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That's very common actually! The mechanism of action for many drugs is unknown. And then it gets even weirder with psychoactive drugs: eventually the answer is

That's very common actually! The mechanism of action for many drugs is unknown. And then it gets even weirder with psychoactive drugs: eventually the answer is "this drug effects this neurotransmitter which gives you this subjective first person experience, and we don't really know why". It brings up a lot of philosophical and existential questions!

lordnacho 2y ago
How do people come to find these drugs then? If you don't have a theory about how something works, what would make you test whether it works?
- MaxDPS 2y ago
  Sometimes there is a theory, but it’s also possible for a drug to help in other (unrelated) ways as well.
- pitpatagain 2y ago
  In the case of metformin, the direct line is from guanidine in french lilac being used since the middle ages for diabetes. Guanidine is effective, but long term liver toxic. Once actual chemistry broke open our ability to analyze that drug, related chemicals could be synthesized and studied, which led to biguanidines, of which metformin is one, which were tested in animals. Many drugs are found this way by looking at chemicals related to ones we already know about, and then testing on animals and humans. Self testing of new drugs by researchers used to be very common. How did folk medicine come to know the effects of guanidine? Dunno.
  - groby_b 2y ago
    > How did folk medicine come to know the effects of guanidine? Dunno. The same way we know a lot about other things in the chemistry domain - somebody tasted it, just to see what happens. "Mendeleyev's Dream" is a great book that contains many fascinating anecdotes of people going "let me just lick this, just to try". (Or, if you want to go more modern, the history of hallucinogens is pretty fun too) Humans seem to have a strong tendency to stuff unknown things into their mouth, just because they can.
    - falcor84 2y ago
      Indeed. I would assume that this is one of the traits that survives due to group selection [0] - it would be bad if everyone in the population was such a risk taker, but groups that have a small percentage of these people will adapt better. [0] https://en.wikipedia.org/wiki/Group_selection https://en.wikipedia.org/wiki/Group_selection
      - elcritch 2y ago
        That's my belief on why ADHD has such similar levels of prevalence (between 5%) around the globe despite drastically different cultures and varying genetics. It's great for the group as a whole as the ADHD members tend to be natural entrepreneurs, inventors, etc. However it often sucks for the individual ADHD folks and leads to higher rates of, well, everything. So the equilibrium settles to a stable fraction of the overall population.
- hmottestad 2y ago
  I think it’s more often «we know that this drug lowers X in blood results, cause we saw that when we trialed it for something a few years ago that didn’t work out, now we’ve found out that disease B shows high values of X…»
- robocat 2y ago
  A fabulous book on this is Phenethylamines I Have Known and Loved (PiHKAL) which can be found as a PDF online (the link I had has died but try Google and filetype:pdf). Summary: a chemist is interested in psychedelics so he starts creating candidate psychoactive substances, and he then tests them on himself and friends. He wrote a lovely book about his journey.
  - amanaplanacanal 2y ago
    Also its mate Tryptamines I Have Known And Loved.
- a_wild_dandan 2y ago
  Expected utility, just like anything else. It's why our ancestors ate willow tree bark (aspirin), for instance.
- sjducb 2y ago
  Mostly enormous libraries of compounds. You take a cell culture model for the disease and see if the compounds affect the cells. Then try it in animals, then humans. Repeat this process until you have good safe drugs for all of the diseases.
- mtlmtlmtlmtl 2y ago
  Sometimes by accident. The original serotonergic antidepressants were antibiotics that happened to have MAO inhibition as a side effect. Initially developed to treat tuberculosis, doctors noticed the drugs had a stimulating side effect. A year later, a psychiatrist decided to trial them for depression, and found some success. It's actually the other way around. They didn't have very serious theories about the etiology of depression back then, the only clue they had was from the pharmacology of these drugs, which led to the situation where for many years the leading theory on depression was that it was caused by low levels of monoamine neurotransmitters(serotonin, norepinephrine and dopamine). The main evidence for this initially was the fact that these drugs seemed to work, and that they increased the levels or effects of monoamines. This theory has since become discredited as we've learned more, although the connection between monoamines and depression is still strong. It's just not the whole picture.

lordnacho 2y ago

How do people come to find these drugs then? If you don't have a theory about how something works, what would make you test whether it works?

