Crossposted from substack.

As we all know, sugar is sweet and so are the $30B in yearly revenue from the artificial sweetener industry.

Four billion years of evolution endowed our brains with a simple, straightforward mechanism to make sure we occasionally get an energy refuel so we can continue the foraging a little longer, and of course we are completely ignoring the instructions and spend billions on fake fuel that doesn’t actually grant any energy. A classic case of the Human Alignment Problem.

If we’re going to break our conditioning anyway, where do we start? How do you even come up with a new artificial sweetener? I’ve been wondering about this, because it’s not obvious to me how you would figure out what is sweet and what is not.

Look at sucrose and aspartame side by side:

Molecular structures of sucrose and aspartame, looking very different

I can’t imagine someone looking at these two molecules and thinking “surely they taste the same”. Most sweeteners were discovered in the 20th century, before high-throughput screening was available. So how did they proceed?

Let’s look into these molecules’ origin stories.

Aspartame was discovered accidentally by a chemist researching a completely unrelated topic. At some point, he licked his finger to grab a piece of paper and noticed a strong sweet taste.

Cyclamate was discovered by a grad student who put his cigarette on his bench, then smoked it again and noticed the cigarette was sweet.

(I know what you’re thinking. The kind of guy who lights up cigarettes in a chemistry lab and places them in the middle of uncharacterised compounds before taking them to his mouth again, must have died young of an interesting death. I checked – he proceeded to live to the old age of 87.)

Saccharine was discovered by a researcher who ate bread without washing his hands and noticed the bread was sweet.

Acesulfame K was also discovered serendipitously by a chemist licking his fingers, although the legends don’t specify the exact circumstances behind the finger-licking.

There’s an exception: sucralose was actually the fruit of rational, deliberate design. The researchers reasoned that, if you do slight modifications to sucrose, you could find a molecule that is no longer metabolized but still activates the sweetness receptors. So they started from the formula for sucrose, then made carefully-designed chemical modifications to the structure until –

Haha, just kidding:

While researching novel uses of sucrose and its synthetic derivatives, Phadnis was told to "test" a chlorinated sugar compound. According to an anecdotal account, Phadnis thought Hough asked him to "taste" it, so he did and found the compound to be exceptionally sweet.

It is therefore a fact of the world that virtually all the popular synthetic sweeteners were discovered accidentally by chemists randomly eating their research topic.[1]

I think this is a suspiciously high amount of serendipity. I see two options:

Super-sweet molecules like aspartame are commonplace – there are plenty of molecules hundreds of times sweeter than sucrose, but we only know the few that were ingested by accident,

Super-sweet molecules are very rare, it’s just that chemists accidentally taste a lot of chemicals. Entire chemistry departments routinely taste the entire space of possible molecules, but they don’t notice unless the molecule has a strong taste.

To get an idea of how often chemists taste the chemicals they are working with, let’s consider how often a molecule taken at random will taste sweet. That’s equivalent to asking: how specific are our sweet taste receptors?

Low-hanging fruits

Why do we have sweet receptors in the first place?

I thought that we craved sugars so much because of their energy content – if we eat plants that contain a lot of sugars, we can break them down into glucose and use it for metabolism. This paper from 1989 destroys this view: for instance, the sweetness of a sugar molecule isn’t a good indicator of its energy content:

Table showing the energy content vs sweetness of sucrose, glucose and fructose
No alpha in sucrose

And the fruits that taste the best tend to be the least nutritive ones! Also, before selection by humans, most plants in the ancestral environment barely contained enough sugars to reach the sweetness detection threshold. This review goes into the rabbithole of the real reasons we like sugar, but I notice I’m still confused.

Anyway, the consensus seems to be that sweetness drives us to eat the good plants, while bitterness keeps us away from the bad ones. Accordingly, a lot of obligatory carnivores (including your cat) have a non-functional sweet receptor, making them indifferent to plants and fruits. Insectivores like armadillos and hedgehogs don’t appear to like sugar so much either.

