Cognitive and neuro

PE-22-28

Little of the selling belongs to the molecule in the vial

7 sections

Top of article
What it actually is
What it is supposed to do
What people take it for
The dose question
How to check you have the right molecule
What people get wrong
What is known about harm

What circulates: 100 to 2,000 mcg per dose, mostly up the nose
What was studied: No human dose I could find, by any route
The gap: No published human dose to compare against
How long it lasts: I could find no published half life for this molecule, in any species, by any route. I found no study measuring how much of it gets into the blood, how far it spreads or how fast it clears. The 23 hours that appears everywhere belongs elsewhere: that experiment injected two modified versions into the abdominal cavity of mice at 3.2 to 40 micrograms per kilogram, ten mice per time point, and PE-22-28 itself was not in it. It is also not a blood level at all but a half effect time, meaning the time at which half the behavioural effect was left, and the paper's own results and discussion disagree about which of the two modified molecules the 23 hours belongs to. Every once daily on a protocol page is therefore a schedule with no measured duration behind it.

What it actually is

PE-22-28 is a lab made chain of seven amino acids, the small building blocks that proteins are made from, and a short chain like that is called a peptide. Its name is a set of coordinates. Sortilin is a receptor protein on cell surfaces, and a cell builds it with a 44 amino acid leader piece at the front, called the propeptide, that gets cut off when the receptor matures. Residues 22 through 28 of that leader piece are this molecule. It is also the tail end of a longer peptide called spadin, and it is also called mini-spadin. It was not designed: its inventors left spadin in mouse serum, watched it fall apart, and built short peptides out of the fragments. It is sold as an antidepressant peptide, and the evidence behind that claim is animal work from one laboratory, in male mice.

What it is supposed to do

The target is TREK-1, a potassium channel, meaning a pore that lets potassium leak out of a nerve cell and so makes that cell harder to fire. A channel sitting open is a brake on firing, and blocking it takes the brake off. The idea did not start with a drug. Heurteaux and colleagues bred mice without the TREK-1 gene and reported they resisted depression in five behavioural models, so everything since has been an attempt to reproduce a lifelong genetic absence with an injection into an adult. Two things complicate the story. The same laboratory later reported that the effect runs both ways in mice, a low dose opening the channel and a dose a hundred times higher closing it, with nothing tried in between, so it is not a blocker in the way a product page implies. And a group at Portsmouth put the channel into frog eggs and could not significantly inhibit the activated channel with the parent peptide at fourteen times the concentration its published figure said should work.

What people take it for

It is sold and talked about as an antidepressant. One of the pages that carries doses splits them between mood and between thinking and memory. That is what it is marketed for rather than what it has been shown to do: the antidepressant result is how long a mouse floats in a cylinder of water, ten male mice per group, timed by hand, half an hour after one injection into the abdominal cavity. I could find no study giving this peptide to a person.

The dose question

What circulates: 100 to 2,000 mcg per dose, mostly up the nose
What was studied: No human dose I could find, by any route; Every published dose is in a mouse: 3.0 to 4.0 mcg/kg into the abdominal cavity, and 1 mg/kg by tube into the stomach in one panel

No studied dose to compare

There is nothing to compare against, because I could find no published or registered study giving PE-22-28, spadin or any analogue of either to a person. Every published dose is in a mouse, and the two routes the market runs on, up the nose and under the skin, returned nothing when I paired either name with them on PubMed. Scaling the mouse dose by the standard body surface area conversion gives about 17 to 23 micrograms for a 70 kilogram adult, which puts the low end of the convention roughly four to six times above that and the high end ninety to a hundred and twenty times. That arithmetic is a check on the method, not a dose.

Reported because it is what people use. Nothing here recommends any amount.

How long it lasts

I could find no published half life for this molecule, in any species, by any route. I found no study measuring how much of it gets into the blood, how far it spreads or how fast it clears. The 23 hours that appears everywhere belongs elsewhere: that experiment injected two modified versions into the abdominal cavity of mice at 3.2 to 40 micrograms per kilogram, ten mice per time point, and PE-22-28 itself was not in it. It is also not a blood level at all but a half effect time, meaning the time at which half the behavioural effect was left, and the paper's own results and discussion disagree about which of the two modified molecules the 23 hours belongs to. Every once daily on a protocol page is therefore a schedule with no measured duration behind it.

Route studied

Injected into the abdominal cavity of mice, at 3.0 to 4.0 micrograms per kilogram, and in one panel by a tube passed into the stomach at 1 milligram per kilogram. No route in a person that I could find.

Route used

Up the nose, and under the skin. My PubMed search pairing either peptide name with the nose, the mouth or the skin returned no records.

How to check you have the right molecule

Read the sequence on the certificate. PE-22-28 is seven building blocks, written GVSWGLR in the one letter shorthand, which is glycine, valine, serine, tryptophan, glycine, leucine, arginine, and the chemistry checked behind this entry puts its weight at 773.9 with the registry number 1801959-12-5. The trap here is not a counterfeit, it is a name. The 2017 paper calls three molecules spadin-analogs together, and several of the most quoted results belong to only two of them: G/A-PE 22-28, which is AVSWGLR, the first glycine swapped for alanine, and a version of that with a biotin group stuck on the front. Both are different molecules. So is spadin, the seventeen building block parent, APLPRWSGPIGVSWGLR, whose last seven letters are this compound. So the paperwork check is the citation as much as the certificate. A page quoting 23 hours of action, or 300 times the potency of spadin, is quoting an experiment that either did not contain PE-22-28 at all or used a denominator its own source contradicts.

Walked through on two real certificates in how to read a certificate of analysis.

What people get wrong

Taking the numbers on the sales page to describe what is in the vial. The 23 hour duration was measured on a modified version at ten times the dose, and the paper cannot decide which of its two modified molecules it belongs to. The potency claim, roughly 300 times spadin, is a ratio whose denominator its own source contradicts: the 2017 paper cites spadin at 40 to 60 nanomolar and credits a 2010 paper that measured 70.7, in a different cell line, while printing its own figure four times as 0.12 twice and 0.10 twice and swapping it with its alanine cousin. Both figures come from channels put into cells in a dish rather than from an animal. And the premise underneath both is a mouse born without the gene, not a mouse given the drug.

What is known about harm

I could find no published human safety data on this at all. No tolerability record, no dose ceiling and no adverse event count came back from my searches, and I found no formal toxicology study in any species, so the record is empty rather than clean. The line that reaches vendor pages as no side effects is a prediction in the primary paper's own words, that they could expect the analogues to be devoid of side effects. The test underneath it was narrow but real: in kidney cells carrying the channels, the peptide left four related potassium channels untouched at 100 nanomolar, and all three analogues left the cardiac channel untouched at a hundred times that concentration. Against it, mice born without TREK-1 are more easily damaged by stroke and seizures and resist being put under with inhaled anaesthetics. The group that made spadin raised that hazard themselves and reported no worsening of pain, seizures, stroke damage, heart function or blood sugar in rodent models, which is as far as the abstract goes, and that was spadin rather than this compound. The anaesthetic finding is not addressed anywhere I could find.

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