Carl read the papersWhat it actually is
The story starts with a channel. Mice with the TREK-1 gene deleted behave like mice already on antidepressants, which pointed at blocking TREK-1 as a route to a faster-acting antidepressant.
Spadin is a 17-amino-acid peptide released when the sortilin receptor is processed, and it blocks TREK-1. Its problem was stability: activity disappeared beyond about seven hours in vivo. Researchers at the CNRS institute in Valbonne studied its blood degradation products and designed a seven-amino-acid peptide, PE 22-28, from what was left.
How it’s thought to work
- TREK-1 blockade — TREK-1 is a two-pore domain background potassium channel. Blocking it makes neurons more excitable, and the serotonin system responds, which is the proposed antidepressant route.
- Much tighter than the parent — In patch-clamp on human TREK-1 expressed in HEK cells, PE 22-28 had an IC50 of about 0.12 nM, against 40 to 60 nM for spadin. That is a large step in potency from shortening the molecule.
- Neurogenesis and synaptogenesis — In mice, four days of treatment increased markers of new neuron formation, and PSD-95 expression rose in cortical neurons, which the authors read as new synapses.
- Longer action — Measured duration of action in mice extended to about 23 hours, against roughly seven for spadin.
- A biphasic twist — In a stroke model, the shortened analogue activated TREK-1 at a very low dose and blocked it at a higher one, so the direction of effect depended on the amount given.
What the research says
All preclinical, all rodent, and nearly all from one research group. The 2017 Front Pharmacol paper is the core document: patch-clamp potency, forced swim and novelty-suppressed feeding tests, neurogenesis and synaptogenesis markers, and duration of action. A 2019 Neuropharmacology paper from the same group extended it to a mouse model of focal ischaemia and post-stroke depression. Supporting the target rather than the molecule, a 2006 Nat Neurosci paper showed TREK-1 deletion produced a depression-resistant phenotype, and a 2017 clinical paper found serum sortilin-derived propeptide levels were lower in patients with major depressive disorder and were restored by antidepressant treatment, which is human evidence for the pathway and not for the peptide. On safety the honest summary is a single reassuring rodent study: spadin did not interfere with the pain, seizure and ischaemia functions TREK-1 is involved in, did not inhibit four related potassium channels, and did not affect cardiac repolarising currents or blood pressure in those experiments. That study was on spadin, not on PE 22-28, and it was in mice. There is no registered clinical trial and no human study of either compound.
- Seven amino acids, designed from the blood degradation products of spadin.
- IC50 about 0.12 nM at human TREK-1, versus 40 to 60 nM for spadin.
- Antidepressant-like effects in mouse forced swim and novelty-suppressed feeding tests after four days.
- Duration of action in mice about 23 hours, against roughly seven hours for spadin.
- TREK-1 knockout mice are depression-resistant, which is the target validation.
- No human trial. A ClinicalTrials.gov search for spadin returns no studies.
Reported protocols
These are the doses the peptide community actually reports running (Reddit & forums), alongside published research — logged for education, not as a recommendation to use.
| Parameter | Commonly reported range |
|---|---|
| Human dose | Not established. Neither spadin nor PE 22-28 has entered a clinical trial, so there is no human dose, route or schedule, and no safety data in people at all. |
| Why there is no number | Everything published is mouse work using injection into the abdominal cavity at microgram-per-kilogram amounts chosen for the experiment. Body-weight scaling from mouse behaviour tests to a human regimen is not a calculation anyone should trust. |
| The biphasic problem | In the stroke work the shortened analogue activated TREK-1 at a low dose and blocked it at a dose a hundred times higher. A compound whose direction of effect flips with dose is a poor candidate for guesswork. |
| Reported online | This one does have a real trail of first-hand posts going back to 2021, on r/Nootropics and r/Peptides, mostly in the range of a few hundred micrograms a day by nose or under the skin. They are informal reports, with no measurement of anything, and they include people who felt nothing and at least one who felt distinctly worse. One of them calls himself the first human trial, which is closer to true than it should be. |
| Safety work is on the parent | The study showing no effect on pain, seizures, ischaemia or cardiac currents tested spadin, in mice. It is reassuring about the mechanism and it is not a human safety file. |
| Carl's position | Depression is a serious illness with treatments that have been tested in thousands of people. A mouse-stage peptide is not a substitute for any of them. |
Common use cases
| Goal | Community protocol notes |
|---|---|
| Following the TREK-1 antidepressant literature | a clean example of a target validated by knockout mice |
| Understanding peptide fragment design | shortening a peptide to its active core, here with a large potency gain |
| Reading the sortilin propeptide work | including the human study showing lower serum levels in major depression |
Mixing it (reconstitution)
Freeze-dried peptides must be reconstituted with bacteriostatic water before they can be measured. Carl’s calculator turns “mg in the vial + ml of water + target dose” into “units on the syringe” — and tells you how long the vial lasts.
→ Open the Reconstitution Calculator
Injection & handling
No administration guide here, and in this case the reason goes past the usual one. There is no human data at all, the published rodent work uses intraperitoneal injection in mice, and the dose-response is biphasic, meaning the same compound pushed the channel in opposite directions depending on how much was given. More importantly: this compound is aimed at depression, which is a medical condition that can get dangerous. Anyone in that position needs a doctor, not a research vial. Established treatments exist, they have human trial evidence behind them, and a clinician can monitor what is happening. If the appeal here is the promise of working in four days rather than three weeks, that promise has so far only been kept in mice.
Stacks it appears in
- With Selank or Semax — the obvious shelf neighbours, both already on this site and both named by SAHPRA. Different mechanisms, same absence of large human trials, and stacking them does not add evidence.
- With prescribed antidepressants — this is the combination to avoid without a doctor. Fluoxetine is itself a TREK-1 inhibitor among its other actions, so the interaction is not hypothetical, and nobody has studied the combination in people.
- With DSIP for sleep — appears in the same stacks. Sleep disturbance in depression is a clinical problem and belongs with a clinician.
Sources
- Djillani A et al. 2017, Front Pharmacol. Shortened spadin analogs display better TREK-1 inhibition, in vivo stability and antidepressant activity (PMID 28955242, PMC5601071)
- Mazella J et al. 2010, PLoS Biol. Spadin, a sortilin-derived peptide targeting rodent TREK-1 channels (PMID 20405001, PMC2854129)
- Heurteaux C et al. 2006, Nat Neurosci. Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype (PMID 16906152)
- Heurteaux C et al. 2004, EMBO J. TREK-1, a K+ channel involved in neuroprotection and general anesthesia (PMID 15175651)
- Moha Ou Maati H et al. 2012, Neuropharmacology. Spadin as a new antidepressant: absence of TREK-1-related side effects (PMID 21807005)
- Pietri M et al. 2019, Neuropharmacology. Protective effects on stroke recovery and post-stroke depression induced by sortilin-derived peptides (PMID 31325429)
- Devader C et al. 2017, J Affect Disord. Serum sortilin-derived propeptide concentrations are decreased in major depressive disorder patients (PMID 27838145)
- Djillani A et al. 2019, Pharmacol Ther. Fighting against depression with TREK-1 blockers, a focus on spadin (PMID 30291907)
- ClinicalTrials.gov search for spadin and for PE 22-28
- WADA 2026 Prohibited List, S0 non-approved substances
- SAHPRA, Peptide Products: Public Information (May 2026)
