alt.hn

2/9/2026 at 9:23:27 PM

A brief history of oral peptides

 https://seangeiger.substack.com/p/a-brief-history-of-oral-peptides

by odedfalik

2/10/2026 at 11:14:52 PM

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

by bonsai_spool

2/11/2026 at 6:09:57 AM

> 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.)

by JumpCrisscross

2/11/2026 at 6:55:35 AM

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.

by bonsai_spool

2/12/2026 at 12:00:59 AM

> I’m not sure why you say cyclic peptides are somehow distinct from other peptides regarding their bioavailability?

I'm saying there are peptides on that list that are bioavailable to non-human mammals.

by JumpCrisscross

2/10/2026 at 7:55:36 PM

It’s a great read but is this really the history of oral peptides?

by celltalk

2/10/2026 at 8:48:09 PM

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."

by abainbridge

2/10/2026 at 10:18:30 PM

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.

by pstuart

2/10/2026 at 10:24:02 PM

Sublingual is even harder. The sublingual mucosa is thin but selective. It strongly favors molecules that are small, lipophilic and uncharged. Semaglutide is about 8-10x too big, highly polar and charged.

Injection is really the only method with any substantial bioavailability. BUT, low (<1%) bioavailability does not necessarily mean useless.

by CGMthrowaway

2/10/2026 at 11:32:40 PM

> BUT, low (<1%) bioavailability does not necessarily mean useless.

Can you say more about that point ?

by cassepipe

2/11/2026 at 12:08:05 AM

If the drug has a relatively low marginal cost of production, and the stomach just breaks down 99% of it without side effects, you can just manufacture 100x more, give it orally, and eat the cost of the 99% that gets lost along the way.

Injectable Semaglutide/Tirzepatide (>99.8% pure) are currently sold at a profit from China for around $2-3/weekly dose. Rybelsus (oral semaglutide) is sold at roughly the same cost per milligram, even though it's made in FDA-approved facilities (you just need to take >= 40x more milligrams per month, bringing it to $1000/month in the USA)

So manufacturing oral doses 100x higher than injectable seems to be economically viable.

by nerdsniper

2/10/2026 at 10:22:13 PM

It would be hilarious if people wound up snorting or boofing their GLP-1s (≧▽≦)

by rodarmor

2/10/2026 at 11:18:52 PM

Insufflation for medicinal purposes if it works and doesn't cause harm seem like a win. Less needles == more use.

by pstuart

2/11/2026 at 12:51:48 AM

Ancedotal but it's really hard for me to do insufflation because of the discomfort. Of course if my life depended on it I could probably do it but otherwise I'd rather not.

by LoganDark

2/10/2026 at 11:27:04 PM

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.

by Nevermark

2/11/2026 at 6:12:35 AM

Is this ChatGPT?

by JumpCrisscross

2/9/2026 at 9:34:08 PM

I'm not sure why the hims investors ever thought that this was legal

by Kaminsk13

2/10/2026 at 8:02:38 PM

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.

by InsideOutSanta

2/11/2026 at 12:12:32 AM

Hims has donated $1M to the current administration, which supports this theory

by sincerely

2/11/2026 at 10:06:26 AM

Pretty sure you don't have to be rich to get away with avoiding Taylor Swift.

by JasonADrury

2/10/2026 at 8:22:49 PM

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?

by badrequest

2/10/2026 at 10:23:52 PM

The process of chlorinating water was first done illegally.

by pixl97

2/10/2026 at 10:30:55 PM

Also:

  human dissection (grave robbing)
  translating the Bible into English
  silk production outside of China (death penalty for exporting worm eggs)
  rubber production in Asia (seeds smuggled out of Brazil)
  the Underground Railroad
  heliocentrism
  AIDS treatment (see Dallas Buyers Club)
  Needle exchange programs for IV drug users
  Ridesharing/airbnb/napster (obvious ones)
  SF gay marriage licenses (in defiance of CA law)

by CGMthrowaway

2/11/2026 at 12:48:13 AM

Translating the Bible into English was not illegal. I very much doubt Bede or the monks of Lindisfarne were breaking the law!

The same for heliocentrism. No one took Copernicus to court.

