PE-22-28 is a seven-amino-acid peptide cut down from spadin, a natural peptide that French researchers proposed as a new kind of fast-acting antidepressant.[1][2] In mice, it blocked a brain potassium channel called TREK-1 and reduced depression-like behavior after only 4 days.[1] It has never been tested in people, and it is not FDA-approved.[12]
What is PE-22-28?
The story starts with sortilin, a protein that sorts cargo inside cells. When sortilin matures, it releases a 44-amino-acid fragment called the propeptide, or PE.[5] In 2010, a team at the Institut de Pharmacologie Moléculaire et Cellulaire, part of France’s CNRS, showed that a 17-amino-acid piece of it, which they named spadin (PE 12-28), blocked TREK-1 and had antidepressant effects in mice.[2]
Spadin wore off within about 7 hours in mice. To make it last longer, the same group studied the fragments left after spadin broke down in blood and designed a shorter version made of the last seven amino acids, PE 22-28.[1] The 2017 paper does not spell out the sequence in its text, so we derived it from spadin’s published sequence (APLPRWSGPIGVSWGLR): the last seven residues are Gly-Val-Ser-Trp-Gly-Leu-Arg (GVSWGLR).[2] That fits the developers’ description of a modified version with the first glycine swapped for alanine (AVSWGLR). They also call PE 22-28 mini-spadin.[5]
How PE-22-28 works
TREK-1 is a “background” potassium channel. It helps keep nerve cells from firing and is involved in depression, pain, anesthesia and protection of brain cells.[11] Mice bred without TREK-1 behave as if they were on an antidepressant, which made blocking the channel an appealing drug target.[2]
- Stronger binding: in human TREK-1 cells, PE-22-28 blocked the channel at an IC50 of 0.12 nM, compared with 40 to 60 nM for spadin.[1]
- Selectivity: PE-22-28 did not block related K2P channels (TREK-2, TRAAK, TRESK, TASK-1) in lab tests.[1]
- Brain plasticity: a 4-day course increased the birth of new neurons in mice, and the peptide raised levels of the synapse protein PSD-95 in cultured neurons.[1] Spadin itself raised BDNF, a growth factor linked to antidepressant response, in the mouse hippocampus.[9]
What the research shows
All PE-22-28 research comes from cells and rodents, and almost all of it from the lab that invented it.
| Model | Result |
|---|---|
| Forced swim test in mice | Less immobility, a standard sign of antidepressant activity[1] |
| Novelty-suppressed feeding test after 4 days | Mice approached food faster, which is read as less anxiety and depression-like behavior[1] |
| Duration of action in mice | Effects of modified PE 22-28 analogs lasted up to about 23 hours, versus about 7 hours for spadin[1] |
| Stroke in mice | Better movement and memory recovery and less post-stroke depression-like behavior[6] |
| Pancreatic beta cells in the lab | Protection from cytokine-induced death and more cell division[7] |
The stroke study found that mini-spadin had a two-sided effect: very low doses activated TREK-1, while higher doses blocked it.[6] That kind of dose-dependent switch is another reason mouse findings cannot simply be scaled to people.
Outside France, a Chinese rat study found that TREK-1 blockers (spadin and another compound) reversed stress-induced depression-like behavior at least a week sooner than fluoxetine.[10] That study tested spadin, not PE-22-28.
Has PE-22-28 been tested in people?
No. In a review published in early 2019, the developers wrote that clinical trials of spadin or its analogs were in progress, but no results have been published since.[5] A ClinicalTrials.gov search for spadin returns no registered studies.[12] Claims online about better mood, focus or memory in people are not backed by any published study.
PE-22-28 dosage: what was studied
There is no studied human dose. In the main mouse study, PE-22-28 and its analogs were injected into the abdomen at about 3 to 4 micrograms per kilogram, as a single dose or once daily for 4 days.[1] In the stroke study, mice got 0.03 micrograms per kilogram after the stroke and 3 micrograms per kilogram later on.[6]
Animal doses do not convert directly to human doses, and no study has tested the nasal sprays or under-the-skin injections sold online. Doses printed on research-chemical labels come from sellers, not from research.
PE-22-28 side effects and safety
- No human safety data: nobody knows its side effects in people.
- Animal safety work was on spadin, not PE-22-28: blocking TREK-1 could in theory raise sensitivity to pain, seizures and stroke damage, because mice without TREK-1 have those problems. In mice, spadin did not change pain, seizures, stroke size, heart rhythm, blood pressure or blood sugar.[3] The 2017 paper found that the shortened analogs did not affect the heart-rhythm channel hERG, but it did not report a formal toxicology study of PE-22-28.[1]
- Wide reach of TREK-1: the channel is also found in the heart, smooth muscle, pancreas and prostate, so effects outside the brain are possible.[11]
- Product quality: research-chemical products are not checked for identity, purity, sterility or dose.
PE-22-28 vs Selank and Semax
| PE-22-28 | Selank | Semax | |
|---|---|---|---|
| Origin | Fragment of the sortilin propeptide[1] | Analog of the immune peptide tuftsin | Fragment of ACTH |
| Main target | TREK-1 potassium channel[1] | GABA and enkephalin systems | BDNF and melanocortin systems |
| Human data | None | Small Russian trials | Small Russian trials |
| Approved anywhere | No | Russia | Russia |
PE-22-28 is often bundled with these Russian nasal peptides in online “nootropic stacks,” but none of the three has been tested alongside the others. Browse more brain-focused compounds on our cognitive peptides page.
Is PE-22-28 legal?
- United States: not FDA-approved for any use, with no registered clinical trials.[12] It is sold online as a research chemical, not as a medicine or supplement.
- Sports: not named on WADA’s 2026 Prohibited List. In our reading it would be banned at all times under S0, which covers substances with no current approval by any government health authority for human use. Athletes should check with their anti-doping organization.[13]
This is general information, not legal advice.
What users report
We did not find user reports on PE-22-28 from sources that meet our standards. Most experience claims online come from sellers, which we do not use. Because the products are unregulated, any reported effect could also reflect a different or contaminated substance.
The bottom line
PE-22-28 is an interesting idea: a tiny peptide from a family of TREK-1 blockers that acted within days in mice, compared with the weeks standard antidepressants need.[4] But the evidence stops at rodents and cells, nearly all from one lab, and there is no human safety or dosing data.
