F tier · safety concern
ClinicalTrials.gov returns zero registered studies for PE 22-28 and zero for spadin, its parent, so neither molecule has ever entered a registered human trial despite the originating group writing in 2018 that clinical use was 'currently in progress'. The compound's defining claim — potent TREK-1 blockade — was contradicted by the only independent electrophysiology study, in which spadin produced no reduction at all in basal mouse TREK-1 current, the currents recorded with and without it being indistinguishable.
pe-22-28
PE 22-28 is a seven-residue fragment (GVSWGLR) of the propeptide released when the sortilin precursor is cleaved by furin, identified in 2017 as the shortest and most potent of a series of truncations of spadin, the 17-residue peptide PE 12-28. In mouse work from the CNRS Institut de Pharmacologie Moléculaire et Cellulaire in Nice it is reported to inhibit TREK-1 potassium channels roughly 300-fold more potently than spadin, and produces antidepressant-like behaviour within days together with increased hippocampal neurogenesis. It has never been given to a human, has no registered clinical trial, and is not an approved medicine anywhere.
// we supply this one
available as a research reagent
≥ 98% HPLC · lyophilised powder · batch certificate published. Grade F above is our own and is not adjusted because we stock it.
the explanation
PE-22-28 is a tiny piece of a natural human protein fragment, and it is the shortened version of an earlier experimental peptide called spadin. In mice it blocks a potassium channel in brain cells and makes the animals behave as though an antidepressant is working, within about four days rather than the weeks a normal antidepressant takes. That is the whole story: no person has ever been given it in a trial, and an outside laboratory that tested the parent peptide could not confirm the channel-blocking effect it is supposed to work by.
regulatory status
Unapproved worldwide; preclinical research chemical only
PE 22-28 has no marketing authorisation in the UK, EU, US or anywhere else, is not a prescription-only medicine, and is not a controlled drug; it is an unlicensed substance which in the UK can lawfully be supplied only as a laboratory research reagent for in vitro and non-human use. Neither PE 22-28 nor spadin appears on ClinicalTrials.gov, so neither has been an investigational medicinal product in a registered trial, and the 2018 statement by the originating group that 'further use of spadin and/or spadin analogs in clinical trials is currently in progress' has produced no registered study in the eight years since. It is not a lawful dietary-supplement ingredient in any jurisdiction — there is no New Dietary Ingredient notification and no novel-food authorisation in Great Britain. Because no government health authority has approved it for human therapeutic use, it is captured by section S0, Non-Approved Substances, of the WADA Prohibited List and is therefore prohibited in sport at all times.
how it works · proposed mechanism
Sortilin (NTSR3) is synthesised with a 44-residue propeptide that is cleaved off by furin. The Nice group's thesis is that this discarded propeptide is itself bioactive, that its 12-28 fragment (spadin) blocks the TREK-1 two-pore potassium channel, and that TREK-1 blockade is antidepressant because Trek-1 knockout mice show a depression-resistant phenotype. PE 22-28 is the shortest fragment retaining that activity.
A fragment of a fragment
PE 22-28 is not a novel design but the last seven residues of spadin, which is itself residues 12-28 of the sortilin propeptide. Truncation was undertaken because spadin is degraded in mouse serum within 15-30 minutes into PE 14-25 and PE 12-27. Everything claimed for PE 22-28 that is not in the 2017 truncation paper or its two follow-ups belongs to spadin, and the two are different molecules of 773.89 and roughly 1878 Da.
Claimed nanomolar TREK-1 inhibition
The originating laboratory reports an approximately 300-fold gain in TREK-1 potency over spadin, with the Gly-to-Ala substituted analogue marginally more potent again and the biotinylated variant roughly an order of magnitude weaker. Tocris, which supplies the peptide as a reference reagent, carries the originating laboratory's potency figure. No laboratory outside that group has published a TREK-1 concentration-response curve for PE 22-28.