With silk and rubber the smuggling was illegal, the actual cultivation was not

Grave robbing was illegal (and still is) but dissection was not.

Needle exchange was illegal in some US states but was legal in many other countries.

by graemep

2/11/2026 at 5:48:46 AM

Reference to support the claim that translating the bible into English was banned (William Tyndale was executed for doing it): https://nobimu.no/en/subject-articles/banned-translations-of...

You can nitpick that "the church executing people for it" is not exactly the same as "illegal" but that's missing the point.

by chihuahua

2/11/2026 at 1:56:07 PM

The context of this is the list of examples was of things done illegally for the first time - it lists these things as "also" in response to a claim that water was *first* chlorinated illegally.

While there were bans or a requirement for authorisation of translations of the Bible in certain times and places (mostly the 1300s to 1500s) the first translations of (parts of the) Bible into English had been done centuries before this, some as early at the 7th century. This makes them some of the oldest written works we know of in English at all. They were also done by the church.

> You can nitpick that "the church executing people for it" is not exactly the same as "illegal" but that's missing the point.

When did this happen? Tyndale was tried and executed by the secular authorities in a place where there were no laws against translating the Bible.

The earliest translations into English were done by the Church.

by graemep

2/11/2026 at 4:11:47 PM

Galileo. You are right about Copernicus.

>Needle exchange was illegal in some US states but was legal in many other countries

I'm not sure what your point is here

by CGMthrowaway

2/10/2026 at 10:42:47 PM

> The process of chlorinating water was first done illegally.

I tried to find a source on this but it doesn't seem to be true? The first chapter of this book describes the history of chlorination: https://upload.wikimedia.org/wikipedia/commons/f/fd/Chlorina... (which is a source Wikipedia cites) and it doesn't appear to mention anything about illegally chlorinating water. After looking in that book I asked ChatGPT to find a source for the claim, and it reported the claim was false. Chlorination was initially controversial but I can't find anything claiming it was illegal?

by maxbond

2/12/2026 at 5:18:31 PM

>Jersey City v. Jersey Water Supply Company

by pixl97

2/12/2026 at 6:57:09 PM

Thank you for replying, I appreciate it. I enjoyed learning more about this history. Making a citation invites the risk of being contradicted, and I respect that.

I do still disagree for the following reasons:

- Jersey City started chlorinating in 1908; Maidstone, England started chlorinating in 1897 and Lincoln, England started chlorinating in 1905. So Jersey City wasn't the first to chlorinate their water.

However, Jersey City seems to be the first deployment in the United States, so perhaps that is what you meant. If this were the only issue I would concede the point.

- This was a civil matter and not a criminal matter.

- The dispute wasn't whether chlorination was legal or acceptable but whether it was sufficient to deliver "pure and wholesome" water. The city wanted them to build a sewer. The utility didn't really dispute that there was a water quality issue but they built a chlorination plant instead of building a sewer (while the lawsuit was still ongoing).

- The water utility won. They demonstrated that chlorination was sufficient.

That's the impression I took from Wikipedia and this writeup: https://www.dolmetsch.com/chlorination_history.pdf (Starting on page 4)

by maxbond

2/11/2026 at 1:12:47 AM

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

by nerdsniper

2/11/2026 at 3:40:04 AM

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.

by overgard

2/11/2026 at 3:49:25 AM

Compounding pharmacies generally operate outside of what we typically think of when we think of "FDA approval".

by nerdsniper

2/11/2026 at 2:30:17 AM

> 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

by refulgentis

2/11/2026 at 3:00:27 AM

Hims offered semaglutide for $99/month. That’s a 90% discount on unsubsidized consumer prices for injectable semaglutide. I also don’t see any evidence that they sold a placebo, but I’m just catching up now, perhaps I missed where they’re selling something with a different active ingredient which does not work.

by nerdsniper

2/11/2026 at 4:25:01 AM

> Hims offered semaglutide for $99/month. That’s a 90% discount on unsubsidized consumer prices for injectable semaglutide.