In that picture, I would expect sweet receptors to be rather specific. For instance, in mammals, we know only one kind of receptor, a dimer of the T1R2 and T1R3 proteins.[2] Meanwhile, we have dozens of different bitterness receptors (that academics helpfully compiled in the BitterDB database). I suppose this reflects the fact that sweetness makes you attracted to a narrow range of chemicals (sugars), while bitterness keeps you away from a wide range of disgusting toxic stuff.

So it’s not surprising that some of our best commercial low-calorie sweeteners don’t look like anything that occurs in nature. If low-calorie sweeteners were common in nature, our taste buds would probably have mutated to become insensitive to them.

There is one documented case of this happening: an African plant, Pentadiplandra brazzeana, contains a peptide called brazzein that is 1,500 times sweeter than sucrose. Presumably, this is to trick the local gorillas into eating the fruits and pooping the seeds into exciting new territories, without spending too much energy on sugars. But a genetic analysis found that western gorillas have a few mutations in their taste receptors that prevent brazzein from binding, and now the apes eat all kinds of fruits but never P. brazzeana.

(Nice story idea for a children’s book: One day, everybody in Gorilla Village ate the delicious New Fruit, except the village’s weirdo grumpy gorilla. Then everybody starved to death, and only the mutant was left to repopulate the world. The moral of the story? “Have superior genetics or die.”)

(There are a few other naturally-occurring low-calorie sweeteners, but there are uncommon and it’s not clear why they exist. My favourite is thaumatin, a protein involved in the immune system of a plant, who just happens to be 100,000 times more potent than sucrose. As far as I can tell, nobody knows why.)

Altogether, this illustrates the fact that it’s not common for our sweet receptors to get activated by small calorieless molecules, and chemists must have eaten a lot of weird things to find the synthetic sweeteners we currently use.

This is when things get out of control.

The big pharma tasting machinery

Hear me out: there are about 4000 clinical trials worldwide each year. Tasting is an important part of drug development – if anything, it may determine how the pill should be coated or whether to use a capsule. Therefore, several thousands of new compounds must be tasted by clinical trial participants every year.

Why didn’t we discover any new artificial sweetener this way? What are the chances that the top 5 most used synthetic sweeteners all come from chemists accidentally ingesting their works in progress, and not a single one from the cohorts of people tasting thousands of molecules all the time in controlled settings?

Let’s do a back-of-the-envelope calculation.

There are more than 19,000 FDA-approved prescription drugs on the market, 40% of which are administered orally,

About half of Phase III clinical trials fail, and this is due to a lack of efficacy 60% of the time.

So, we can estimate that the number of inactive/non-toxic oral drugs that were tasted by people in Phase III trials is upwards of 4,000.

How many were sweet? I looked at clinical trials search engines and wasn’t able to find any report of a strong sweet taste (the only hit was dextroamphetamine-saccharate, which basically contains sucrose). And of course, zero of these 4,000 chemicals ended up being commercialized as artificial sweeteners.

Meanwhile, rule-breaking chemists accidentally found the five commercial molecules mentioned above. Therefore, chemists must have tasted at least 20,000 molecules to find all five of them, and that’s only counting the ones which were actually commercialized. That’s pretty impressive.

I hear your objections

What if pharma companies are scared to use a potential medicine as a culinary additive?
The estimate above only counts drugs that were found to be ineffective, but maybe they still had some activity, at least theoretical, and that doesn’t sound safe. However, it happened in the past that a drug developed for something ended up repurposed for something else entirely. A famous case is minoxidil, which was developed to treat ulcers, but ended up being used to prevent hair loss. So that doesn’t seem to be a huge barrier.

What if people have already fully optimized sweeteners and there’s no market for new ones?
Our current sweeteners are not bad – at least we’re not using straight-up motherfucking lead like in Ancient Rome – but they are not perfect either. First, all the sweeteners I know taste bad. Second, aspartame is (lightly) suspected to cause cancer. Third, people are looking for new sweeteners: there’s no lack of studies using in-silico screening or machine learning to find them.

What if participants don’t report it when they find a drug is delicious?
Clinical trials are usually very thorough when it comes to reporting side effects – remember the guy in the Moderna vaccine trial who was struck by lightning and they had to report it as a Serious Adverse Effect? But, fine, maybe people don’t report something as benign as a sweet taste.

