PE-22-28: What It Is, Where to Get It Prescribed, and What It Costs

PE-22-28 is a short peptide, seven amino acids long — a fragment of a larger, naturally occurring protein piece called the sortilin propeptide. Sortilin (also written NTSR3) is a receptor found throughout the nervous system, and when the body makes it, a 44-amino-acid propeptide is clipped off and released. Researchers in Nice, France — the group around Catherine Heurteaux, Marc Borsotto and Jean Mazella — found that a section of that propeptide binds and blocks a potassium channel in nerve cells called TREK-1. They named that fragment, residues 12 to 28, spadin. PE-22-28 is a shorter version: residues 22 to 28 only.

That origin matters. This is not a drug designed against a target from scratch; it is a piece of a protein already circulating in people, trimmed to the shortest part that still works in cells and mice.

"PE" stands for propeptide; "22-28" is the fragment's position within it. The same group published spadin (PE 12-28) in PLoS Biology in 2010, then in Frontiers in Pharmacology in 2017 described shorter analogs, of which PE 22-28 was the shortest retaining TREK-1 blocking activity and, in their hands, the most potent. It appears as PE 22-28, PE-22-28 and PE22-28; the same peptide.

It is not an antidepressant medication in the regulatory sense. No drug agency has approved it for depression, or for anything, and it has not been through human trials. It is not a stimulant, not a sedative, and not a nootropic in the sense of a compound with human cognitive-performance data. It does not act on serotonin transporters the way SSRIs do, and it is not a replacement for treatment you already receive for a diagnosed mood disorder.

TREK-1 is a two-pore-domain potassium channel — a background "leak" channel that helps set how excitable a neuron is. The more open TREK-1 channels a neuron has, the harder it is to fire. The starting observation, in Nature Neuroscience in 2006, was that mice bred without the TREK-1 gene behaved across standard behavioural tests as though given an antidepressant, and that drugs such as fluoxetine reduce TREK-1 activity as one of their downstream effects. That made TREK-1 blockade a candidate mechanism in its own right.

Spadin, and then PE-22-28, were characterised as direct TREK-1 blockers. The 2017 paper reported PE-22-28 inhibiting TREK-1 in cultured cells at sub-nanomolar concentrations against tens of nanomolar for spadin — why the shortened fragment became the one of interest.

The proposed chain, again from rodent work, runs through serotonin. TREK-1 is expressed on serotonergic neurons in the dorsal raphe, which supplies serotonin to the cortex and hippocampus. Blocking TREK-1 in the rodent studies was associated with increased firing of those neurons — the same direction of effect SSRIs are thought to produce, by a different route. Brain Structure and Function (2016) described spadin interacting with prefrontal 5-HT4 and mGluR2 receptors in rats, and a 2015 European Neuropsychopharmacology paper from a separate group reported TREK-1 blockade producing an antidepressant-like response in rodents that synergised with 5-HT1A signalling.

The 2010 PLoS Biology paper reported spadin-treated mice showing increased hippocampal neurogenesis after four days, a window the authors contrasted with the several weeks conventional antidepressants take for the same change in animals. A 2015 British Journal of Pharmacology paper described spadin regulating synaptogenesis — the formation of connections between neurons — in cultured neurons and in mice. The 2017 paper reported PE-22-28 retaining the neurogenesis effect.

TREK-1 does several jobs beyond mood: pain signalling, protection against seizures, and protection of neurons during reduced blood flow. A 2012 paper in Neuropharmacology tested spadin in mice against exactly those endpoints and reported no pro-pain, pro-seizure or ischaemia-worsening signal at the doses that produced the behavioural effect. The 2017 work reported PE-22-28 also having a longer half-life in the mouse — roughly a day rather than several hours — the practical reason a seven-residue fragment was pursued over the original seventeen.

This is the core of the literature. The 2010 PLoS Biology paper reported antidepressant-like effects of spadin in mice across the forced-swim, tail-suspension, novelty-suppressed feeding and learned-helplessness tests, appearing after four days. The 2017 Frontiers in Pharmacology paper reported PE-22-28 reproducing those effects after a four-day course and, in that study, also intranasally. A 2018 ACS Chemical Neuroscience paper compared TREK-1 blockers with fluoxetine in a chronic unpredictable mild stress model in rats. These are the standard rodent screens across antidepressant development: an entry point, not proof of clinical efficacy.

