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Peptide — TREK-1 Potassium Channel Blocker

PE-22-28

Preclinical

Gray market · No FDA ruling — not on any list

Sold as a research chemical. Some clinics and pharmacies still supply it; that’s their risk, not a change in the rule.

PE 22-28  |  Mini-spadin  |  Gly-Val-Ser-Trp-Gly-Leu-Arg (GVSWGLR)  |  a peptide of seven amino acids

The last seven amino acids of spadin, cut down by a French academic lab to block the TREK-1 potassium channel, a target chosen because mice born without that channel resist depression tests (Heurteaux et al., 2006; Djillani et al., 2017). Four papers have used it: three from that lab, in mice and in cells, and one from an unrelated laboratory in Los Angeles, in human lung cells (Majumder et al., 2026); no published study has given it to a person.

Reconstituting this? Do the math.

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Molecular Weight
773.9 (C35H55N11O9); the lab reagent is the acetate salt
Sequence
7 amino acids (GVSWGLR) — residues 22–28 of the sortilin propeptide
Half-life
Not measured · its two modified analogs had half-effect times of 14–23 h in mice
Route (studied)
IP, oral (mice) · no human study
Route (sold)
Nasal spray shipped as powder (research chemical); lab reagent (research only)
FDA Status
Not approved · not on FDA’s 503A or 503B lists
Developer
A CNRS lab at Valbonne, France — designed from spadin, published 2017
Published Studies
1 PubMed record for “PE 22-28” (Oct 4, 2026); 4 papers used it
Human Studies
None · no trial of it has ever been registered
WADA Status
Not named — prohibited at all times under S0 (no government has approved it for human use)
Evidence Strength
Human: none
Animal and cell: four papers, three from one lab
Cost & Access
No approved product; research-chemical nasal spray shipped as powder; lab-reagent powder

Gray market · not on any FDA 503A list · Tell me if this changes →

The other four questions

What does it do? In cells carrying the human TREK-1 channel it blocked that channel at 0.12 nM against 40–60 nM for spadin, which the paper calls an affinity more than 300-fold better, and it left four other channels of the same family and the heart’s hERG channel alone (Djillani et al., 2017). In mice it shortened immobility in the forced swim test within 30 minutes of an injection of 3.0 µg/kg into the abdominal cavity, and after four days it roughly doubled the number of newly labelled cells in the hippocampus (Djillani et al., 2017). Whether it does anything in a person is unknown: no study has given it to one.
Who uses it? Nobody in a trial — none has ever been registered (ClinicalTrials.gov, October 4, 2026). The experiments used male C57BL/6J mice, mouse neurons, beta cells and, in the one paper from outside that lab, human lung cells (Djillani et al., 2017; Daziano et al., 2021; Majumder et al., 2026). Outside the laboratory it is sold: one seller’s listing read for this page offers a PE-22-28 spray, supplied as powder, for “in vitro research applications only”, while an affiliate page promoting that same product calls it a 10 mL nasal spray “for mood and cognitive support” that, “unlike traditional antidepressants that require weeks to take effect”, produces “rapid mood-modulating effects in research models”; a laboratory reagent supplier’s insert labels the powder for research only. Outside its developers’ own papers, one published paper names it as something to give patients: a 2023 proposal for an “Interventional Mental Health” service — built on nerve blocks, magnetic stimulation and ketamine — says in passing that studies suggest “anxiolytic peptides” such as PE-22-28, Selank and Semax “may serve as potential adjunct therapies”, and cites work on nerve blocks and ketamine rather than on the peptides (Kuo et al., 2023).
Does the evidence hold up? Every mood result is one lab’s work, and it stops at mice. The CNRS group at Valbonne that designed the peptide (Djillani et al., 2017) then used it in a mouse stroke study (Pietri et al., 2019) and, with other colleagues, in beta cells (Daziano et al., 2021); all three papers share the senior authors Heurteaux and Mazella. One outside group has used the peptide, in human lung cells, on a question unrelated to mood (Majumder et al., 2026), and another could not block TREK-1 with its parent, spadin, directly at all (Ma & Lewis, 2020). The 2017 paper’s headline durability figure, up to 23 hours, was measured for two chemically modified versions of the peptide, not for PE-22-28 itself (Djillani et al., 2017).
Bottom line? A seven-amino-acid fragment with a sharp number behind it in a dish, a handful of mouse behavior tests, and nothing else. No trial of it has been registered or published, and no government has approved it.

Dosing from the Literature

Published for depression: mouse doses only — 3.0 µg/kg injected into the abdominal cavity, acutely or for four days, and 1 mg/kg by gavage (Djillani et al., 2017). Not published: any dose given to a person, and any measurement of how much of a nasal dose reaches the blood.

The table records doses as each study gave them (Djillani et al., 2017; Pietri et al., 2019). The mouse doses are per kilogram of body weight; they are not human doses, and none of the rows is a recommendation.