In that case, here is something they cannot hide: a psychedelic trip.

High probability

Like aspartame, LSD was discovered by a chemist who ingested it by accident. LSD binds to serotonin receptors, which are also the target of highly-lucrative classes of antidepressants, anti-emetics, and anti-migraine medication. So you can imagine the massive number of serotonin analogues that the pharma industry has fed to clinical trial participants. But, unless they’re hiding things from us, none of these trials resulted in participants tripping balls. From this, I conclude that LSD-level psychedelic molecules must be exceedingly rare.

Just to be sure, I checked the FDA’s side-effect database – it doesn’t have a “walls are breathing” search term, but it has “visual hallucinations”. Most of the results are boring psychiatric drugs like zolpidem or bupropion, with limited recreative potential. I mean, yes, there is a case report of a 5-years-old seeing helicopters in her room after taking antibiotics, but I don’t think this has much street value.

Meanwhile, the Psychonaut Wiki lists about a gazillion psychedelic compounds with cool names like LSM-775 (they even have one that smells like Pokémon cards – a drug taken only by the really cool kids). This is the result of extensive systematic testing by the stoner research community, most notably the Shulgin family.

Here’s the thing: among the many close analogues of LSD, most are less potent than the original LSD. Did Albert Hofmann hit the most powerful LSD variant on the first try, just by chance? More likely, chemists must also have exhausted a substantial part of all possible molecules in the configuration space around LSD. Generations of chemists must have routinely ingested all kinds of mild psychedelics, felt mildly in communion with the Universe, had a mild encounter with God, and went on with their research without telling anyone. LSD was just the only one strong enough to be noticed.

If you add the history of LSD to the history of artificial sweeteners, it follows that chemistry researchers are constantly tasting everything they touch, and I will believe that until someone gives me a better explanation. If you are a chemist, explain yourself.

  1. ^

    There are a few instances of synthetic sweeteners discovered by researchers who were actually looking for synthetic sweeteners, like alitame or neotame, but these were follow-ups to aspartame.

  2. ^

    Needless to say, the sweetness receptor was discovered by the team of Pr Zuker. I told you, this keeps happening.

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I think artificial sweeteners are so often discovered serendipitously because artificial sweeteners also tend to be insanely sweet (you usually find them mixed with a higher volume of filler because of how sweet they are), which makes them easy to notice even with standard safety measures.

this predicts that if a chemist accidentally creates an extremely deadly chemical they probably basically just drop dead. anyone able to weigh on this

Looking at this and this, I'd guess that it's just harder to produce super toxic toxins artificially than it is to produce super sweet sweeteners. IIRC the mass of neotame it takes to taste any sweetness is lower than the mass of VX it takes to kill someone.

You are correct. If one estimates that one requires a milliliter of that 0.5% saccharine solution from that paper cited above to detect the sweetness, that would come around to 50mg of sugar. If neotame is 6000 times more potent, that would mean about 800ng. Even if we switch from VX to the more potent botulinum toxin A, we would need a whole whopping microgram per kilogram orally, so perhaps a 100x more than what we need for neotame. (If we change the route of administration to IV, then botox will easily win, of course.)

Of course, this is highly dependent on the ratio of saliva in the mouth (which will dilute the sweetener) to the weight of the organism (which will affect the toxin dose needed). I don't think this ratio will change overly much when going to elephants or mice, though. 

In a way, this should be unsurprising. Both the taste molecule and the neurotoxin interact with very specific receptor molecules. Only in one case, the animal evolved to cooperate with the molecule (by putting the receptors directly on the tongue) while in the other case the evolutionary pressure was very much not to allow random molecules from the environment access to the synapses. 

On that note, it looks like people have deliberately engineered artificial sweeteners, but for whatever reason they aren't in use.

I think people typically use the naturally occurring nondigestible sweeteners anyway, stevia and erythritol mainly

I used to work in a chemistry research lab. For part of that I made Acetylcholinesterase inhibitors for potential treatment of Parkinson's Alzhiemer's. These are neurotoxins. As a general rule I didn't handle more than 10 lethal doses at once, however on one occasion I inhaled a small amount of the aerosolized powder and started salivating and I pissed my pants a little. 

