PE-22-28

Spadin analog / TREK-1 channel blocker

Also known as: PE 22-28, PE22-28, spadin analog, shortened spadin, mini-spadin

Evidence level: Early/animal research

What it is

PE-22-28 is a short, lab-designed peptide studied for depression. In mouse studies, it produces antidepressant-like effects noticeably faster than standard antidepressants. It works by blocking a brain potassium channel called TREK-1, and it's an engineered, more stable version of 'spadin,' a natural fragment the body makes from the sortilin protein. All of the evidence is preclinical, with no human trials, and it is not FDA-approved for any use.

What the research found

PE-22-28 has been studied for depression, targeting a potassium channel called TREK-1. The approach began with a related peptide (spadin) that produced fast antidepressant-like effects in mice, including increased hippocampal neurogenesis within days; because spadin faded within hours, researchers designed shorter analogs, and PE-22-28 showed stronger, more selective TREK-1 blockade, better stability, and antidepressant-like effects in mouse behavioral tests after only 4 days. No human studies exist.

Status and regulatory position

Not FDA-approved for any indication. Investigational; evidence is entirely preclinical (cell electrophysiology and mouse behavioral models) — there are no human trials of PE-22-28 or its parent peptide spadin. WADA status: not specifically named on the Prohibited List; as a non-approved research peptide it is best treated as captured under S0 (non-approved substances), prohibited at all times in regulated sport — verify with your anti-doping organization. Not DEA-scheduled.

Safety

PE-22-28 has no human safety data — all studies are in cells and mice. It is not FDA-approved. As a non-approved research peptide it is best treated as prohibited in regulated sport at all times under the WADA S0 category; verify with your anti-doping organization. Anything affecting mood and brain signaling carries real risk if self-experimented with, and there is no human dosing or safety information to rely on. VialWise is a research and educational reference, not medical advice — anyone dealing with depression should seek qualified care.

Disclosures

⚠️ For research and educational purposes only. PE-22-28 is not approved by the FDA for any indication. Its entire evidence base is preclinical (cells and mice) — there are no human trials of PE-22-28 or its parent peptide spadin. Information here is informational, not medical advice. Always confirm any dose calculation with the in-app calculator and consult appropriate professional guidance.

⚠️ All evidence is preclinical, from one research group. Every finding below comes from cell electrophysiology and mouse behavioral studies, primarily from the CNRS Institut de Pharmacologie Moléculaire et Cellulaire.[¹][²][³] Antidepressant candidates with strong mouse data very often fail in human trials. There is no human dose, safety, or efficacy data for PE-22-28.

⚠️ This concerns depression — a serious condition. PE-22-28 is a research peptide, not a treatment. Anyone experiencing depression should seek qualified mental-health care. Self-experimenting with an unproven compound that alters brain signaling is a real risk, and no human guidance exists.

Quick reference

Compound class	A 7-amino-acid synthetic analog of spadin, itself a sortilin (NTSR3)-derived peptide. Acts as a selective TREK-1 potassium-channel blocker, the mechanism linked to fast-acting antidepressant effects in animals.[¹][²]
Common vial sizes	Research-supply lyophilized vials, commonly ~. No FDA-approved product exists.
Frequency	Mouse studies used short daily courses. PE-22-28 was designed for a longer duration of action than spadin (activity out to ~23 h vs ~7 h for spadin).[²] No established human regimen.
Half-life	Improved over spadin by design; spadin's activity faded within ~7 h, PE-22-28's out to ~23 h in mice.[²] Specific human PK is not established. (Preclinical/estimated.)
Route	Injection (intravenous/intraperitoneal) in the animal studies; research-community use is often subcutaneous. No approved route.[¹][²]
Onset of action	In mice, antidepressant-like effects and neurogenesis appeared within a few days, faster than standard antidepressants.[¹][²] No validated human effect exists.

