How did famous chemists know how drugs would affect the brain?

[sghouston5]

This is a question that has always bothered me a bit, so I figured some here may be knowledgable about it.

For example, Dr. Shulgin "rediscovered" MDMA in the 70s and tried it on himself. How did he have any way of knowing what affinity the chemical would have for which receptors in the brain? How could he have possibly known or guessed any of the effects? Was it just "blindfolded luck" ?

That is to say, what if someone synthesized a chemical, tried it, then it immediately like melted their brain (figureatively speaking of course) but you get the picture. Was there some sort of evidence that suggested it might have an effect on the brain in any way? I know Hoffman discovered LSD by accident, then took it thereafter intentionally, but can you imagine what they must have been feeling? They had no previous experiences to base it from, nothing to go by? It must have been terrifying at first, not knowing what the hell is happening to you?

 

[endotropic]

The short answer is they didn't.

Shulgin read about MDMA in old Merck patent literature. It had gone through animal testing already so he knew it wasn't acutely toxic (to rats at least). He also knew how related chemicals like meth worked in humans, but it was really the animal testing that let him know he wasn't swallowing poison. I think he talks about that discovery more in the first half of PiHKAL.

And as strange as it sounds that's pretty much how all drug discovery worked until relatively recently (especially with psychoactive drugs, the brain being something of a black box to this day). If you know the drug improves an illness, and the side effects are tolerable, do you really need to know how it works at a molecular level before you start treating sick people with it?

 

[sghouston5]

Makes enough sense. I suppose that explains the billions over the course of history who have likely sacrificed their lives through the trial and error of eating different plants or chemical combinations to lead us in the right direction. It's just a "guessing game" then? Think of all those primitives who died eating poisonous berries dying a terrible death, and then think of those who used poppy plants and noticed the pain was gone.

What a coincidence that an infamous and reknowned chemist like Shulgin would "rediscover" MDMA, and go on to synthesize even more psychoactive chemicals. Just bewilders me that someone on the frontier of all that would even know where to start. I know it was first synthesized in 1912, but even then it's like, what did they think would happen, what theory did they have to combine just the right chemicals to synthesize MDMA and for what purpose. It's all very interesting to think about the way drugs came about into our modern culture.

 

[endotropic]

What a coincidence that an infamous and reknowned chemist like Shulgin would "rediscover" MDMA, and go on to synthesize even more psychoactive chemicals. Just bewilders me that someone on the frontier of all that would even know where to start. I know it was first synthesized in 1912, but even then it's like, what did they think would happen, what theory did they have to combine just the right chemicals to synthesize MDMA and for what purpose. It's all very interesting to think about the way drugs came about into our modern culture.

That's a great question. It might have been in trials as a potential weight loss drug, but I haven't seen anything conclusive one way or another. Here's some more info about the timeline of MDMA's discovery: http://thedea.org/drughistory.html

(so where did that UCSF student find it??)

 

[sekio]

(so where did that UCSF student find it??)

If Shulgin and the US Army etc could find it, why not one more enterprising young lad who surfs patent literature?

 

[endotropic]

If Shulgin and the US Army etc could find it, why not one more enterprising young lad who surfs patent literature?

That's just the thing though - according to that link the UCSF student turned Shulgin on in the first place. I don't know whether that's accurate or not (I can't remember what Sasha said about it in PiHKAL) but it does make you wonder who that student was.

 

[sekio]

I thought Shulgin synthesized it but never tested it until the UCSF student told him about it?

 

[Jonneh]

This question gets at a couple of related issues I'm curious about - how did Shulgin establish an initial dose and titration progression for newly synthesised compounds? Did he take some sort of 'nearest neighbour' approach to make a best-guess, or perhaps addition and substitution is more predictable than I had imagined in terms of its effect on dose and dose-response curve shape?

 

[BlueBull]

This question gets at a couple of related issues I'm curious about - how did Shulgin establish an initial dose and titration progression for newly synthesised compounds? Did he take some sort of 'nearest neighbour' approach to make a best-guess, or perhaps addition and substitution is more predictable than I had imagined in terms of its effect on dose and dose-response curve shape?

IIRC he always started with a µg, then 2µg, then 4µg... until he reached a dose where first effects were felt. I think he reasoned that there would be no drug with an active dose under 1 µg. Don't know if this is correct though, it's been years since I read Pikhal so I could be completely wrong. Should read that book again actually...

 

[Jonneh]

IIRC he always started with a µg, then 2µg, then 4µg... until he reached a dose where first effects were felt. I think he reasoned that there would be no drug with an active dose under 1 µg. Don't know if this is correct though, it's been years since I read Pikhal so I could be completely wrong. Should read that book again actually...

That would imply 15-18 dose doublings for an average compound, giving time with each dose for things to come on. It's hard work being a psychedelic chemist! I imagined he would have started at the low end of a rough guess based on the effects of similar compounds and the changes relative thereto.

 

[BlueBull]

^
Don't know if he doubled at every step or if he used any added deduction to determine starting dose. I just know he titrated upwards starting from a dose that would most definitely not have any effects. I know that's what he proposed in the vice documentary on him when he asked the interviewer what dose he would suggest starting at but I can't remember if that was also the way he tested new compounds in PiHKAL. I just looked for my copy of the book but can't find it among the countless boxes of books left packed after I moved

A quote I came across in the vice article accompanying their documentary

Shulgin created a series of sulfur-containing psychedelic amphetamines named after the Hebrew letter א. ALEPH-1 was the first. True to his method of vigilant titration, his first dose was 250 nanograms. Over the course of 18 trials he worked up to a single milligram. It detonated an intellectual hydrogen bomb in his prefrontal cortex.

 

[Jonneh]

Thanks for the info BlueBull.

No wonder nothing ever really went wrong then! I suppose he got one or two surprises with things with steep dose-response curves, but caution certainly worked for him.

 

[irobeth]

^
I can't remember if that was also the way he tested new compounds in PiHKAL.

Keeping in mind he explored mostly one substitution at a time - I remember reading either in AskShulgin or one of the books a passage with him describing why he was comfortable testing things on himself, and it included him mentioning his doses and something along the lines of 'in pharmacological history, no small change in a molecule has radically changed its pharmacological profile' (the last part w/r/t effects, not doses - would we could NBOMe against this? that change isn't 'small' by any means)