SourceAmountFrequencyDurationPopulationNotes
Mouse dose (Djillani et al., 2017)3.0 µg/kg, into the abdominal cavity (intraperitoneal)Once, 30 minutes before the test; or once a dayOne dose, or 4 daysNaïve male C57BL/6J mice, 7–9 weeks old, 10 per groupForced swim test immobility 91.8 ± 6.1 s against 161.7 ± 6.5 s on saline (p < 0.0001). The paper prints 3.0–4.0 µg/kg for PE 22-28 and its two modified analogs together.
Mouse dose, by mouth (Djillani et al., 2017)1 mg/kg by gavageOnce a day4 daysThe same miceStill shortened immobility in the forced swim test; the paper reads this as a sign it can be given by mouth.
Mouse dose, low (Pietri et al., 2019)0.03 µg/kg intraperitoneallyOnce a day, from 30 minutes after the stroke7 daysMice after focal brain ischemiaThe low dose was chosen to activate TREK-1, not to block it.
Mouse dose, higher (Pietri et al., 2019)3 µg/kg intraperitoneallyOnce a day, 4 days a weekUntil the animals were killedThe same mice, after the first 7 daysChosen to block TREK-1 and test post-stroke depression.
Dosing Disclaimer

No dose of PE-22-28 has been given to a person in any published study, and no dose of it is approved anywhere. Every published dose is a mouse dose, per kilogram of body weight: micrograms injected into the abdominal cavity (intraperitoneal), or 1 mg given by gavage. None was sprayed into the nose, which is how the affiliate page read for this page describes the spray product. In the mouse stroke study the direction of the effect changed with the amount: the low dose activated the TREK-1 channel and the higher dose blocked it (Pietri et al., 2019). None of this is a dosing guide. Always work with a licensed healthcare provider.

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What It Is

PE-22-28, written “PE 22-28” in the papers, is a synthetic peptide of seven amino acids: glycine-valine-serine-tryptophan-glycine-leucine-arginine (GVSWGLR; C35H55N11O9, 773.9 g/mol, PubChem CID 165437303). Its name is its address. Sortilin, a sorting protein of nerve cells also known as the neurotensin receptor 3, is made as a precursor: its first 33 amino acids are a signal peptide, and the next 44 are cut off when the enzyme furin matures it; that 44-amino-acid piece, residues 34 to 77, is called the propeptide, or PE (Mazella et al., 2018; UniProt Q99523, propeptide 34–77). PE-22-28 is residues 22 to 28 of it. The same seven residues end spadin, the 17-amino-acid peptide (PE 12-28, APLPRWSGPIGVSWGLR) that the same group described in 2010 (Mazella et al., 2010). Later papers from the group call PE-22-28 “mini-spadin” (Mazella et al., 2018; Pietri et al., 2019; Daziano et al., 2021). A laboratory reagent supplier’s product insert gives the same sequence and formula weight for the acetate salt and labels it for research only.

The story starts with a potassium channel. In 2006 a CNRS group at the Institut de Pharmacologie Moléculaire et Cellulaire in Valbonne (Sophia Antipolis), France, reported that mice with the gene for the TREK-1 channel deleted were resistant to depression in five different models, with more effective serotonin signalling and a smaller rise in corticosterone under stress, and behaved like untreated mice given fluoxetine (Heurteaux et al., 2006). In 2010 the group reported that sortilin interacts with TREK-1 and that the propeptide released from sortilin blocks the channel; it designed spadin from that propeptide and reported antidepressant effects in mice within four days, where fluoxetine took weeks (Mazella et al., 2010). Spadin’s drawback was time: after a 10 µg/kg injection into a vein, 30% of its effect in the forced swim test remained at seven hours and none at sixteen, a half-life of about six hours (Veyssiere et al., 2015).

PE-22-28 came out of that problem. The group incubated spadin in mouse serum, identified the two shortened peptides that appeared, PE 14-25 and PE 12-27, and from them designed still shorter sequences. PE 22-25 and PE 22-27 did not block TREK-1 significantly; PE 22-28 did, cutting the channel’s current by 55.5 ± 4.6% at 100 nM (n = 13 cells, p < 0.0001). It became the core for 16 chemically modified analogs (Djillani et al., 2017). The paper’s authors declared no commercial or financial relationships, and its stated goal was “to make spadin-analogs drugs usable in clinics” (Djillani et al., 2017). Reviewing its own work two years later, the group wrote that the shortened analogs “present increased inhibition potency for TREK-1, an improved AD activity, and prolonged in vivo bioavailability” (Djillani, Pietri et al., 2019).

Nine years on, that has not happened. PubMed holds one record whose title or abstract names “PE 22-28” — the 2017 paper itself — against 41 for spadin (searched October 4, 2026). Four experimental papers have used the peptide. Three came from the same group: the 2017 design paper, a 2019 mouse stroke study and a 2021 beta-cell study (Djillani et al., 2017; Pietri et al., 2019; Daziano et al., 2021). The fourth is from an unrelated laboratory at the University of California, Los Angeles, which used the peptide at 7.8 µM to block TREK-1 in human lung cells, in a 2026 study of lung injury caused by high oxygen and stretch (Majumder et al., 2026). No clinical trial of PE-22-28 or of spadin is registered (ClinicalTrials.gov, October 4, 2026), and no health authority has approved either (see Legal Status). What exists for sale is a research chemical.

Mechanism of Action

Everything below comes from cells, cell lines, brain slices or mice. Nothing has been measured in a person, and the peptide’s own measurements come from one group (Djillani et al., 2017; Pietri et al., 2019; Daziano et al., 2021).

