PE 22-28

Also known as PE22-28, mini-spadin, shortened spadin analog, Gly-Val-Ser-Trp-Gly-Leu-Arg

Spadin-derived heptapeptide, a TREK-1 potassium-channel blocker with antidepressant effects in rodents only.

preclinical Neuro & cognition research chemical

At a glance

Category: Neuro & cognition
Status: research chemical
Route: intravenous, intraperitoneal and intracerebroventricular in the rodent studies; subcutaneous or nasal in grey-market self-experimentation
Half-life: No human pharmacokinetics. In mice the in vivo duration of action of PE 22-28 was reported as up to about 23 hours, compared with roughly 7 hours for spadin, which was the point of shortening it 2. Human figures are unsourced.
Onset: In rodent behavioural models an antidepressant-like effect appeared after a few days of dosing, faster than the weeks required by SSRIs 1 2; there are no human data on time course
Molecular weight: Approximately 774 g/mol for the free heptapeptide (calculated); spadin, the 17-residue parent, is approximately 1849 g/mol 9
Sequence: Gly-Val-Ser-Trp-Gly-Leu-Arg (GVSWGLR) - residues 22-28 of the sortilin/NTSR3 propeptide, that is the C-terminal seven residues of spadin 2 9

PE 22-28 is a synthetic seven-residue peptide developed by the CNRS group in Nice as a shortened, more stable analogue of spadin 2. Spadin (PE 12-28) is itself a fragment of the propeptide released when sortilin, also called neurotensin receptor-3 (NTSR3), is processed, and it blocks the TREK-1 potassium channel 1 4. Neither peptide is an approved medicine or an investigational drug in any public trial: a ClinicalTrials.gov search for spadin returns no registered study 10. PE 22-28 exists as a preclinical research compound and is sold on the grey market to the nootropic and self-experimentation scene as a supposed fast-acting antidepressant. All of its published effects are in rodents and cell systems.

Doping status: Not listed by name; as a non-approved substance it falls under the S0 residual category and is therefore prohibited at all times - an inference from its regulatory status, not a listing

Checked against the WADA 2026 Prohibited List. For a specific product and country, Global DRO is the lookup athletes are expected to use — the List names substances, not brand names.

This is a short entry. There is little or no published research on this compound, so there is correspondingly little to report. Empty dosing or reconstitution sections mean no credible figures exist — not that they were left out.

Mechanism of action

PE 22-28 blocks TREK-1, a two-pore-domain (K2P) potassium channel encoded by KCNK2. TREK-1 emerged as an antidepressant target when mice lacking the channel were found to show a depression-resistant phenotype resembling the result of antidepressant treatment, so an antagonist of the channel was predicted to act as an antidepressant 1 3. Spadin was identified as the endogenous peptide that does this: it derives from the sortilin/NTSR3 propeptide, binds TREK-1 and inhibits it, and in mice raised the firing rate of serotonergic neurons in the dorsal raphe and produced antidepressant-like effects together with hippocampal CREB phosphorylation and neurogenesis after a four-day treatment 1 4.

PE 22-28 was engineered from the breakdown products of spadin in blood, keeping the seven C-terminal residues 2. In patch-clamp recordings on human TREK-1 it inhibited the channel with substantially higher potency than spadin (a reported IC50 near 0.12 nM versus 40-60 nM), and in mice it reproduced spadin's antidepressant-like profile in the forced swim and novelty-suppressed-feeding tests while inducing neurogenesis and synaptogenesis after only four days, with a longer duration of action 2. The proposed appeal is a fast-acting antidepressant mechanism distinct from monoamine reuptake inhibition.

Two cautions belong next to that account. All of it is rodent behaviour and in vitro electrophysiology from essentially one research group; the forced swim and novelty-suppressed-feeding tests are screening assays sensitive to many manipulations, not models of human depression, and an effect in them does not establish antidepressant efficacy in people. And a small linear peptide faces the usual obstacles of proteolytic stability and access to the brain, which improved stability mitigates but does not by itself resolve for human use.

What the research shows

The evidence is preclinical and concentrated in one group. Spadin and its analogues, including PE 22-28, have a coherent and reasonably developed rodent and in vitro literature around TREK-1 inhibition and antidepressant-like behaviour 1 2 3 4. There is no human trial of PE 22-28 or of spadin, no human pharmacokinetic or safety data, and no independent clinical replication 10. The compound is a promising-looking preclinical lead, not a demonstrated antidepressant in people.

Research in humans

No human study of PE 22-28 exists. Spadin itself has never completed a registered clinical trial 10. The only human connection is indirect and observational - serum concentrations of the sortilin-derived propeptide that gives rise to spadin have been reported to differ in people with major depression - which is a biomarker association, not a test of giving the peptide to patients.

Animal and lab research

The core findings are in mice: antidepressant-like effects of spadin across several behavioural tests with increased dorsal raphe serotonergic firing, CREB phosphorylation and hippocampal neurogenesis 1; and, for PE 22-28 specifically, greater TREK-1 potency in vitro, antidepressant-like effects in the forced swim and novelty-suppressed-feeding tests, induction of neurogenesis and synaptogenesis, and a longer duration of action than spadin 2. Related rodent work covers retro-inverso spadin analogues 5, spadin's regulation of synaptogenesis 6, protective effects of sortilin-derived peptides on stroke recovery and post-stroke depression 7, and the selectivity of spadin for arachidonic-acid activation of TREK-1 8.

