PE-22-28

What it is

PE-22-28 is a synthetic peptide of 7 amino acids, described in 2017. Nobody found it by chance; it is the result of deliberate shortening: an endogenous fragment was trimmed until the remainder did better what the original was supposed to do.

The original is called spadin. It is produced in the body when a receptor called sortilin is cleaved — a by-product that blocks a particular potassium channel. A French research group described this in 2010 in PLoS Biology, under a title that states the ambition: a new concept in antidepressant drug design.

Where the idea comes from

The starting point lies in 2006, with mice that lack the potassium channel TREK-1. These animals do better in the usual behavioral tests than their peers: they behave as if they had received an antidepressant, without having received one. Channel gone, mood better.

This raises an obvious question: if the absence of the channel works, does blocking it work too? The appeal lies in the target. All common antidepressants work on the serotonin or noradrenaline system; a potassium channel is something fundamentally different — and a third of patients do not respond well to what exists.

How it is supposed to work

PE-22-28 blocks TREK-1 considerably more strongly than its model: 0.12 nanomolar compared with 40 to 60 for spadin, that is, several orders of magnitude. Added to this is its persistence in the body: 23 hours instead of 7.

Together, these two properties have put the shortened version in place of the original. In mice, PE-22-28 reduced depression-like behavior and promoted the formation of new nerve cells.

The rapid onset of action

The point quoted everywhere is speed, and it is stated as such in the original paper: the substance worked in the behavioral tests after 4 days. The authors contrast this with a second number, namely the 3 to 4 weeks that conventional antidepressants need in humans before they take effect.

The waiting time is one of the hardest problems in treating depression: someone who is at rock bottom is supposed to take something for weeks that first causes side effects and then perhaps helps. Many stop during this period.

The two numbers, however, do not belong in the same table. The 4 days come from behavioral tests in mice; the 3 to 4 weeks are a clinical empirical value from humans — not comparable measures. In marketing, the comparison is nevertheless passed on as if they were.

Why the step to humans is missing

The basic idea dates from 2006, the substance from 2010, the improved version from 2017. The line of research has thus existed for almost 20 years and has not reached humans in that time. That is not a verdict on the effect. It means that the hurdle at which the vast majority of candidates fail has not been cleared.

In depression this hurdle is particularly high, and the reason lies in what is measured in animal experiments: how long an animal keeps struggling in an unpleasant situation. This is called depression-like behavior, and the tests respond reliably to antidepressants. A mouse, however, has no hopelessness, no self-reproach, no loss of joy. What is captured is a shadow of the disease, not the disease. The path from the mouse model to depression in humans is considered the most notorious graveyard in pharmacology.

What is missing is a small step: a phase 1 study with 20 or 30 healthy volunteers, ascending doses, tolerability and blood levels. That it has not been taken in 20 years can have many reasons — money, patents, lack of interest in a peptide that has to be injected. As long as it is missing, everything else is speculation.

What gets lost in the retelling

Anyone looking for studies in humans ends up almost exclusively on sales pages and on guides styled to look like specialist sites. No university, no scientific journal. They talk about effects, dosing and rapid onset of action.

The tricky part is that the numbers are usually not made up. The 4 days are stated as such in the paper. What is missing is the word that changes everything — that it was mice. A sentence about an animal model becomes a sentence about you by dropping three words.

What the studies show

TREK-1 knockout in the mouse model, 2006

Animal experiment without treatment: mice genetically lacking the potassium channel TREK-1 performed in the usual behavioral tests as if they had received an antidepressant. The finding provided the target, but no statement about a substance.

Spadin, PLoS Biology 2010

A French research group showed that cleavage of the receptor sortilin produces a peptide that blocks TREK-1, and named it spadin. The work was done in cell systems and in animals.

PE-22-28 as a shortened analog, 2017

Spadin was turned into a peptide of 7 amino acids. Measured were the blocking potency at the channel, 0.12 nanomolar compared with 40 to 60, and the residence time in the body, 23 instead of 7 hours. In behavioral tests in mice, there was less depression-like behavior and more newly formed nerve cells after 4 days.

Search for studies in humans

A review of the scientific literature and the accessible trial registries found no completed, no ongoing and no terminated study in humans. Not a side finding, but the central finding.

Where the data stop

Not supported is everything concerning PE-22-28 in humans: no efficacy data, no tolerability data, no tested dose, no known interactions. Transferring the animal experiments to a human rests on assumptions that nobody has checked. That not even a small tolerability study came about in 20 years is itself a piece of information.

Status, approval and legal

PE-22-28 is not approved as a medicine anywhere, because there are no studies in humans on which an approval could be based. It is nevertheless widely traded, through peptide shops that label it as a research substance — a label that enables the sale and shifts the responsibility. Anyone who orders it buys a preparation whose content and purity nobody checks. In sport the substance plays no role; it targets mood, not performance.

Safety

On safety in humans there is simply nothing. In animal work, blocking the channel looked unremarkable, but unremarkable in mice is not a safety statement for a human. Added to this is a risk that appears on no list of side effects: lost time. Depression is very treatable — with psychotherapy, with medicines that have been tested in humans, usually with both. Weeks with a gray-market peptide are weeks without the treatment that helps. If the topic affects you because you are feeling bad, the next step is an appointment, not a vial.

Sources

• Heurteaux et al., Nature Neuroscience 2006 — TREK-1 knockout and depression-like behavior in the mouse model
• Mazella et al., PLoS Biology 2010 — spadin as an endogenous TREK-1 blocker
• Djillani et al., Frontiers in Pharmacology 2017 — PE-22-28: shortened spadin analog with higher binding affinity and longer half-life
• Moha Ou Maati et al., Neuropharmacology 2012 — animal data on the tolerability of TREK-1 blockade
• Search of the scientific literature and accessible trial registries: no human study on PE-22-28