As for tasting things, we made an effort to not let that happen. However as mentioned above, some sweeteners are very potent, a few micrograms being spilt on your hands, followed by washing, could leave many hundred nanograms behind. I could see how someone would notice this if they ate lunch afterwards. 

While tasting isn't common, smelling is. Many new chemicals would be carefully smelt as this often gave a quick indication if something novel had happened. Some chemical reactions can be tracked via smell. While not very precise, it is much faster than running an NMR. 

Some questions I absolutely wouldn't blame you for not answering, but I'm curious about: How old are you? How long ago was this? Have you had any complications yet?

I'm thirty-something. This was about 7 years ago. From the inhibitors? Nah. From the lab: probably.

They can't weigh in, they're dead!

Most of us aren't dead. Just busy somewhere else.

Selection Bias Rules (Debatably Literally) Everything Around Us

This also tracks with LSD, measured in micrograms rather than milligrams like other psychedelics like psylocibin and 2c-b

I think that “rational, deliberate design”, as you put it, is simply far less common (than random chance) than you think; that the vast majority of human knowledge is a result of induction instead of deduction; that theory is overrated and experimentalism is underrated.

This is also why I highly doubt that anything but prosaic AI alignment will happen.

Yeah. Here's an excerpt from Antifragile by Taleb:

One can make a list of medications that came Black Swan–style from serendipity and compare it to the list of medications that came from design. I was about to embark on such a list until I realized that the notable exceptions, that is, drugs that were discovered in a teleological manner, are too few—mostly AZT, AIDS drugs.

This was apparently a bust:

It is likely that no new materials were discovered. Most of the materials produced were misidentified, and the rest were already known. This happened because of problems in both the computational and the experimental portions of the work.

The computational predictions suffered as they generated structures with ordered cations, where in fact the same or very similar compounds are known with disordered cations. This inability to deal with compositional disorder is an important limitation of the methods used here. When the predicted, ordered, compounds were synthesised experimentally, the known, disordered, compounds were produced instead. This accounted for 2/3 of the whole list of compounds in the paper.

(...)

My personal view hasn't changed from my initial analysis. This paper is incorrect in its headline claims. No new materials were discovered. The best thing to happen here is for the paper to be retracted while these fundamental issues are fixed, both on the computational and experimental side. 

Does this count as “rational, deliberate design”? I think a case could be made for both yes and no, but I lean towards no. Humans who have studied a certain subject often develop a good intuition for what will work and what won’t and I think deep learning captures that; you can get right answers at an acceptable rate without knowing why. This is not quite rational deliberation based on theory.

But it shows that you don't necessarily need to rely strictly on experimentation! Certainly it still relies on it, but humans have been doing this sort of thing for a while. While I agree it's the case that people still have to do a lot of experiments historically, it's quite possible to have very detailed sketches of what can and can't be done.

Doesn't have any bearing historically. Also seems more like a brute force search, where the component of studying the materials properties has been made more efficient (by partially replacing lab experiments with deep learning).

The entire purpose of the paper is eliminating a brute force search. It wouldn't be possible to identify these materials with brute force. Deep learning lets you bypass brute force by zooming in on the shapes in the energy landscape that are relevant to what you're doing. A similar thing is possible with human intuition. It's certainly not the case that this has allowed people to completely avoid experimentation, but I share it to point out that it's not actually impossible to have very strong models of the energy landscape.

Sorry, low effort comment on my side. Still, I think the original link seems misleading in the point it's purportedly trying to make.

I studied chemistry and worked in Pharma research for half a year (Germany, 2018). Standard safety procedures are there, but it's no biology lab. Stuff gets spilled, you breath in vapors of solvents, and the lunch break happens in the office next to the lab, after a quick hand wash.