  • TREK-1 (KCNK2, K2P2.1), the target — In a HEK cell line carrying the human TREK-1 channel, PE-22-28 blocked the current with a half-blocking concentration of 0.12 nM, against 40–60 nM for spadin; the paper’s figure legend prints 0.1 nM for the same curve (Djillani et al., 2017). The channel sits in the background of nerve cells, holding the membrane below the threshold for firing (Djillani, Mazella et al., 2019). Mice without it resist depression tests (Heurteaux et al., 2006), which is why the group went looking for blockers.
  • It blocks an open channel, and one outside lab could not block it at all — The developers reported that spadin and its analogs block TREK-1 better after arachidonic acid has opened the channel, reading this as a need for the open state (Djillani et al., 2017). An independent lab then tested spadin on mouse TREK-1 and TREK-2 in frog eggs: spadin blocked neither the resting current nor currents already opened by arachidonic acid or two other activators, and only disturbed later activation by arachidonic acid, which the authors read as an indirect, allosteric action (Ma & Lewis, 2020). That test used spadin, not PE-22-28; no outside lab has published an electrophysiology experiment with PE-22-28.
  • Selectivity, as far as it was tested — At 100 nM, PE-22-28 did not change currents from TREK-2, TRAAK, TRESK or TASK-1 in cells carrying the human channels, and at 10 µM the peptides did not change the hERG current that repolarizes the heart (Djillani et al., 2017).
  • Low doses do the opposite of high doses — In the mouse stroke study, electrophysiology showed a biphasic action: the channel’s activity rose with low doses of the peptide and was inhibited at higher ones, and the experiment used a low dose for the first week to protect the brain and a higher one afterwards to act against depression (Pietri et al., 2019). A 2026 letter to the Chinese Medical Journal summarizing TREK-1 research notes the same split and that the field disagrees over whether opening or blocking TREK-1 helps after a stroke (Chen et al., 2026).
  • New cells and new synapses (mice) — Four days of 3.0 µg/kg a day into the abdominal cavity raised the count of BrdU-labelled cells per hippocampus to 1,736 ± 126 against 899 ± 109 in saline-injected mice (n = 5 per group, p < 0.0001), and 0.1 µM on cultured mouse cortical neurons about doubled PSD-95, a synapse protein, between 5 and 36 hours (Djillani et al., 2017). For spadin, the same group reported that this runs through the MAPK and PI3K pathways and a rapid rise in BDNF in the hippocampus (Devader et al., 2015).
  • The sortilin side of the story — Sortilin and TREK-1 bind each other, and the propeptide blocks the channel’s activation (Mazella et al., 2010; Mazella et al., 2018). Mice lacking sortilin showed less depressive-like behavior, less TREK-1 at the cell surface and more BDNF signalling (Moreno et al., 2018). Spadin also reduces the passive potassium conductance of astrocytes by blocking TWIK-1/TREK-1 pairs in brain slices, an independent group’s finding about the parent peptide (Bae et al., 2020).
  • Insulin-secreting cells — The group reported that the propeptide and its derivatives, mini-spadin among them, protected beta cells from death caused by interleukin-1β through CaM-kinase and the transcription factor CREB, and that mini-spadin also made beta cells proliferate (Daziano et al., 2021). Earlier, spadin raised insulin release from an insulin-secreting cell line and mouse islets, and raised plasma insulin in mice given glucose (Hivelin et al., 2016).

What the Research Shows

Four experimental papers have used PE-22-28, and all are in mice or cells: three from its developers, in mice and in cells (Djillani et al., 2017; Pietri et al., 2019; Daziano et al., 2021), and one from an unrelated group, in human lung cells (Majumder et al., 2026). The human section below is short because it is empty.

  • Mouse depression tests, acute — Thirty minutes after 3.0 µg/kg injected into the abdominal cavity (intraperitoneal), immobility in the forced swim test was 91.8 ± 6.1 s against 161.7 ± 6.5 s in saline-injected mice (10 mice per peptide, p < 0.0001); the paper gives the dose as a 3.0–4.0 µg/kg range covering PE 22-28 and its two modified analogs. Spadin, at 100 µg/kg, gave 88.3 ± 7.0 s (Djillani et al., 2017).
  • Mouse depression tests, four days — Four days of 3.0 µg/kg intraperitoneally shortened the escape latencies in the learned helplessness test, and the peptide still worked when given by gavage at 1 mg/kg (Djillani et al., 2017).
  • A chemical model of depression — In mice treated with corticosterone for seven weeks, one injection of 3.0 µg/kg brought immobility to 98.1 ± 8.8 s against 164.9 ± 6.0 s in controls, and four days of it to 89.6 ± 7.7 s against 158.3 ± 7.2 s; in the novelty-suppressed feeding test the latency to eat was 153.2 ± 5.4 s against 226.1 ± 35.0 s in controls (10 mice per group; p < 0.0001 for both forced-swim comparisons, p < 0.05 for the feeding test) (Djillani et al., 2017).
  • How long it lasted, and for which molecule — The duration experiment injected the two chemically modified analogs, G/A-PE 22-28 and its biotinylated form, at 3.2 to 40 µg/kg, and calculated half-effect times of 14 to 23 hours in the forced swim test, against about 6 hours for spadin, which the earlier paper measured after 10 µg/kg into a vein (Veyssiere et al., 2015); the 2017 paper prints that figure as a 100 µg/kg dose (Djillani et al., 2017). PE-22-28 itself was not in that experiment, although the paper’s abstract reports the improvement for “PE 22-28 and its analogs”.
  • Mouse stroke and post-stroke depression — In mice with focal brain ischemia, 0.03 µg/kg injected into the abdominal cavity (intraperitoneal) from 30 minutes after the stroke, once a day for seven days, then 3 µg/kg once a day on four days a week, prevented weight loss and the delayed loss of dopamine neurons in the substantia nigra, improved the motor and cognitive deficits the stroke caused, and prevented post-stroke depression in the forced swim and novelty-suppressed feeding tests, with more new cells and more synapse proteins (Pietri et al., 2019). Apart from the corticosterone model of depression above, this is the only disease model the peptide has been put through in an animal.
  • Beta cells — Mini-spadin and the propeptide protected beta cells against death caused by interleukin-1β, and mini-spadin promoted their proliferation (Daziano et al., 2021).
  • Human lung cells, by an unrelated group — A laboratory at the University of California, Los Angeles used PE-22-28 at 7.8 µM as a TREK-1 blocker in primary human alveolar epithelial cells exposed to high oxygen and stretch. Blocking the channel raised reactive oxygen species, caspase-8 and caspase-1 activity, interleukin-1β production and the secretion of two inflammatory signals, CXCL-10/IP-10 and MIP-1α; removing the channel genetically did the same, and the paper reports no behavior or mood measurement (Majumder et al., 2026).
  • The target, tested by other groups with other molecules — In rats screened for sensitivity to chronic mild stress, spadin and a second TREK-1 blocker reversed depression-like behavior at least a week earlier than fluoxetine and restored impaired neurogenesis (Qi et al., 2018). In mice, knocking TREK-1 down in hippocampal neurons, or blocking it long-term, reduced depression-like behavior and protected synapses after chronic stress (Wu et al., 2021). Neither study used PE-22-28.
Research Limitations — One Lab for the Animal Work, Four Papers, and a Disputed Block

