Scythian hemp-seed-smoke sauna, but we know from other sources they ingested the stuff too - http://classics.mit.edu/Herodotus/history.4.iv.html). "Cannabis" is from the Scythian language, and likely originated near Tibet (https://en.wikipedia.org/wiki/Cannabis#Phylogeny). For a long time the only way to get really buzzed was to make and east hashish, because the concentration of THC-family cannabinoids in hemp was fairly low (almost nothing in fiber-hemp itself), and horticultural techniques of the time took a long time to make any progress on the challenge of identifying and cultivating varieties for higher concentrations that they could only assess subjectively and couldn't really measure. You can't just look at the plants to know the slight differences to seed another iteration of selective breeding, and there are many genes involved, so there was a lot of luck involved overcoming multiple hard-steps, and that was a slow process. (Compare, for example, the problem of trying to breed oaks which produce the highly-prized non-bitter acorns.) Smoking cannabis apparently did not become really popular as the preferred route of administration until tobacco smoking became popular and cannabis came along for the ride.
One interesting question is why wasn't there a thriving international trade in long-distance shipments of hashish like there was in a bunch of other spices and substances. When the colonial-era Europeans were eventually exposed to it they apparently liked it, at least, when they couldn't get alcohol. My wild guess is that the hashish of the time didn't keep well and couldn't be transported profitably in long journeys, combined with it being probably that THC-concentrations were still very low back then and so the stuff probably wasn't all -that- good if one was looking to get intoxicated, indeed, it is only in the post-WWII era that modern techniques have pushed THC levels from "stinks, takes a lot, and is barely worth it," to levels that now, ahem, sky high.
Great piece, thank you. David Courtwright has always been a favourite historian of mine.
Fascinating! I'm reminded also of the Black Death research of recent years, in which documentary historical research and lab science have come together in exciting ways. And I'm remembering Beth Macy's DOPESICK, which opens with a shocking narrative of how industrial chemists both purified a different addictive compound and sounded the alarm decades ago - to no avail: this is the story of opioids.