I am pretty sure up to a microgram of almost anything we made ended up in somebody... Usually we handled 10mg up to 10g batches. Surprisingly, the lab Assistents are overall pretty fine and don't appear to suffer any consequences more than the average population well into their 50s and 60s. (And those guys worked there last century with even LESS protocols!). I guess we would need an extensive study on the health effects of working in the chemical industry, I suspect there to be SOME consequences...

Another point I might add: University is much worse! The lower semesters are all over the place and the students need to buy new jeans regularly because of all the sulfuric acid holes after washing... Even later I clearly remember being positively euphoric after distilling or refilling DCM, Chloroform or Ether more than once...

Last defense for the sweeteners: I do have a sample of Neotame and in my experience, everyone who "smells" the powder (light breathing from 10-20cm away) after opening the package spends the next 5 Minutes being weirded out with eeeeverything being sweet and having this weirdly sweet taste run down the back of your throat. It is hard to describe how sweet it is and how hard it is to avoid making everything in the vicinity or that you touch lightly sweet as well. If you touch the powder at all, even after a diligent hand wash with soap, your fingers are still notably sweet 😉 (And that is just 10.000x Sucrose)

it's no biology lab

I'm afraid you're overestimating how well biologists follow the safety procedures. I wouldn't be surprised if we all had fluorescent bacteria in our guts.

I think that all bacteria are evolutionary optimized in favor of replication speed, so any unnecessary piece of DNA get ditched.

A guess - most compounds are not that toxic, but LSD is potent in very small doses. So that if chemists are routinely exposed to small enough not to kill you doses of whatever they're working with, when they work with LSD they will notice.

 

like, chlorine is not that toxic, and a routine step in analysing an unknown compound is to add acid and take a quick sniff to see if chlorine is coming off.

 

( and one time, the unknown compound we were given to analyse was some benzene derivative, and what you get a sniff of is way, way worse than chlorine).

 

I am an old person. They may not let you do that in chemistry any more.

I am an old person. They may not let you do that in chemistry any more.

Absolutely! In my first chemistry lab, a long time ago, our teacher warned us that she had just lost a colleague to cancer at the age of forty, and she swore that if we didn't follow the security protocols very seriously, she would be our fucking nightmare.

I never heard her swear after that.

The extreme potency of LSD is indeed a critical part of the story; synthesizing it is difficult in part because it's very hard to produce it in any large quantity without incidentally ingesting active doses through the air. According to Wikipedia, the threshold dose to feel effects is about 25µg. Not milligrams, like the active dose of most medicines, _micro_grams. I am sure chemists over the years have gotten accidental doses of 25µg of many tens of thousands of chemicals without ever noticing it. Albert Hoffman's original accidental dose was consistent with a ~threshold effect, so it doesn't seem to be especially serendipitous. He just happened to be the lucky chemist who was working with a chemical which is psychoactive in such trace amounts. (He then intentionally tested a dose of 250µg, which he thought was very small but which is in fact a solid dose.)

Also: Did Albert Hoffman hit the most powerful variant on the first try? No, he was systematically investigating similar compounds for pharmacological properties (not psychedelic properties, just regular drug discovery). LSD is just the one that had significant novel effects at low doses, and so it is the one which became famous.

Oh, that's a really good point. Actually, it might be common for chemists to work with panels of related molecules, while in clinical trials they only work with one purified drug candidate. This makes it less likely for them to discover things by accident. Surely a piece of the puzzle!

We still smell plenty of things in a university chemistry lab, but I wouldn't bother with that kind of test for an unknown compound. Just go straight to NMR and mass spec, maybe IR depending on what you guess you are looking for. 

As a general rule don't go sniffing strongly, start with carefully wafting. Or maybe don't, if you truly have no idea what it is.

Promoted to curated: I really enjoyed this post, and it has also nerdsniped me into thinking about this question a lot since it came out. I feel like this post hits a great middle ground between being engaging, giving me useful background knowledge on a bunch of different topics, and focusing on something that does actually seem like a kind of important puzzle.

What will the next curated post be? Any Manifold user can add an answer

I wonder if sweet things tend to smell sweet and that's why they end up giving it a taste.

As anecdotal support for "constantly tasting everything", I offer my high school scientific calculator. After one year of 2 hrs per day of chemistry class, its crevices around the display had a permanent collection of precipitate.