Three of the four experimental papers come from the same CNRS group at Valbonne, and every animal result is theirs: the 2017 design paper, the 2019 stroke study and the 2021 beta-cell study share the senior authors Heurteaux and Mazella, with Borsotto on the first two (Djillani et al., 2017; Pietri et al., 2019; Daziano et al., 2021). One laboratory outside the group has published an experiment with it: a team at the University of California, Los Angeles used PE-22-28 at 7.8 µM to block TREK-1 in primary human alveolar epithelial cells in a lung-injury study, with no behavior or mood measurement (Majumder et al., 2026). No outside laboratory has published an electrophysiology experiment with PE-22-28. Its mechanism is not settled either: an independent lab working with the parent peptide, spadin, found no direct block of TREK-1 at all, only interference with later activation by arachidonic acid (Ma & Lewis, 2020). The behavioral results rest on the forced swim, novelty-suppressed feeding and learned helplessness tests in groups of ten mice, with no measurement of the peptide in blood or brain. No published study has given it to a person, and no toxicology study of it has been published in any species (PubMed and Europe PMC, searched October 4, 2026).

Human Data

There is none. No published study has given PE-22-28, or spadin, to a person, and no trial of either has been registered (PubMed, Europe PMC and ClinicalTrials.gov, searched October 4, 2026). What follows is what has been measured in people around this molecule, all three studies measured with the Valbonne group’s own assay and co-authored by it, and the one published document outside its developers’ own papers that names it as something to give patients.

  • No registered trial — ClinicalTrials.gov returns no record for spadin and none for PE-22-28; its two records for “TREK-1” are a pain-psychology class and a study of anti-TREK-1 antibodies in a heart condition, neither involving this peptide (searched October 4, 2026). The 2017 paper’s stated goal was a drug “usable in clinics”; nine years later nothing has been registered (Djillani et al., 2017). In 2018 the group wrote that “the further use of spadin and/or spadin analogs in clinical trials is currently in progress” (Mazella et al., 2018); no trial of either has been registered or published since (ClinicalTrials.gov, October 4, 2026).
  • The parent propeptide as a blood marker of depression — Serum levels of the sortilin-derived propeptide were lower in patients with major depressive disorder than in healthy controls (p = 0.035), and antidepressant treatment brought them back to normal; the authors call their patient samples relatively small (Devader et al., 2017). The study measured the natural propeptide and gave nobody a peptide.
  • The parent propeptide as a blood marker, after electroconvulsive therapy — In 45 patients with major depressive disorder resistant to treatment, serum levels of the sortilin-derived propeptide did not differ from controls, but rose significantly between the measurement just before electroconvulsive therapy and one about a month after it (p = 0.005); the rise reached significance only in those who responded (p = 0.01), and it correlated with the fall in depression scores (p = 0.03) (Roulot et al., 2018). The study measured the natural propeptide and gave nobody a peptide.
  • The same marker after a stroke — In the STROKDEM cohort, 204 stroke patients were followed at 6, 12, 36 and 60 months with serum propeptide measurements. Propeptide levels showed a significant effect on depression scores (p = 0.006) and none on anxiety scores (p = 0.75); the authors suggest the marker could be useful in post-stroke depression and name spadin, the peptide designed from this propeptide, as a possible approach to it (Mazella, Mendyk et al., 2025). Again, no peptide was given.
  • One clinic paper names it — A 2023 paper in Cureus proposing an “Interventional Mental Health” model, by a New York clinic group, listed PE-22-28 with Selank and Semax among “anxiolytic peptides” that “may serve as potential adjunct therapies” for post-traumatic stress disorder, major depression and generalized anxiety. The references attached to that sentence are studies of stellate ganglion blocks and of ketamine, not of any peptide (Kuo et al., 2023). The paper reports no patient given PE-22-28.

