PE-22-28
A short peptide that selectively blocks the TREK-1 potassium channel — studied in animal models as a fast-acting antidepressant candidate.
A 7-amino-acid peptide derived from the propeptide of sortilin that selectively inhibits the TREK-1 two-pore potassium channel, producing antidepressant-like effects in rodent models with an onset of hours rather than weeks.
Mechanism of action
Selective blockade of the TREK-1 (TWIK-related potassium-1) channel, a two-pore-domain potassium channel implicated in mood regulation. TREK-1 knockout mice show a depression-resistant phenotype; pharmacological inhibition with PE-22-28 reproduces this phenotype in wild-type rodents, with antidepressant-like effects appearing within hours — substantially faster than SSRIs.
Primary uses
- Rodent depression models
- TREK-1 channel pharmacology research
Typical dosing
No human dosing established. Community use carries unknown risk; not medical guidance.
Regulatory status
Not approved. Preclinical-stage research peptide. No completed human clinical trials identified.
Status as of this entry's last review, October 4, 2026. Approvals, compounding rules and sport rules change; the regulatory tracker is checked more often.
What we checked
PE-22-28 is indexed on PubMed in its developers' papers on spadin, the antidepressant peptide it was shortened from, but only in animals and cells. This section records what can be checked.
Identity, computed
| Sequence | Gly-Val-Ser-Trp-Gly-Leu-Arg (GVSWGLR) |
| Formula | C35H55N11O9 |
| Average mass | 773.89 g/mol |
| Monoisotopic mass | 773.4184 Da |
| Isoelectric point | 10.55 (net charge +0.98 at pH 7) |
The developers' 2017 paper describes PE 22-28 as a seven-residue peptide designed from spadin's breakdown products; the dataset's formula and mass agree with the calculator for Gly-Val-Ser-Trp-Gly-Leu-Arg.
Regulatory status, read October 5, 2026
Drugs@FDA: 0 records for “PE-22-28”. EMA medicines list: 0 records for “spadin”. Run for semaglutide, the same queries return 6 and 5 records (and the registry search 84 trials), so a zero here is an absence, not a broken search. Not named on the WADA 2026 and 2027 Prohibited Lists. As a substance with no current approval for human therapeutic use, it falls under section S0 (non-approved substances), which is prohibited at all times; the lists were read on September 27, 2026.
What the maker or sellers claim
Claim, from research-chemical sellers: PE-22-28 is a fast-acting nasal antidepressant or nootropic for people. It has only been tested in mice and cells.
About spadin, its parent peptide
PE-22-28 was cut down from spadin, a fragment of the sortilin propeptide that blocks the TREK-1 potassium channel; mice lacking TREK-1 resist depression-like behaviour. Spadin's effect lasted only about seven hours, which is why the shorter, more stable analogue was designed. Both papers are described in the study cards below.
What we looked for and did not find
No human study, no registry record, no pharmacokinetic data in people and no dose from a controlled human study.
| Source | Query | Results, October 5, 2026 | What it was |
|---|---|---|---|
| PubMed | PE 22-28 | 31 | the 2017 analogue paper |
| PubMed | spadin TREK-1 | 37 | the parent-peptide papers |
| ClinicalTrials.gov | spadin | 0 | |
| Drugs@FDA (openFDA) | PE-22-28 | 0 | |
| EMA medicines list | spadin | 0 |
What the studies show
PE 22-28 was designed from the breakdown products of spadin, an antidepressant peptide studied in rodents. Its own evidence is one paper; the others below are about spadin and are labelled as such. No study has given either peptide to people.
In Vitro · 2017
PE 22-28 itself
The 7-residue PE 22-28 inhibited the TREK-1 channel with better specificity and affinity than spadin in human cell assays, showed antidepressant-like effects in mouse tests including forced swimming and novelty-suppressed feeding, induced neurogenesis after four days, and acted for up to 23 hours against spadin's 7.
Animal · 2010
Spadin, the parent peptide
Spadin, a peptide from the sortilin propeptide, blocked TREK-1 channels and had a rapid-onset antidepressant effect in rodents; the authors called it the first natural antidepressant peptide identified.
Review · 2019
TREK-1 blockers
A review of spadin's development as an antidepressant, noting that shortened analogs such as PE 22-28 inhibit TREK-1 more potently, act better in animal models and last longer in the body.
References
- [pubmed] Mazella J, et al. "Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design." PLoS Biol, 2010;8(4):e1000355. PMID: 20405001.
- [pubmed] Djillani A, et al. "Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant Activity." Front Pharmacol, 2017;8:643. PMID: 28955242.
- [review] Djillani A, et al. "Fighting against depression with TREK-1 blockers: Past and future. A focus on spadin." Pharmacol Ther, 2019;194:185-198. PMID: 30291907.
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Guides & tools
This entry is for educational purposes only and does not constitute medical advice. Dosing information reflects published regulatory or research data and is not a recommendation. Many compounds described here are not approved for human use in the United States. Consult a licensed medical professional before considering any peptide therapy.