This article kind of grinds my gears. I feel like there is an unstated assumption that people in pharma R&D are idiots and haven’t thought of this stuff.
Pharma companies care very much about off target effects. Molecules get screened against tox targets, and a bad tox readout can be a death sentence for an entire program. And you need to look at the toxicity of major metabolites too.
One of the major value propositions of non small molecule modalities like biologics is specificity, and alternative metabolism pathways; no need to worry about the CYPs.
Another thing they fail to account for is volume of distribution. Does it matter if it hits some receptor only expressed in microglia if it can’t cross the blood brain barrier?
Also the reason why off targets for a lot of FDA approved drugs are unknown is because they were approved in the steampunk industrial era.
To me this whole article reads like an advertisement for a screening assay.
I work in drug discovery (like for real, I have a DC under my belt, not hypothetical AI protein generation blah blah) and had the opposite experience reading it. We understand so little about most drugs. Dialing out selectivity for a closely related protein was one of the most fun and eye opening experiences of my career.
Of course we've thought of all these things. But it's typically fragmented, and oftentimes out of scope. One of the hardest parts of any R&D project is honestly just doing a literature search to the point of exhaustion.
Interestingly, it does not seem to have any controlled substances - even Schedule V drugs like Lyrica (pregabalin). So they've mapped estradiol and estrone, but not testosterone or drostanolone. Also cabergoline and pramipexole, but not amphetamine or methylphenidate.
All steroids have a very high risk of misuse, it's incredibly easy to get your body addicted one way or another and it's one of those things that's very hard to fix after the fact.
Steroid abuse indicates body dysmorphia. There isn’t an addictive property like other abused drugs, unless you’re considering it addictive via its effects on dopamine production.
Your body doesn’t become addicted, though. The potential for harm is real if you are not taking it under medical supervision or without proper knowledge of usage, like any other drugs.
The addictive component makes sense, does that mean men who are injured and produce less go through withdrawal? Or like men as they age? That sounds miserable.
This is absolutely false. There's thousands of gym bros who've done absolutely stupid cycles with absolutely no post cycle therapy who've recovered and are producing testosterone again.
I personally know of several early 20s guys who were between light and heavy cycles all under the supervision of doctors (or at least getting blood tested periodically).
All of them have renal issues, kidney issues, adrenal system issues, thyroid issues. Some have heart problems. Not one of them is unscathed.
It's a steroid, so body builders would use it constantly. It's a sex hormone, so people would use it to masculinize themselves and amp up their sex drive, and it's part of the pubertal cycle so children exposed to it pre-puberty can have masculinizing pubertal side effects before their actual puberty starts.
I'm not saying to sell it over the counter but surely just bring a prescription would be sufficient. I see medspa clinics advertising it to men for its masculinizing effects so it can't be that hard to acquire.
It's not hard to acquire. Doesn't mean that it's not a controlled substance.
And in fact it is sold over the counter in other countries like Mexico. You get a "prescription" from the "on-site pharmacist" who is actually just some person who works the register.
Is that how that works?! I've always wondered what legal trickery they used since Mexico isn't listed on the WHO's list of countries who don't require Rx for antibiotics.
Yes, but the DEA is unrelentingly cranky and likes to tell physicians how to practice medicine despite swearing up and down that they would never, ever do that.
This article kind of grinds my gears. I feel like there is an unstated assumption that people in pharma R&D are idiots and haven’t thought of this stuff.
Pharma companies care very much about off target effects. Molecules get screened against tox targets, and a bad tox readout can be a death sentence for an entire program. And you need to look at the toxicity of major metabolites too.
One of the major value propositions of non small molecule modalities like biologics is specificity, and alternative metabolism pathways; no need to worry about the CYPs.
Another thing they fail to account for is volume of distribution. Does it matter if it hits some receptor only expressed in microglia if it can’t cross the blood brain barrier?
Also the reason why off targets for a lot of FDA approved drugs are unknown is because they were approved in the steampunk industrial era.
To me this whole article reads like an advertisement for a screening assay.
I work in drug discovery (like for real, I have a DC under my belt, not hypothetical AI protein generation blah blah) and had the opposite experience reading it. We understand so little about most drugs. Dialing out selectivity for a closely related protein was one of the most fun and eye opening experiences of my career.
Of course we've thought of all these things. But it's typically fragmented, and oftentimes out of scope. One of the hardest parts of any R&D project is honestly just doing a literature search to the point of exhaustion.
>molecules get screened against tox targets
sure! i cover this in the essay, the purpose of this dataset is not just toxicity, but repurposing also
>toxicity of major metabolites
this is planned (and also explicitly mentioned in the article)
>no need to worry about CYP’s
again, this is about more than just toxicity
>volume of distribution
i suppose, but this feels like a strange point to raise. this dataset doesnt account for a lot of things, no biological dataset does
>advertisement
to some degree: it is! but it is also one that is free for academic usage and the only one of its kind accessible to smaller biopharmas
Interestingly, it does not seem to have any controlled substances - even Schedule V drugs like Lyrica (pregabalin). So they've mapped estradiol and estrone, but not testosterone or drostanolone. Also cabergoline and pramipexole, but not amphetamine or methylphenidate.
Is testosterone a controlled substance? But why?
All steroids have a very high risk of misuse, it's incredibly easy to get your body addicted one way or another and it's one of those things that's very hard to fix after the fact.
Steroid abuse indicates body dysmorphia. There isn’t an addictive property like other abused drugs, unless you’re considering it addictive via its effects on dopamine production.
Your body doesn’t become addicted, though. The potential for harm is real if you are not taking it under medical supervision or without proper knowledge of usage, like any other drugs.
The addictive component makes sense, does that mean men who are injured and produce less go through withdrawal? Or like men as they age? That sounds miserable.
It means the body stops producing it and won't ever again.
This is absolutely false. There's thousands of gym bros who've done absolutely stupid cycles with absolutely no post cycle therapy who've recovered and are producing testosterone again.
That's the tag-line but it isn't true.
I personally know of several early 20s guys who were between light and heavy cycles all under the supervision of doctors (or at least getting blood tested periodically).
All of them have renal issues, kidney issues, adrenal system issues, thyroid issues. Some have heart problems. Not one of them is unscathed.
Because it can be dangerous if misused.
It's a steroid, so body builders would use it constantly. It's a sex hormone, so people would use it to masculinize themselves and amp up their sex drive, and it's part of the pubertal cycle so children exposed to it pre-puberty can have masculinizing pubertal side effects before their actual puberty starts.
Everything can be dangerous if misused
I'm not saying to sell it over the counter but surely just bring a prescription would be sufficient. I see medspa clinics advertising it to men for its masculinizing effects so it can't be that hard to acquire.
You asked why it was a controlled substance.
It's not hard to acquire. Doesn't mean that it's not a controlled substance.
And in fact it is sold over the counter in other countries like Mexico. You get a "prescription" from the "on-site pharmacist" who is actually just some person who works the register.
Is that how that works?! I've always wondered what legal trickery they used since Mexico isn't listed on the WHO's list of countries who don't require Rx for antibiotics.
Wouldn't needing a prescription be... a control?
Yes, but the DEA is unrelentingly cranky and likes to tell physicians how to practice medicine despite swearing up and down that they would never, ever do that.
This substack has a serious fraud smell
People have been doing this for literally decades. Check out work by Tattonetti
EvE Bio dataset and explorer: https://data.evebio.org/
Novartis dataset paper: https://doi.org/10.1038/s41467-023-40064-9