The evidence meter on the PE-22-28 card reads “Animal only”: it counts published human data on the compound itself, and there is none. The mouse results are specific and the cell number is sharp, but neither is a human result, and the disease models it has been through are a corticosterone model of depression and a stroke, both in mice (Djillani et al., 2017; Pietri et al., 2019).

Reconstitution & Storage

There is no label and no clinical-trial document for PE-22-28, so neither gives a mixing or storage instruction. What exists is a laboratory reagent specification, one seller’s listing and an affiliate page for the same product, all read for this page.

  • The laboratory reagent — A reagent supplier’s product insert for PE-22-28 (acetate) lists the peptide as a solid of at least 98% purity, with storage at −20 °C, stability of at least 4 years, and solubility in methanol and acetonitrile. It carries the line “THIS PRODUCT IS FOR RESEARCH ONLY — NOT FOR HUMAN OR VETERINARY DIAGNOSTIC OR THERAPEUTIC USE.” The animal studies give no formulation beyond the carrier: 0.9% saline was the vehicle throughout, and in the one experiment where the 2017 paper gives a volume the dose was a 100 µL bolus (Djillani et al., 2017).
  • What is sold — A spray, shipped as powder. The one seller’s listing read for this page offers a PE-22-28 spray in a 20 mg size with a glass spray bottle, in two grades it defines as lyophilized (freeze-dried) powder and dry raw powder; it claims at least 99% purity by HPLC and a shelf life of 36 months from manufacture, publishes purity, sterility and endotoxin certificates for a lyophilized batch, and says the product is for “in vitro research applications only”. An affiliate page for the same product calls it a 10 mL nasal spray and claims at least 98% purity and third-party testing, with no dose and no research-use wording. The peptide is also sold as a laboratory reagent (above). No label, trial record or published study gives directions for mixing or storing any of it; no published study has tested a product sold this way, no independent analysis of one has been published, and no published study has measured whether PE-22-28 crosses the lining of the nose (PubMed and Europe PMC, searched October 4, 2026).
  • Identity check — The mass of PE-22-28 is 773.9 for the free peptide (C35H55N11O9; PubChem), and a reagent supplier’s insert for the acetate prints the same formula weight. Spadin, the 17-amino-acid parent, is a different and heavier molecule, and no published analysis has compared what is sold under either name with the peptide in the papers.

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Side Effects & Risks

What This Page Cannot Tell You

Anything about safety in people. No person has been given PE-22-28 in a published study, and no toxicology study of it has been published in any species (PubMed and Europe PMC, searched October 4, 2026). The safety work that exists is a set of negative results in cells from its developers — no effect on four related potassium channels or on the heart’s hERG channel — plus one independent cell result pointing the other way (below), plus the authors’ own forecast that, sharing spadin’s targets, “spadin analogs would be devoid of side effects” (Djillani et al., 2017). That is a prediction, not a finding. What is in a product bought online is also unknown: no independent analysis of one has been published.

  • Nothing reported in people — There is no trial, no case report and no published series (PubMed and Europe PMC, searched October 4, 2026).
  • What the cell work rules out, and what it does not — At 100 nM the peptide did not change TREK-2, TRAAK, TRESK or TASK-1 currents, and at 10 µM it did not change the hERG current whose blockade causes the heart-rhythm problem seen with some antidepressants (Djillani et al., 2017). Those are single measurements in cell lines, not a safety assessment.
  • An independent lab’s cell result — In primary human lung cells exposed to high oxygen and stretch, blocking TREK-1 with PE-22-28 at 7.8 µM raised reactive oxygen species, caspase-8 and caspase-1 activity, interleukin-1β and two inflammatory signals; removing the channel genetically did the same, so the direction is the channel’s, not an artefact of the peptide (Majumder et al., 2026). These are lung cells in a dish, not a person, and the study was about the channel, not about this peptide’s safety.
  • The parent’s rodent safety record — For spadin, the group reported no effect on pain, on kainate-induced seizures, on blood glucose, on systolic pressure or cardiac pulses, and no change in infarct size after focal ischemia, in mice (Moha Ou Maati et al., 2012); a 2026 letter to the Chinese Medical Journal summarizing TREK-1 research gives the seizure test’s dose as 100 µg/kg (Chen et al., 2026). The 2012 paper also states the reason these were tested: deleting TREK-1 “is known to increase sensitivity to pain, seizures and ischemia”, so blocking it was expected to carry those risks. PE-22-28 has not been through those tests.
  • Insulin, where the reports differ — Spadin raised insulin release from insulin-secreting cells and mouse islets and raised plasma insulin in mice given glucose (Hivelin et al., 2016), while the earlier mouse work found glycemia unchanged by spadin treatment (Moha Ou Maati et al., 2012); mini-spadin made beta cells proliferate in culture (Daziano et al., 2021). None of this has been measured in a person.
  • The amount decides the direction — In mice, low doses activated the TREK-1 channel and higher doses blocked it (Pietri et al., 2019), so the same peptide produced opposite effects on its target depending on the dose. No study has mapped where that switch sits in any species other than the mouse.
  • The sold forms are the untested ones — Every published dose went into a mouse’s abdominal cavity or down its throat (Djillani et al., 2017; Pietri et al., 2019). No study has given the peptide into a nose, and no published study has measured whether it crosses the lining of the nose (PubMed and Europe PMC, searched October 4, 2026).
  • WADA — PE-22-28 is not named on the 2026 Prohibited List. Section S0 prohibits at all times any pharmacological substance not addressed elsewhere on the List “with no current approval by any governmental regulatory health authority for human therapeutic use (e.g. drugs under pre-clinical or clinical development or discontinued…)” (World Anti-Doping Agency, 2026). No approval of PE-22-28 anywhere turned up for this page, so S0 covers it.