MaxDPS 2y ago
Sometimes there is a theory, but it’s also possible for a drug to help in other (unrelated) ways as well.
pitpatagain 2y ago
In the case of metformin, the direct line is from guanidine in french lilac being used since the middle ages for diabetes. Guanidine is effective, but long term liver toxic. Once actual chemistry broke open our ability to analyze that drug, related chemicals could be synthesized and studied, which led to biguanidines, of which metformin is one, which were tested in animals. Many drugs are found this way by looking at chemicals related to ones we already know about, and then testing on animals and humans. Self testing of new drugs by researchers used to be very common. How did folk medicine come to know the effects of guanidine? Dunno.
- groby_b 2y ago
  > How did folk medicine come to know the effects of guanidine? Dunno. The same way we know a lot about other things in the chemistry domain - somebody tasted it, just to see what happens. "Mendeleyev's Dream" is a great book that contains many fascinating anecdotes of people going "let me just lick this, just to try". (Or, if you want to go more modern, the history of hallucinogens is pretty fun too) Humans seem to have a strong tendency to stuff unknown things into their mouth, just because they can.
  - falcor84 2y ago
    Indeed. I would assume that this is one of the traits that survives due to group selection [0] - it would be bad if everyone in the population was such a risk taker, but groups that have a small percentage of these people will adapt better. [0] https://en.wikipedia.org/wiki/Group_selection https://en.wikipedia.org/wiki/Group_selection
    - elcritch 2y ago
      That's my belief on why ADHD has such similar levels of prevalence (between 5%) around the globe despite drastically different cultures and varying genetics. It's great for the group as a whole as the ADHD members tend to be natural entrepreneurs, inventors, etc. However it often sucks for the individual ADHD folks and leads to higher rates of, well, everything. So the equilibrium settles to a stable fraction of the overall population.
hmottestad 2y ago
I think it’s more often «we know that this drug lowers X in blood results, cause we saw that when we trialed it for something a few years ago that didn’t work out, now we’ve found out that disease B shows high values of X…»
robocat 2y ago
A fabulous book on this is Phenethylamines I Have Known and Loved (PiHKAL) which can be found as a PDF online (the link I had has died but try Google and filetype:pdf). Summary: a chemist is interested in psychedelics so he starts creating candidate psychoactive substances, and he then tests them on himself and friends. He wrote a lovely book about his journey.
- amanaplanacanal 2y ago
  Also its mate Tryptamines I Have Known And Loved.
a_wild_dandan 2y ago
Expected utility, just like anything else. It's why our ancestors ate willow tree bark (aspirin), for instance.
sjducb 2y ago
Mostly enormous libraries of compounds. You take a cell culture model for the disease and see if the compounds affect the cells. Then try it in animals, then humans. Repeat this process until you have good safe drugs for all of the diseases.
mtlmtlmtlmtl 2y ago
Sometimes by accident. The original serotonergic antidepressants were antibiotics that happened to have MAO inhibition as a side effect. Initially developed to treat tuberculosis, doctors noticed the drugs had a stimulating side effect. A year later, a psychiatrist decided to trial them for depression, and found some success. It's actually the other way around. They didn't have very serious theories about the etiology of depression back then, the only clue they had was from the pharmacology of these drugs, which led to the situation where for many years the leading theory on depression was that it was caused by low levels of monoamine neurotransmitters(serotonin, norepinephrine and dopamine). The main evidence for this initially was the fact that these drugs seemed to work, and that they increased the levels or effects of monoamines. This theory has since become discredited as we've learned more, although the connection between monoamines and depression is still strong. It's just not the whole picture.