I suspect that even without intentionally tasting things, nearly everything in a lab is ingested as an aerosol. It would be unsurprising if months of such exposure led someone to develop a hunch about a molecule.

There's also the possibility these stories are just folklore, and there was some non-serendipitous way the chemicals were discovered, but people had more fun presenting it as if it were serendipitous.

Sure, all these stories totally sound like urban legends, but the sweeteners are out there and I don't see how they could have been discovered otherwise (unless they were covertly screening drugs on a large number of people).

Does anyone know why thaumatin and the sweetest chemicals on the Wikipedia sweetness table aren't more common? With sweetness more than 100k times that of sucrose they should both save on costs and have lower risk of adverse health effects compared to e.g. aspartame.

I'd expect artificial sweeteners are already very cheap, and most people want more tested chemicals.

Indeed. The incentives to put new ones on the market are very limited, due to legalities and economics.

A corporation has a limited window of patent monopoly, so a fairly short time period to recoup their investment to develop, licence and build out manufacturing capacity - thus need to sell it for a high price or sell high volumes.

It is a long and expensive process to get a new compound approved for use as a food additive, and it needs to be done separately in each major jurisdiction - at least China, USA and EU.

A new sweetener is directly competing against all the other ones that are already on the market - merely 'being much sweeter' isn't enough.
It has to be significiantly better in some other way, if only because it will be considerably more expensive at first.

That's a great question, this is totally mysterious to me. There are a lot of examples of people putting thaumatin in transgenic fruits or vegetables (and somehow in the milk of transgenic mice because there's always one creepy study), but I don't know why it hasn't been commercialized. It sounds like superfruits would make a nice healthy alternative to palm-oil-and-chocolate-based comfort foods. Maybe it's a regulatory problem?

and somehow in the milk of transgenic mice because there's always one creepy study

"Ow! My bones are so brittle. But I always drink plenty of... 'malk'‽"

This is both interesting and (I think) an important thing to know about science: plans and strategies are systematic, but discoveries sometimes are and sometimes aren't. In particle physics, the Omega baryon and Higgs boson were discovered in deliberate hunts, but the muon and J/psi were serendipitous. The ratio might be about half-and-half (depending on how you count particles).

Thinking about this, I have two half-answers, which may be leads as to why sweetener discovery might be discovered by serendipity, even though there are systematic searches for new drugs.

  1. Discovery depends, to a great degree, on your detector, and I don't think there's a better detector of sweetness than the ones in our mouths. Presumably, searches through virtual (not synthesized) molecules can be faster, and if the identification algorithm can accurately predict activation of the sweetness receptor, then it could outperform detection by taste only because it's faster than synthesis. But virtual drug discovery is still an open problem, still under development...
  2. Maybe there are, in nature, only a few sweet molecules, and they were discovered early. Going through the list of artificial sweeteners you mentioned, below are the discovery dates. When were most of the systematic drug searches? Did it cover this timespan, which seems to be in the early and mid-20th century?
    1. Saccharin: 1897
    2. Cyclamate: 1937
    3. Aspartame: 1965
    4. Acesulfame potassium: 1967
    5. Sucralose: 1976

(This suggestion also has an analogy with particle physics: hundreds of particles were discovered in the 1950's because accelerators had just been invented that could illuminate the strong-force mass range, which has rich phenomenology. At the current frontier, though, there are very few particles.)

Other comments in the comments section that sound quite likely to me are: (1) perhaps the very sweet compounds could be smelled, which prompted chemists to try tasting them (@mako-yass), and (2) maybe some of these origin stories are scientific folklore (@d0themath). Scientists, who are very concerned to get the description of physical reality right, are surprisingly cavalier about describing their own history in an accurate way.

There is story, possibly apocryphal, that the first person to isolate fluorine gas died in the attempt.

 

=====

In an introductory course on stained glass.. "some watercolour painters like to lick their brushes to get a good point. When you are painting toxic heavy metals on to glass, do not do this."

 

some time later...