Bloodwork & Monitoring

No monitoring guidance for PE-22-28 has been published, because no one has been given it in a study. These are the measurements the research used:

  • Mouse behavior — The forced swim test, the novelty-suppressed feeding test and the learned helplessness test, in groups of ten mice (Djillani et al., 2017).
  • Tissue counts, not blood — BrdU-labelled new cells per hippocampus, and PSD-95 on western blots of cortical neurons (Djillani et al., 2017); dopamine neurons in the substantia nigra, and motor and cognitive tests after a stroke (Pietri et al., 2019).
  • The blood test that exists is for the natural propeptide — A research assay measures the sortilin-derived propeptide in serum, used in the mouse work and then in people: before and after electroconvulsive therapy (Roulot et al., 2018) and across five years after a stroke (Mazella, Mendyk et al., 2025). It measures the body’s own propeptide, not PE-22-28, and it is a research assay, not a clinical one.
  • Nothing for the peptide itself — No published method measures PE-22-28 in human blood, and no study has reported its levels in any species.
  • Which tests fit a given person — A question for a licensed healthcare provider. This page can’t answer it.

Commonly Stacked With

No study has tested PE-22-28 as a treatment combined with another compound: the mice were given it alone (Djillani et al., 2017; Pietri et al., 2019), and in cells it was combined only with laboratory tools, for example in one lung-cell study the antioxidant N-acetylcysteine, or 2-APB or nifedipine, which block two sources of the cell’s calcium, each added at the same time as the peptide to trace how its effect arose, none of them a compound on this site (Majumder et al., 2026); searches of PubMed and Europe PMC for it with each peptide on this site find no study of the two together (October 4, 2026). One published document names it beside two compounds here: a 2023 proposal for an “Interventional Mental Health” service listed PE-22-28 with Selank and Semax among “anxiolytic peptides” it put forward as possible add-on treatments, citing studies of nerve blocks and ketamine rather than of the peptides, and describing no patient given any of them (Kuo et al., 2023).

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Legal Status

Current Status — October 2026

Not FDA-approved; not on FDA’s 503A or 503B lists. Drugs@FDA holds no application for PE-22-28 or for spadin (openFDA, searched October 4, 2026). Neither name is in part 216 of the Code of Federal Regulations — not on the 503A bulks list (21 CFR 216.23) or the withdrawn-or-removed list (216.24) — and neither is on FDA’s 503A categories list (updated May 14, 2026) or on its 503B categories list (updated March 21, 2025). No FDA warning letter or import alert naming PE-22-28 or spadin turned up in searches for this page (October 4, 2026).

Elsewhere: no approval by any health authority turned up for this page. The peptide has never been in a registered clinical trial: ClinicalTrials.gov holds no record for PE-22-28 or spadin (October 4, 2026), and the only development history is the 2017 academic paper and the two studies that followed it (Djillani et al., 2017; Pietri et al., 2019; Daziano et al., 2021).

WADA does not name PE-22-28 on its 2026 Prohibited List; because no government has approved it for human therapeutic use, section S0 prohibits it at all times (Prohibited List 2026; see Side Effects & Risks).

Cost & Access

There is no approved PE-22-28 product and no prescription form of it. What a reader meets instead is a research chemical (one seller’s listing and an affiliate page for the same product, read October 4 and 5, 2026): a 20 mg spray with a glass spray bottle, supplied as powder and labelled for in vitro research only, which the affiliate page calls a 10 mL nasal spray, with claims of at least 98% purity and third-party testing; a laboratory reagent supplier sells the acetate salt as a solid, labelled for research use only. No study has tested any of these products, and no independent analysis of one has been published.

Pricing and availability vary and are set by the seller. Kalios does not sell compounds.

