I'm not a specialist but I think there are some stapled peptides that do show appreciable uptake, so the blog post is not a complete history; this review reports bioavailability of up to 70% for some agents.
Nielsen DS et al. 2017. Orally Absorbed Cyclic Peptides. Chemical Reviews.
Yep, I think it is. The point is there's almost no history of oral peptides, other than stomachs destroying them.
FTA: "So to summarize the state of the art in oral peptide delivery: there are exactly two FDA-approved products that use permeation enhancers to get peptides into your bloodstream through your GI tract. Both achieve sub-1% bioavailability. Both required over a decade of development, thousands of clinical trial participants, and hundreds of millions of dollars."
Would a sublingual dose be possible/more effective? Research in other (um, yeah, medicinal!) compounds shows that it can be an effective pathway to the bloodstream rather than trying to survive the digestive system.
Local buffering — pH microenvironment control (semaglutide)
One I take, PEP19, apparently is unique in being naturally bioactive. Evidence is early stage, but I get noticably better sleep with it (by some non-drowsiness mechanism), taking 6mg, 3x the recommended dosage for sleep, but the higher dose may promote fat burning and fat browning at night (only 1 study). It only has 10 residues which apparently avoid having typical cleavage points, fragments may retain bioactivity, and it has extreme potency in very small doses so any absorption means a lot.
Despite a plethora of peptides, successes are not common.
They probably didn't, they just took the bet that this was one of the crimes that are currently legal, like crypto scams, environmental crimes, bribery, and tay evasion for the rich.
Some of the most profitable ventures this century have been objectively illegal, but when you know you won't go to prison for violating the law, why would you care to follow it?
It probably is legal at the moment, but the rules may be changed to make it illegal. But also Uber and Lyft were super illegal when they were invested in. To some extent, YCombinator partners are on the record[0] supporting the idea of their startups doing illegal things.
Generally they'll frame this as challenging outdated regulations, but they acknowledge that the founders whose strategies they fully support sometimes come into office hours and discuss how they're worried that the strategy puts them at risk of going to jail.
There are different kinds of illegal, and Hims/Hers may end up getting blocked from their current business model, or they may end up entrenching new ways for consumers to get affordable care. The jury is very much still out.
Pretty sure it's illegal. You can get peptides (even GLP-1's) legally from various sources for "Research Purposes", but they're marked as "Not For Human Consumption" (even though, on the sly, I'm sure they're aware people are buying these for human consumption and they provide purity tests etc.) What makes it illegal though, is when you say it is for human consumption, or worse market it as a treatment for a disease. That's when you actually need FDA approval.
I am bored to tears by this and it is simultaneously heart-breaking. My MD friend wasted $100K on MicroStrategy, ignoring my advice when he asked for it a couple months ago, and he's like "It's fine I'm not 65." and then proceeded to explain he absolutely should hold it because Trump will add it to Bitcoin strategic reserve.
Been following the market for 30 years and I've never seen loss per share > $10. They lost $42/share. Didn't make a dent in our conversation, I think he just ignored it twice.
Of note: They all basically run off the backs of 1099’d “contracted” “doctors” (nurse practitioners and other low-to-midlevels that can rubber stamp scripts).
Do they actually make a proper assessment? Questionable, they’re going based on the lies you tell them over text and video. Here’s your script for your dick pills, come back soon!
I'm not a specialist but I think there are some stapled peptides that do show appreciable uptake, so the blog post is not a complete history; this review reports bioavailability of up to 70% for some agents.
Nielsen DS et al. 2017. Orally Absorbed Cyclic Peptides. Chemical Reviews.
https://sci-hub.ru/10.1021/acs.chemrev.6b00838
> this review reports bioavailability of up to 70% for some agents
To save us some skimming, could you specify which ones? (The review covers cyclic peptides that are absorbed by all mammals.)
There are several - I’m not sure why you say cyclic peptides are somehow distinct from other peptides regarding their bioavailability?
All peptides face similar challenges with absorption; the cyclic peptides simply have less liability to proteolysis.
The text covers dozens of agents with varied biochemical properties.
It’s a great read but is this really the history of oral peptides?
Yep, I think it is. The point is there's almost no history of oral peptides, other than stomachs destroying them.
FTA: "So to summarize the state of the art in oral peptide delivery: there are exactly two FDA-approved products that use permeation enhancers to get peptides into your bloodstream through your GI tract. Both achieve sub-1% bioavailability. Both required over a decade of development, thousands of clinical trial participants, and hundreds of millions of dollars."