The independent electrophysiology does not agree
Ma and Lewis at the University of Portsmouth reported in 2020 that spadin does not block basal mouse TREK-1 current at all — the recorded currents with and without spadin were indistinguishable — and that it acts instead as a selective allosteric antagonist of arachidonic-acid activation, with no effect on activation by BL-1249, CDC or DHA. They did not test PE 22-28. If spadin is not a channel blocker, the framework in which PE 22-28 is described as a 300-fold more potent blocker requires re-examination.
Downstream neurogenic and synaptic readouts
After four days of treatment in mice, BrdU-positive dentate-gyrus cells rose from 899 +/- 109 in saline controls to 1736 +/- 126, and PSD-95 expression in cortical neurons roughly doubled by 36 hours. The same laboratory has since reported effects outside the brain — protection of pancreatic beta cells via CREB signalling (2021) and improved stroke recovery with reduced post-stroke depressive behaviour in mice (2019). All of these are the same group, in rodents or cells.
what’s reported
evidence shape
7 sourcesThe composition of the cited literature by study type. This describes the shape of the evidence, not its quality — and it does not by itself set the grade.
⚠ the catch
Almost everything attractive about PE 22-28 is borrowed from spadin, and what is genuinely its own has never been independently reproduced. Spadin is the molecule with the 2010 PLOS Biology paper, the fast-onset antidepressant narrative and the 'no TREK-1-related side effects' claim; PE 22-28 is a 773.89 Da heptapeptide first described in 2017, and its entire in vivo dossier is three papers from one laboratory in Nice — Djillani 2017 on truncation, Pietri 2019 on stroke, Daziano 2021 on beta cells. Neither peptide has ever been in a registered human trial: ClinicalTrials.gov returns zero studies for PE 22-28 and zero for spadin, and the group's own 2018 review asserting that clinical use was 'currently in progress' has been followed by eight years of nothing. Worse for the mechanism, the only independent electrophysiological test found that spadin does not inhibit basal TREK-1 current at all — the currents recorded with and without it were indistinguishable — and behaves merely as an allosteric antagonist of arachidonic-acid activation — so the very framework in which PE 22-28 is marketed as a potent TREK-1 blocker is unconfirmed outside its originators. The only human data anywhere near this pathway are observational serum measurements of sortilin-derived propeptides in depressed and post-stroke patients; nobody has ever administered PE 22-28 to a human being.
key published findings
- The chemistry is fully verifiable: GVSWGLR, C35H55N11O9, 773.89 Da, CAS 1801959-12-5, exactly matching propeptide residues 22-28 of human sortilin (UniProt Q99523 residues 55-61), and supplied as a reference reagent by Tocris at greater than or equal to 95% HPLC purity.
- Zero registered clinical trials exist for PE 22-28 and zero for spadin; the originating group's 2018 claim that trials were 'currently in progress' has produced no registered study in eight years.
- The originating laboratory reports an approximately 300-fold TREK-1 potency gain for PE 22-28 over spadin, with behavioural half-effect times extending from about 6 hours (spadin) to 14-23 hours for the shortened analogues.
- In mice, four days of treatment raised BrdU-positive dentate-gyrus cells from 899 +/- 109 to 1736 +/- 126 and roughly doubled cortical PSD-95 by 36 hours; behavioural testing used forced swim, novelty-suppressed feeding and learned helplessness in male C57Bl/6J mice at n=10 per peptide.
- The single independent electrophysiology study (Ma and Lewis, University of Portsmouth, Frontiers in Pharmacology 2020) found spadin did not inhibit basal mouse TREK-1 current and acted only as an allosteric antagonist of arachidonic-acid activation, with no effect on BL-1249, CDC or DHA activation; PE 22-28 itself was not tested.
- Every in vivo PE 22-28 result — antidepressant behaviour, stroke recovery, pancreatic beta-cell protection — comes from the same CNRS group in Nice; no outside laboratory has published an in vivo study of this peptide.
limitations of the evidence
- Zero human exposure: no phase 1, no pharmacokinetics, no bioavailability, no immunogenicity, no toxicology in humans.