 

"hmmm..  looks like the particular kind of glass you have chosen for this project doesn't take silver nitrate very well. Let's try antimony instead...."

The danger of attempting to isolate fluorine gas is not apocryphal.  From Wikipedia:

Progress in isolating the element was slowed by the exceptional dangers of generating fluorine: several 19th century experimenters, the "fluorine martyrs", were killed or blinded. Humphry Davy, as well as the notable French chemists Joseph Louis Gay-Lussac and Louis Jacques Thénard, experienced severe pains from inhaling hydrogen fluoride gas; Davy's eyes were damaged. Irish chemists Thomas and George Knoxdeveloped fluorite apparatus for working with hydrogen fluoride, but nonetheless were severely poisoned. Thomas nearly died and George was disabled for three years. French chemist Henri Moissan was poisoned several times, which shortened his life. Belgian chemist Paulin Louyet and French chemist Jérôme Nicklès tried to follow the Knox work, but they died from HF poisoning even though they were aware of the dangers.

This suggests a general rule/trend via which unreported but frequent phenomenon can be extrapolated. If X phenomenon is discovered accidentally via method Y almost all the time, then method Y must be done far more frequently than people suspect. 

I’m not sure on the discussion about clinical trials.

In any given oral medicine, on average about 90%, and often more, of the material is excipient (usually bulking/binding agents) rather than the active pharmaceutical ingredient being tested. Further, the excipients might have flavours or sweetness themselves, as many are sugars. I’m not sure how much you can conclude about the taste of the tested molecules from clinical trial observations.

Relevant source: https://australianprescriber.tg.org.au/articles/pharmaceutical-excipients-where-do-we-begin.html

These tastings must not have always ended well. What comes to mind is the Parkinson-inducing desmethylprodine which was discovered by "accident", although the chemist in question (Barry Kidston) tasted it on purpose -- he thought he was developing a recreational drug. But you would expect more chemists dying randomly, if they were tasting their lab contents at this rate -- but maybe I just don't know enough.

EDIT: Noticed that some comments above discuss the likelihood of random chemicals being lethal

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Nice post but the idea that Albert Hofmann's famous chemical ingestion was absolutely accidental is debatable. That is if you consider why he synthesized LSD-25 for the second time 5 years after it failed at the purpose for which he was researching. You would have to believe that a failed compound was accidently synthesized for the episode to fit into the theme of this. Notice the name that he gave it, LSD-25. It wasn't for whim that he included the sequence number from his notebook. It was because he had a long series of dreams revolving around the number 25 that propelled him back into the lab to figure out which compound was the 25th compound in his ergot-derived chemical quest, and of course after bicycle day, he had no more dreams of 25. This is told in his autobiographical 'LSD My Problem Child'.

Perhaps the properties of the original LSD as seen in the human body are just a side effect due to some biological role it plays in nature. Do animals have anything like what the humans do, after eating the infected wheat, behaviourally speaking? Perhaps the "feeling" part of it is not important compared to the "acting" part, from the fungus's point of view.

LSD as such does not occur in nature, so it has no evolved biological role. It is a semi-synthetic chemical, meaning that it is synthesized in a lab by chemical reactions, but that the usual starting material is biological (typically ergotamine, which is, as you allude, found in ergot).

What happens to substances in ergot as it is metabolized (by a nonhuman body)? (I think it strange that humans have this strong reaction to e.g. bread made with the infected flour.)

Ergot is toxic and eating contaminated bread has been a historical problem, but the results of ergot poisoning, contrary to pop science/history accounts, don't seem to be much like the results of LSD, although there is a neurological component. It is plausible that the evolutionary "purpose" of the alkaloids is to poison animals that eat it, but whether the benefit to the fungus comes from decreased predation, improved dispersal, or something else is unclear.

Certainly there exist fungi which produce psychoactive compounds in order to alter the behavior of an animal, such as the charming Massospora cicadina, aka the cicada sex zombie fungus.

Maybe the chemists had had an inkling before they tasted things. Do the sweeteners smell of something? Maybe a chemist has a stronger sense of smell.

You could rename this post to, "Sweet, Sweet Serendipity".