Would a sublingual dose be possible/more effective? Research in other (um, yeah, medicinal!) compounds shows that it can be an effective pathway to the bloodstream rather than trying to survive the digestive system.
7 replies →
Here is a list of ways bioactivity is achieved in 6 cases via 7 mechanisms:
Cyclization + N-methylation — lipophilicity, protease resistance (cyclosporine)
D-amino acid substitution — protease evasion (desmopressin)
Permeation enhancers — transient tight-junction opening or membrane fluidization (semaglutide/SNAC, insulin formulations)
Extreme potency — tolerating <1% bioavailability (desmopressin)
Minimizing size to di/tripeptides — exploiting PepT1 active transport (collagen hydrolysates)
Prodrug masking — protecting reactive groups, intracellular unmasking (S-acetyl-glutathione)
Local buffering — pH microenvironment control (semaglutide)
One I take, PEP19, apparently is unique in being naturally bioactive. Evidence is early stage, but I get noticably better sleep with it (by some non-drowsiness mechanism), taking 6mg, 3x the recommended dosage for sleep, but the higher dose may promote fat burning and fat browning at night (only 1 study). It only has 10 residues which apparently avoid having typical cleavage points, fragments may retain bioactivity, and it has extreme potency in very small doses so any absorption means a lot.
Despite a plethora of peptides, successes are not common.
Is this ChatGPT?
I'm not sure why the hims investors ever thought that this was legal
They probably didn't, they just took the bet that this was one of the crimes that are currently legal, like crypto scams, environmental crimes, bribery, and tay evasion for the rich.
Hims has donated $1M to the current administration, which supports this theory
Pretty sure you don't have to be rich to get away with avoiding Taylor Swift.
Some of the most profitable ventures this century have been objectively illegal, but when you know you won't go to prison for violating the law, why would you care to follow it?
The process of chlorinating water was first done illegally.
7 replies →
It probably is legal at the moment, but the rules may be changed to make it illegal. But also Uber and Lyft were super illegal when they were invested in. To some extent, YCombinator partners are on the record[0] supporting the idea of their startups doing illegal things.
Generally they'll frame this as challenging outdated regulations, but they acknowledge that the founders whose strategies they fully support sometimes come into office hours and discuss how they're worried that the strategy puts them at risk of going to jail.
There are different kinds of illegal, and Hims/Hers may end up getting blocked from their current business model, or they may end up entrenching new ways for consumers to get affordable care. The jury is very much still out.
0: https://www.youtube.com/watch?v=Hm-ZIiwiN1o&t=8m46s
Pretty sure it's illegal. You can get peptides (even GLP-1's) legally from various sources for "Research Purposes", but they're marked as "Not For Human Consumption" (even though, on the sly, I'm sure they're aware people are buying these for human consumption and they provide purity tests etc.) What makes it illegal though, is when you say it is for human consumption, or worse market it as a treatment for a disease. That's when you actually need FDA approval.
1 reply →
> Hims/Hers may end up getting blocked from their current business model, or they may end up entrenching new ways for consumers to get affordable care
Well, no: the thing that's a lot cheaper is a placebo at best, and they were just referred to the DOJ for prosecution.
The rest is more expensive
6 replies →
The charitable assumption is that investors weren't aware it was a problem.
AFAIK it's a meme stock, reality doesn't matter anymore than it matters for Tesla or Gamestock.
I am bored to tears by this and it is simultaneously heart-breaking. My MD friend wasted $100K on MicroStrategy, ignoring my advice when he asked for it a couple months ago, and he's like "It's fine I'm not 65." and then proceeded to explain he absolutely should hold it because Trump will add it to Bitcoin strategic reserve.
Been following the market for 30 years and I've never seen loss per share > $10. They lost $42/share. Didn't make a dent in our conversation, I think he just ignored it twice.
Investors, or management?
Appreciate the perspective on the risk of dubious formulations. Consequences are far more than cosmetic.
Informative article but I feel like it could have benefited from a paragraph about what Hims is. I had never heard of them before.
An online pharmacy that advertises pretty aggressively, with men being the target audience. Hair loss, erectile dysfunction, that sort of thing.
https://en.wikipedia.org/wiki/Hims_%26_Hers_Health
Of note: They all basically run off the backs of 1099’d “contracted” “doctors” (nurse practitioners and other low-to-midlevels that can rubber stamp scripts).
Do they actually make a proper assessment? Questionable, they’re going based on the lies you tell them over text and video. Here’s your script for your dick pills, come back soon!
wait till you discover soviet bioregulators (peptides by dr khavinson). all designed for oral.
great read!
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