Caveats. The work comes almost entirely from one laboratory and its collaborators, with no independent replication of the behavioural effects; the models are acute behavioural-despair and anxiety screens rather than validated models of depression; sample sizes are typical of preclinical pharmacology; there is no toxicology programme, no human pharmacokinetics and no clinical safety data; and grey-market material is of unverified identity and purity.

What it is used for

Preclinical research tool for probing TREK-1 inhibition as an antidepressant mechanism 1 2 3
Sold and self-administered on the grey market as a supposed fast-acting antidepressant or mood nootropic, with no human efficacy or safety data 10

Dosing

There is no validated human dose. The rodent studies dosed by intravenous, intraperitoneal or intracerebroventricular routes on milligram- or microgram-per-kilogram scales that do not translate to a human protocol, and no human pharmacokinetic study exists to bridge them 1 2.
No maximum tolerated dose, no dose-response data in people and no clinical protocol exist. Left null rather than manufacturing one.
Figures that circulate in the nootropic scene are user-reported, unverified, and track the vial size rather than any pharmacology; they are recorded in the protocol section below only because they circulate.

These figures describe what the literature and published protocols report. They are not advice and not a dosing instruction.

Protocols

Nootropic self-experimentation (user-reported)

user protocol — not validated

Source: forum posts and vendor material; no published human basis

This is not a validated schedule. It is a pattern that circulates among users and sellers, reproduced because it is what people actually follow — not because it has been tested. No trial established these doses, this interval or this duration, and nobody is checking what is in the vial. Treat every number below as an assertion, not a finding.

Daily course	commonly a few hundred micrograms per day, taken nasally or by subcutaneous injection, over roughly two to four weeks in user reports
Basis	no human study; figures vary widely between sources and track the vial size rather than any pharmacology

These figures are unverified and self-reported. They do not derive from any human study - there is none - and they contradict one another between sources, which is what one expects of numbers that follow the size of the vial sold rather than a pharmacokinetic finding. The rodent work used parenteral routes and per-kilogram doses that cannot be converted into a human nasal or subcutaneous schedule 1 2.

Schedules are reproduced as their source states them. Units, IU and milligrams explains why the figures are not interchangeable between products.

Reconstitution

Vial sizes: 5 mg, 10 mg (lyophilised powder, research chemical)
Solvent: bacteriostatic water for the powder; the nasal-spray scene disperses the reconstituted solution into a spray bottle
Storage: Supplier guidance: powder at 2-8 °C short term or -20 °C long term, protected from light; reconstituted solution refrigerated and used within a few weeks. These are handling conventions, not pharmacopoeia specifications.

No validated dose or route exists, so no calculator is offered. Grey-market peptides are regularly mislabelled or underdosed, and self-issued certificates of analysis cannot be independently verified. The nasal and subcutaneous routes used by self-experimenters were not the routes used in the animal studies.

This is administered as nasal drops or spray, not by injection, so there is no syringe volume to work out.

Safety

Side effects

Unknown in humans - no person has been monitored on PE 22-28 in any published study 10. The absence of a side effect profile reflects the absence of human research, not safety
No toxicology, carcinogenicity or reproductive-toxicity programme has been published
TREK-1 is expressed well beyond mood circuits - in the cardiovascular system, gut and nociceptive pathways - so systemic blockade of it in a person could have effects the antidepressant screens were never designed to detect; this is a mechanistic concern, not an observed one
Reported at user level only, uncontrolled and unverifiable: nasal irritation, headache, injection site reactions

Do not use if

Everyone, in the practical sense: there is no human indication for which the risk-benefit ratio has been established 10
Depression severe enough to involve suicidality - self-treating a serious psychiatric illness with an unstudied grey-market peptide instead of evidence-based care is the central hazard here, not a side effect
Concurrent antidepressant or other serotonergic medication - the rodent mechanism increases serotonergic firing 1 and any interaction is unstudied
Pregnancy, breastfeeding, children and adolescents - no data of any kind

Interactions

Not studied in humans. On the rodent mechanism, additive effects with serotonergic antidepressants are conceivable, and one rodent study reported synergy between TREK-1 blockade and 5-HT1A receptor signalling - a reason for caution around serotonergic drugs, not a characterised human interaction 1 3.

Sources

Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug designPLoS Biology, 2010 - Mazella et al.; the foundational spadin study
Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant ActivityFrontiers in Pharmacology, 2017 - Djillani et al.; the paper that designed and characterised PE 22-28
Fighting against depression with TREK-1 blockers: Past and future. A focus on spadinPharmacology & Therapeutics, 2019 - Djillani et al.; review
The Involvement of Sortilin/NTSR3 in Depression as the Progenitor of Spadin and Its Role in the Membrane Expression of TREK-1Frontiers in Pharmacology, 2018 - Mazella et al.
Retroinverso analogs of spadin display increased antidepressant effectsPsychopharmacology (Berlin), 2015 - Veyssiere et al.
In vitro and in vivo regulation of synaptogenesis by the novel antidepressant spadinBritish Journal of Pharmacology, 2015 - Devader et al.
First evidence of protective effects on stroke recovery and post-stroke depression induced by sortilin-derived peptidesNeuropharmacology, 2019 - Pietri et al.
Spadin Selectively Antagonizes Arachidonic Acid Activation of TREK-1 ChannelsFrontiers in Pharmacology, 2020 - Ma et al.
Sortilin (SORT1), human - propeptide sequence used to derive spadin and PE 22-28UniProt Q99523; signal peptide 1-33, propeptide 34-77, from which spadin (propeptide positions 12-28) and PE 22-28 (positions 22-28) are taken
ClinicalTrials.gov registry search for spadinUS National Library of Medicine - returns zero registered studies as of July 2026