It's not a 90% discount. Novo charges $350/mo or less.

by loeg

2/11/2026 at 3:13:41 AM

Its in the article that you didn't read lol

by simulator5g

2/11/2026 at 3:34:31 AM

I've since read TFA, as well as many other articles, official correspondence, and case law around the issue. I understand that without the additional ingredients of SNAC/sodium caprate/sodium caprylate, the bioavailability is probably too low to have a clinical effect at oral doses <15mg/day.

I read the actual FDA referral to the DOJ. They don't mention anything about any of what this article touches on. It's not clear that the referral makes correct claims about anything illegal going on. In statements, the FDA says that compounding pharmacies "cannot state compounded drugs use the same active ingredient as the FDA-approved drugs". That's a very brand-new interpretation of rules, and might not stand up to judicial scrutiny. In the context of "shouldn't investors have known that Hims business model is illegal??" -- it makes sense that investors couldn't have known ahead of time that the FDA would claim this.

https://www.fda.gov/inspections-compliance-enforcement-and-c...

by nerdsniper

2/11/2026 at 7:40:45 AM

i haven't read the article. is the question, can hims ship a clone of 25mg oral wegovy? yes, it can.

> ... at oral doses <15mg/day.

well it's not a clone of rybelsus, it's a clone of wegovy 25mg. so i suppose it will be bioavailable at 25mg.

> That's a very brand-new interpretation of rules

this is true. Tidmarsh, the whole Novo Nordisk deal with Trump, it's now about, well we'll do the patent enforcement we didn't want to do before. The simple fact of the matter is, these are lifestyle products, so it's not so black and white if they ought to have the same patent and payment protections as typical therapeutics.

by doctorpangloss

2/11/2026 at 6:11:42 PM

> well it's not a clone of rybelsus, it's a clone of wegovy 25mg. so i suppose it will be bioavailable at 25mg.

No. RTFA. Feed it into an LLM with the first thought off the top of your head. Skim it quick. Whatever. (tl;dr: the clone skips the ingredient that makes the contents bioavailable)

by refulgentis

2/11/2026 at 10:14:50 PM

i have a feeling that what actually happened is that absence of the ingredient in the text that the article is talking about is a documentation error, and that's why the FDA makes no mention about it at all (as you discovered). i think the thing that is getting shipped has the ingredient and this is a nothingburger.

indeed, the only evidence that the clone is missing the ingredients is the guy read a Reuters article about it, and asked the chatbot (presumably) to do research. the clones in this sector are pretty faithful. i'm going to chalk it up to, "declined to elaborate" doesn't mean, as the author insinuates, that Hims has a bad clone, i think they just didn't answer the question and there's nothing more to this.

this is coming from my place as knowing a lot about this sector and the simple fact of the matter is, they just make a clone and they do it faithfully.

by doctorpangloss

2/12/2026 at 5:32:55 AM

“What’s more likely is they’re sitting on an unknown breakthrough that took pharmaceutical companies billions and years and just launched.” - you sure you read it this time?

by refulgentis

2/11/2026 at 7:31:46 AM

Not sure why you're being downvoted, it was clear they hadn't based on their post, and they admit they didn't.

by refulgentis

2/10/2026 at 8:01:12 PM

The charitable assumption is that investors weren't aware it was a problem.

by kps

2/11/2026 at 2:04:06 AM

AFAIK it's a meme stock, reality doesn't matter anymore than it matters for Tesla or Gamestock.

by marticode

2/11/2026 at 2:31:19 AM

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.

by refulgentis

2/11/2026 at 4:26:40 AM

Investors, or management?

by loeg

2/9/2026 at 10:41:16 PM

Appreciate the perspective on the risk of dubious formulations. Consequences are far more than cosmetic.

by Boot2Root

2/10/2026 at 9:31:57 PM

Informative article but I feel like it could have benefited from a paragraph about what Hims is. I had never heard of them before.

by badc0ffee

2/10/2026 at 11:19:25 PM

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

by maxbond

2/11/2026 at 3:21:01 PM

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!

by kotaKat

2/9/2026 at 9:30:22 PM

great read!

by ydai0531

2/11/2026 at 7:25:42 AM

wait till you discover soviet bioregulators (peptides by dr khavinson). all designed for oral.

by parthsuthar

2/10/2026 at 8:07:19 PM

[flagged]

by ftchd