References

  1. Djillani A, Pietri M, Moreno S, Heurteaux C, Mazella J, Borsotto M. Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant Activity. Front Pharmacol. 2017;8:643. PMID: 28955242. DOI: 10.3389/fphar.2017.00643. (Full text at PMC5601071, read October 4, 2026: the serum degradation products PE 14-25 and PE 12-27, the 55.5 ± 4.6% block at 100 nM, the saline bolus, the conflict-of-interest statement and the goal “to make spadin-analogs drugs usable in clinics”.)
  2. Pietri M, Djillani A, Mazella J, Borsotto M, Heurteaux C. First evidence of protective effects on stroke recovery and post-stroke depression induced by sortilin-derived peptides. Neuropharmacology. 2019;158:107715. PMID: 31325429. DOI: 10.1016/j.neuropharm.2019.107715.
  3. Daziano G, Blondeau N, Béraud-Dufour S, Abderrahmani A, Rovère C, Heurteaux C, Mazella J, Lebrun P, Coppola T. Sortilin-derived peptides promote pancreatic beta-cell survival through CREB signaling pathway. Pharmacol Res. 2021;167:105539. PMID: 33737242. DOI: 10.1016/j.phrs.2021.105539.
  4. Majumder N, Lopez B, Kasparian A, Taylor J, et al. Role of the two-pore domain potassium channel TREK-1 in hyperoxia- and mechanical stretch-induced alveolar epithelial injury. Am J Physiol Lung Cell Mol Physiol. 2026;330(1):L49-L65. PMID: 41252294. DOI: 10.1152/ajplung.00143.2025. (Full text at PMC12716432, read October 4, 2026: PE 22-28 at 7.8 µM as the TREK-1 blocker, and the results in primary human alveolar epithelial cells.)
  5. Mazella J, Pétrault O, Lucas G, Deval E, 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. DOI: 10.1371/journal.pbio.1000355. (Full text at PMC2854129, read October 4, 2026: spadin’s sequence, APLPRWSGPIGVSWGLR.)
  6. Mazella J, Borsotto M, Heurteaux C. The Involvement of Sortilin/NTSR3 in Depression as the Progenitor of Spadin and Its Role in the Membrane Expression of TREK-1. Front Pharmacol. 2018;9:1541. PMID: 30670975. DOI: 10.3389/fphar.2018.01541. (Full text at PMC6331531, read October 4, 2026: “the sequence 22–28, called mini-spadin”.)
  7. Heurteaux C, Lucas G, Guy N, El Yacoubi M, et al. Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype. Nat Neurosci. 2006;9(9):1134-1141. PMID: 16906152. DOI: 10.1038/nn1749.
  8. Moha Ou Maati H, Veyssiere J, Labbal F, Coppola T, et al. Spadin as a new antidepressant: absence of TREK-1-related side effects. Neuropharmacology. 2012;62(1):278-288. PMID: 21807005. DOI: 10.1016/j.neuropharm.2011.07.019.
  9. Veyssiere J, Moha Ou Maati H, Mazella J, Gaudriault G, et al. Retroinverso analogs of spadin display increased antidepressant effects. Psychopharmacology (Berl). 2015;232(3):561-574. PMID: 25080852. DOI: 10.1007/s00213-014-3683-2.
  10. Devader C, Khayachi A, Veyssière J, Moha Ou Maati H, et al. In vitro and in vivo regulation of synaptogenesis by the novel antidepressant spadin. Br J Pharmacol. 2015;172(10):2604-2617. PMID: 25598009. DOI: 10.1111/bph.13083.
  11. Ma R, Lewis A. Spadin Selectively Antagonizes Arachidonic Acid Activation of TREK-1 Channels. Front Pharmacol. 2020;11:434. PMID: 32317978. DOI: 10.3389/fphar.2020.00434.
  12. Bae Y, Choi JH, Ryoo K, Kim A, et al. Spadin Modulates Astrocytic Passive Conductance via Inhibition of TWIK-1/TREK-1 Heterodimeric Channels. Int J Mol Sci. 2020;21(24):9639. PMID: 33348878. DOI: 10.3390/ijms21249639.
  13. Moreno S, Devader CM, Pietri M, Borsotto M, Heurteaux C, Mazella J. Altered Trek-1 Function in Sortilin Deficient Mice Results in Decreased Depressive-Like Behavior. Front Pharmacol. 2018;9:863. PMID: 30127743. DOI: 10.3389/fphar.2018.00863.
  14. Hivelin C, Béraud-Dufour S, Devader C, Abderrahmani A, et al. Potentiation of Calcium Influx and Insulin Secretion in Pancreatic Beta Cell by the Specific TREK-1 Blocker Spadin. J Diabetes Res. 2016;2016:3142175. PMID: 28105440. DOI: 10.1155/2016/3142175.
  15. Roulot M, Minelli A, Bortolomasi M, Maffioletti E, et al. Increased serum levels of sortilin-derived propeptide after electroconvulsive therapy in treatment-resistant depressed patients. Neuropsychiatr Dis Treat. 2018;14:2307-2312. PMID: 30233189. DOI: 10.2147/NDT.S170165.
  16. Mazella E, Mendyk AM, Accart B, Borsotto M, et al. Serum sortilin-derived propeptide concentrations as markers of depression in chronic stroke. J Neurol Sci. 2025;472:123459. PMID: 40107034. DOI: 10.1016/j.jns.2025.123459.
  17. Djillani A, Pietri M, Mazella J, Heurteaux C, Borsotto M. Fighting against depression with TREK-1 blockers: Past and future. A focus on spadin. Pharmacol Ther. 2019;194:185-198. PMID: 30291907. DOI: 10.1016/j.pharmthera.2018.10.003.
  18. Djillani A, Mazella J, Heurteaux C, Borsotto M. Role of TREK-1 in Health and Disease, Focus on the Central Nervous System. Front Pharmacol. 2019;10:379. PMID: 31031627. DOI: 10.3389/fphar.2019.00379.
  19. Chen M, Wang Y, Xiong Z, Fang Y, Zhu Z. TREK-1 in central nervous system diseases. Chin Med J (Engl). 2026;139(4):620-622. PMID: 40539288. DOI: 10.1097/CM9.0000000000003662. (Letter to the editor. Full text at PMC12908831, read October 4, 2026.)