In depth

PE-22-28 is a shortened synthetic analog of spadin, a naturally occurring peptide. Its story starts with a target: the TREK-1 potassium channel. Mice lacking the TREK-1 gene are resistant to depression in a way that mimics antidepressant treatment, which made TREK-1 antagonists attractive as potential fast-acting antidepressants.[¹]

Spadin, the parent peptide. According to PubMed, Mazella and colleagues (2010) identified spadin — a peptide derived from the propeptide released when sortilin (also called neurotensin receptor-3, NTSR3) matures — as a natural TREK-1 blocker. Spadin bound TREK-1 with ~10 nM affinity, blocked the channel in neurons, increased serotonin-neuron firing, and in five behavioral tests produced a depression-resistant phenotype like that of TREK-1-deficient mice. Notably, a 4-day IV course of spadin produced a strong antidepressant-like effect and increased hippocampal CREB phosphorylation and neurogenesis — markers usually seen only after weeks of SSRIs — suggesting a rapid onset. The authors called spadin "the first natural antidepressant peptide."[¹]

PE-22-28, the optimized analog. Spadin's practical problem was short duration — its activity disappeared beyond ~7 hours. Djillani and colleagues (2017) screened spadin analogs and, from studying spadin's blood-degradation products, designed a 7-amino-acid peptide, PE-22-28. In patch-clamp studies it showed stronger and more selective TREK-1 inhibition than spadin (IC₅₀ ~0.12 nM vs ~40–60 nM). In mouse behavioral models (forced-swim and novelty-suppressed-feeding tests) PE-22-28 and its derivatives reduced immobility and latency, induced neurogenesis after only a 4-day treatment, and enhanced synaptogenesis (increased PSD-95). Crucially, its duration of action was extended to ~23 hours.[²] A later review by the same group summarizes the sortilin/spadin/TREK-1 axis in depression and notes that soluble sortilin and the sortilin-derived propeptide are detectable in human serum and altered in major depressive disorder — interesting as a biomarker link, though not a therapeutic trial.[³]

Evidence quality. The PE-22-28 evidence is entirely preclinical — cell electrophysiology and mouse behavior — and comes largely from a single research group. No human trials of PE-22-28 or spadin have been published. The TREK-1 mechanism is genuinely interesting and the rapid-onset animal data are striking, but the translation gap for antidepressants is large, so PE-22-28 should be viewed as an early research candidate, not a treatment.

Regulatory status (US). PE-22-28 is not FDA-approved and is not DEA-scheduled. It is available only as a research-supply peptide outside the FDA-recognized supply chain.

Regulatory status (sport — WADA). PE-22-28 is not specifically named on the WADA Prohibited List. As a non-approved research peptide it is best treated as captured under S0 (non-approved substances), prohibited at all times. Verify current status via the WADA Prohibited List and your National Anti-Doping Organization.

Common research interests. Fast-acting antidepressant mechanisms (TREK-1 blockade), neurogenesis, and synaptic plasticity. All are extrapolated from animal studies and are not established human uses.

Reported side effects

Commonly reported

Unknown human tolerability — no human has been studied
Mood/CNS effects — anything modulating brain potassium channels and serotonergic firing could have unpredictable psychiatric effects in humans
Interaction with psychiatric medication — a specific theoretical risk
Research-supply purity — variable quality of non-pharmaceutical material is a general risk

Contraindications and warnings

Existing psychiatric conditions / psychiatric medication use — a specific concern given the mechanism; do not self-experiment, seek qualified care

Pregnancy and lactation — no data; default to contraindicated

Pediatric use — no data; should not be used in researchers under 18

Known hypersensitivity — contraindicated

Regulatory note (US): Not FDA-approved; available only as research-supply material outside the FDA-recognized supply chain. Not DEA-scheduled.

Regulatory note (sport): Not specifically named on the WADA Prohibited List, but best treated as S0 (non-approved substances), prohibited at all times. Verify with your anti-doping organization.

Key terms

TREK-1 channel: A potassium channel in the brain. Blocking it produces antidepressant-like effects in animals — the target of spadin and PE-22-28.
Spadin: The natural peptide (derived from the sortilin protein) that PE-22-28 is a shortened, optimized version of.
Sortilin (NTSR3): A cellular sorting protein; its maturation releases the propeptide that gives rise to spadin.
Neurogenesis: The birth of new neurons. Both spadin and PE-22-28 increased it in mouse hippocampus, a marker associated with antidepressant action.
Preclinical: Research done in cells or animals, before any human testing. Preclinical antidepressant findings frequently do not translate to people.

Sources

Related entries

Cerebrolysin — same mechanism class
Oxytocin — same mechanism class
P021 — same mechanism class
Selank — same mechanism class
Semax — same mechanism class
Glutathione — shared research area

Entry last updated 2026-09-03. Sourced from published literature and regulatory labelling; see Sources above.