A 2019 paper in Neuropharmacology from the Nice group reported sortilin-derived peptides, including the shortened analog, associated with improved functional recovery and reduced depression-like behaviour in a mouse stroke model — one study, in mice, framed by its authors as a first indication.

This is the part to understand before starting. There are no randomised controlled trials of PE-22-28 in humans, and no published human trials of any kind, of any size. Everything above is animal or cell research.

The closest thing to human data is observational. A 2017 paper in the Journal of Affective Disorders reported serum levels of the natural sortilin propeptide being lower in patients with major depressive disorder than in controls, and a 2018 paper reported them rising after electroconvulsive therapy in treatment-resistant patients. Those concern the body's own propeptide as a possible marker; they are not studies of giving PE-22-28 to anyone.

Prescribing rests on the mechanism, the rodent data and clinical judgement — a legitimate basis for a physician prescribing under supervision, but not evidence that it works in people. Any source implying otherwise is overselling it.

• It does not establish that PE-22-28 has any effect on mood, cognition or anything else in humans. That study has not been run.
• It does not establish a human dose. The directions in use are a prescriber's translation from animal work, not a dose-finding trial.
• It does not establish an effect size or a timeline in people.
• It does not establish safety in humans beyond the absence of problems in the animal work, and says nothing about long-term use.
• It does not establish that it can replace or be combined with any antidepressant. Those interactions are unstudied.
• It does not establish efficacy for any condition as an FDA-approved treatment. It is not approved for anything.

The rodent work reports behavioural change after four days. That is a mouse result, not a promise. Most of what people report in the first week is the injection routine settling in, and injection-site effects if any. Noticing nothing in this window is normal.

If any change in how someone feels is reported, prescribers generally describe it in this window, which is why a vial is sized at about four weeks. Because the compound has no human evidence, be honest with your physician about what you are noticing, including nothing.

PE-22-28 is not a treatment for depression, and no existing antidepressant should be stopped on the strength of a rodent literature. If you are under treatment, the physician managing it needs to be part of the decision. Thoughts of harming yourself are an emergency that no peptide addresses; contact a crisis line or emergency services.

No withdrawal and no rebound have been described — but only because the human studies that would find them have not been run. Whether to continue past a first vial is your physician's call.

The directions are written in millilitres and insulin-syringe units because that is what you read off the barrel. 0.25 mL is 25 units on a U-100 syringe. You are not calculating anything — the number is printed on your medication.

Subcutaneous means into the fat layer, not the muscle. Abdomen and thigh are the usual sites, rotated so the same spot is not reused. There is no reason to inject near any particular body part: the proposed mechanism is in the brain, reached through the circulation or not at all.

The reviewed directions are once daily on weekdays, weekends off. That gives twenty doses a vial, about four weeks, which is why refills run on a 28-day cycle. It is a prescriber's schedule, not a trial-derived one — the rodent studies used short daily courses — and your own directions may differ. One vial per fill, always; not a stockpile.

Refrigerated, and it ships that way in insulated packaging with ice packs. Beyond-use dating runs from first puncture and is on the label. Keep the vial upright, do not freeze it, and do not use it past that date.

Different targets. PE-22-28 is a TREK-1 blocker with rodent data only. Selank is a synthetic analogue of the immune peptide tuftsin, described around GABA and serotonin modulation, with published human use behind it as well as animal work. Selank is the more established choice for anxiety-type complaints and comes as a nasal spray; PE-22-28 is a vial only.

Semax is a fragment of ACTH described around BDNF and attention, with a long clinical record in its country of origin, and is usually the conversation when the goal is focus rather than mood. PE-22-28 has no human record at all. They are not interchangeable, and no published work covers using them together.

An SSRI or SNRI has decades of randomised human trials, an established side-effect profile, known interactions and FDA approval for specific diagnoses. PE-22-28 has none of those. The research interest in it is that it is proposed to reach one of the same downstream effects — reduced TREK-1 activity — by a different route and, in mice, faster. That is a hypothesis about a future drug class, not a reason to substitute it for treatment that works. If you have a diagnosis, this comparison belongs to the physician managing it.