  20. Kuo J, Block T, Nicklay M, Lau B, Green M. Interventional Mental Health: A Transdisciplinary Approach to Novel Psychiatric Care Delivery. Cureus. 2023;15(8):e43533. PMID: 37719598. DOI: 10.7759/cureus.43533. (Full text at PMC10501497, read October 4, 2026: the sentence naming Selank, Semax and PE 22-28, and its references 47–51.)
  21. Qi X, Xu H, Wang L, Zhang Z. Comparison of Therapeutic Effects of TREK1 Blockers and Fluoxetine on Chronic Unpredicted Mild Stress Sensitive Rats. ACS Chem Neurosci. 2018;9(11):2824-2831. PMID: 29952548. DOI: 10.1021/acschemneuro.8b00225.
  22. Wu F, Sun H, Gong W, Li X, et al. Genetic and pharmacological inhibition of two-pore domain potassium channel TREK-1 alters depression-related behaviors and neuronal plasticity in the hippocampus in mice. CNS Neurosci Ther. 2021;27(2):220-232. PMID: 32864894. DOI: 10.1111/cns.13450.
  23. National Library of Medicine. PubChem: PE 22-28, CID 165437303 (C35H55N11O9, 773.9 g/mol; Gly-Val-Ser-Trp-Gly-Leu-Arg). pubchem.ncbi.nlm.nih.gov. Read October 4, 2026.
  24. UniProt Consortium. UniProtKB Q99523 (SORT1_HUMAN), sortilin: signal peptide residues 1–33, propeptide residues 34–77 (“removed in mature form”), 831-residue sequence. rest.uniprot.org/uniprotkb/Q99523. Read October 4, 2026.
  25. A laboratory reagent supplier’s product insert for PE 22-28 (acetate): peptide sequence GVSWGLR-OH, C35H55N11O9 · XC2H4O2, formula weight 773.9, purity ≥98%, supplied as a solid, storage −20 °C, stability ≥4 years, soluble in methanol and acetonitrile, and “THIS PRODUCT IS FOR RESEARCH ONLY - NOT FOR HUMAN OR VETERINARY DIAGNOSTIC OR THERAPEUTIC USE.” Read October 4, 2026. (Supplier not named: this site names no sellers.)
  26. One seller listing for a PE-22-28 spray, read October 5, 2026: “PE-22-28 Spray”, a 20 mg size, two grades the seller defines as lyophilized (freeze-dried) powder and dry raw powder, “Presentation: Glass Spray Bottle”, “Purity: ≥99% (HPLC)”, a 36-month shelf life from manufacture, purity, sterility and endotoxin certificates naming a lyophilized batch, and the statement that it is for “qualified research institutions conducting in vitro research applications only”. An affiliate page for the same product, read October 4, 2026: a 10 mL nasal spray, “≥98% Purity”, “Third-party verified”, no dose and no research-use statement, described as being “for mood and cognitive support” and as producing, “unlike traditional antidepressants that require weeks to take effect”, “rapid mood-modulating effects in research models”. (Neither named: this site names no sellers.)
  27. FDA. Drugs@FDA through openFDA (api.fda.gov/drug/drugsfda.json): searches for spadin and PE 22-28, October 4, 2026 (no applications). FDA warning letters and import alerts: no document naming PE-22-28 or spadin found, October 4, 2026.
  28. FDA. Bulk Drug Substances Nominated for Use in Compounding Under Section 503A of the Federal Food, Drug, and Cosmetic Act (categories 1–3). Updated May 14, 2026. fda.gov/media/94155/download.
  29. FDA. Bulk Drug Substances Nominated for Use in Compounding Under Section 503B of the Federal Food, Drug, and Cosmetic Act (categories 1–3). Updated March 21, 2025. fda.gov/media/94164/download.
  30. Code of Federal Regulations. 21 CFR 216.23 (bulk drug substances that can be used under section 503A) and 21 CFR 216.24 (drug products withdrawn or removed because they were found to be unsafe or not effective). ecfr.gov. Read October 4, 2026.
  31. World Anti-Doping Agency. Prohibited List 2026 (in effect January 1, 2026). S0, Non-approved substances. wada-ama.org.
  32. ClinicalTrials.gov. Searches for “spadin”, “PE 22-28” and “TREK-1”, October 4, 2026: no record of a trial of PE-22-28 or spadin; the two “TREK-1” records are NCT03985436 (a pain-psychology class) and NCT06943365 (anti-TREK-1 autoantibodies). clinicaltrials.gov, API v2.
  33. Devader C, Roulot M, Moréno S, Minelli A, Bortolomasi M, Congiu C, Gennarelli M, Borsotto M, Heurteaux C, Mazella J. Serum sortilin-derived propeptides concentrations are decreased in major depressive disorder patients. J Affect Disord. 2017;208:443-447. PMID: 27838145. DOI: 10.1016/j.jad.2016.10.049.
  34. Searches of October 4, 2026: PubMed, “PE 22-28”/“PE22-28” (1 record, reference 1) and the same in title or abstract (1 record); PubMed, “spadin” (81 records, 41 with spadin in the title or abstract, the rest by authors named Spadin or Padin); PubMed, “mini-spadin” in title or abstract (2 records, references 2 and 3); Europe PMC full text, “PE 22-28”, “PE22-28” and “mini spadin” (14 records; references 1–4, 6, 18–20); PubMed and Europe PMC, PE-22-28 or spadin with toxicology, pregnancy and drug-interaction terms, and with each peptide on this site (no study); ClinicalTrials.gov (reference 32); openFDA Drugs@FDA (reference 27); FDA’s 503A and 503B categories lists and 21 CFR 216 (no entry for either name).

Checked 5 Oct 2026 |  Profile authored by Kalios Peptides research team

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