- Borrowed evidence is the dominant problem — spadin's 2010 founding paper, its side-effect-profile studies and its fast-onset narrative are routinely presented as PE 22-28 data despite the two being different molecules.
- No independent laboratory has reproduced any PE 22-28 finding, and the one independent test of the parent compound contradicted the core channel-blocking mechanism.
- No plasma pharmacokinetic parameter has ever been published for PE 22-28 in any species; the widely quoted 'about 14 hours' is a behavioural half-effect time, and the parent peptide is degraded in mouse serum within 15-30 minutes.
- Efficacy readouts are rodent behavioural despair paradigms (forced swim, novelty-suppressed feeding, learned helplessness) at small group sizes; these assays have a long record of failing to predict human antidepressant efficacy.
- TREK-1 is expressed in heart, vasculature, gut and sensory neurons as well as brain, so a genuinely potent systemic TREK-1 modulator would need a cardiovascular and nociceptive safety package that does not exist for this peptide.
documented safety signals
- No human safety data of any kind — no adverse-event profile, no tolerated exposure range, no laboratory-monitoring precedent, and no published repeat-dose, genotoxicity or reproductive toxicology study in any species.
- The 'absence of TREK-1-related side effects' claim widely attached to this peptide is a finding about spadin, not PE 22-28, and its interpretation is undermined by the independent finding that spadin does not block basal TREK-1 current in the first place.
- TREK-1 is a mechano- and lipid-sensitive channel with cardiac, vascular, gastrointestinal and nociceptive roles; the theoretical consequences of potent systemic blockade — including on cardiac repolarisation and pain thresholds — have never been characterised for this compound in any species.
- Absence of reported harm in humans reflects the complete absence of human study, not evidence of safety.
identity
| full name | PE 22-28 (mini-spadin), the heptapeptide Gly-Val-Ser-Trp-Gly-Leu-Arg corresponding to residues 22-28 of the human sortilin/NTSR3 propeptide |
| category | Cognitive |
| modality | peptide |
| formula | C35H55N11O9 |
| molar mass | 773.89 g/mol |
| cas | 1801959-12-5 |
| half-life | No pharmacokinetic half-life has been published in any species. The frequently quoted 'about 14 hours' is a pharmacodynamic half-effect time for the antidepressant-like behavioural response in mice after a single injection, not a plasma half-life; spadin itself was shown to be degraded in mouse serum within 15-30 minutes. |
| sequence | Gly-Val-Ser-Trp-Gly-Leu-Arg (GVSWGLR) — propeptide residues 22-28 of human sortilin/NTSR3, corresponding to residues 55-61 of UniProt Q99523. The parent peptide spadin is PE 12-28, APLPRWSGPIGVSWGLR. |
laboratory handling
| storage | Lyophilised powder is stored desiccated at -20 °C and protected from light. Once reconstituted, laboratory practice is refrigeration at 2-8 °C for short-term use, or aliquoting and freezing to avoid repeated freeze-thaw cycles. Handling information only; this material has no approved human use. |
| solubility | Short hydrophilic peptide, readily soluble in sterile or bacteriostatic water and in dilute aqueous buffer. Lot-specific solubility is stated on the certificate of analysis. |
| co-studied with | No combination study exists in any species. The peptide has never been co-administered with a conventional antidepressant, ketamine or any other agent in a published experiment, so combination claims are unsupported. |
Handling information describes laboratory practice for a research reagent. It is not a preparation guide for use in humans.
the receipts
7 citedU.S. National Library of Medicine, ClinicalTrials.gov · 2026 · official
World Anti-Doping Agency · 2025 · official
Frontiers in Pharmacology 9:1541 · 2018 · review
Frontiers in Pharmacology 8:643 · 2017 · preclinical
Frontiers in Pharmacology 11:434 · 2020 · preclinical
PLOS Biology 8(4):e1000355 · 2010 · preclinical
Tocris Bioscience (Bio-Techne) product data sheet · 2026 · reference
others in Cognitive