PE-22-28

Mini-spadin · residues 22–28 of spadin · sortilin-derived heptapeptide

"A 7–amino-acid analog of spadin that selectively blocks the TREK-1 potassium channel — the mechanism behind a fast-onset antidepressant concept. Rodent studies show antidepressant-like effects and hippocampal neurogenesis within days. No human trials conducted to date."

Type

TREK-1 channel blocker (spadin analog)

Origin

Spadin lineage · IPMC / CNRS (France)

Status

UK: not illegal to buy or possess · WADA: not specifically listed · Research-use only · no human trials

Action

~23 h duration · SubQ / intranasal (community)

Protocol summary

Dose

No validated human dose

Route

SubQ · intranasal

Cycle

Experimental only

Community-reported

~200–500 mcg (community, varies widely)

Extrapolated from rodent studies — no human PK or dose-finding data exists

How we read the evidence

Genuine fast-onset mechanism · rodent antidepressant + neurogenesis data · zero published human trials · highly experimental

Animal evidence

The mechanism is real and well-characterised in rodents. PE-22-28 is a shortened analog of spadin that blocks the TREK-1 potassium channel with high potency (IC50 ≈ 0.12 nM, roughly 300× more potent than spadin). In mouse behavioural models — forced swim and tail suspension tests — TREK-1 blockade produced antidepressant-like effects, and TREK-1 knockout mice are themselves resistant to depression. PE-22-28 also stimulated hippocampal neurogenesis within about four days and increased synaptic markers (PSD-95). Its action lasts ~23 h versus spadin's ~7 h (Djillani et al., 2017).

Community & clinical practice

There is no established human dose. Community protocols are experimental and highly variable, typically microgram-range subcutaneous or intranasal, extrapolated from rodent studies with no human pharmacokinetic or dose-finding data to validate them. Pep IQ does not endorse a specific dose because the human evidence does not exist.

Human trial data

No completed, published human efficacy trials as of early 2026. Every efficacy and neurogenesis finding is rodent or in vitro. The fast-onset antidepressant concept is genuinely interesting — classic SSRIs take weeks — but the leap from mouse forced-swim data to human depression is unproven. A separate line of rodent work has also explored TREK-1 blockade in stroke recovery and post-stroke depression.

Regulatory status

Not approved as a medicine anywhere. Sold only by research-peptide vendors, research-use-only. In the UK it is not a licensed medicine and not a controlled drug — legal to possess, but "legal to possess" is not "approved or safe". PubChem CID 165437303.

Convergence

PE-22-28 has one of the more elegant mechanisms in the research-peptide space — a potent, selective TREK-1 blocker with a fast-onset antidepressant rationale and rodent neurogenesis data to match. But the human evidence base is empty: no efficacy trials, no safety trials, no established dose. TREK-1 is also expressed outside the brain (cardiovascular, gastrointestinal tissue), so systemic blockade could have off-target effects that short rodent studies would not capture. Pep IQ flags this as promising but firmly experimental — the science is genuine, the human data is absent.

Origin & The Concept

A fast-onset antidepressant idea

PE-22-28 traces back to a 2010 PLoS Biology paper (Mazella and colleagues, IPMC/CNRS, France) that identified spadin — a 17-amino-acid fragment cleaved from the propeptide of sortilin (the SORT1 gene product) during its processing. Spadin's key property: it selectively blocks the TREK-1 potassium channel and produced fast-onset antidepressant-like effects in mouse behavioural tests, a striking contrast to the multi-week delay of conventional antidepressants.

Spadin's problem was pharmacokinetic — its activity faded beyond about seven hours. To fix that, the same group screened spadin's blood-degradation products and engineered a seven-amino-acid peptide, PE-22-28 (residues 22–28 of spadin), reported in Djillani et al., 2017. The shortened peptide blocked TREK-1 far more potently than the parent (IC50 ≈ 0.12 nM vs 40–60 nM) and stayed active roughly three times as long (~23 h).

The appeal is the mechanism: if blocking TREK-1 relieves depressive behaviour quickly in animals, a stable, potent TREK-1 blocker is an attractive research tool for a fast-acting antidepressant. The unresolved question is whether any of that translates to humans — which has not been tested.

Important caveat: Every claim above is from rodent behavioural models (forced swim, tail suspension) and in vitro channel assays. These are validated screening tools, not evidence of a human antidepressant effect. "Antidepressant-like in mice" is not "antidepressant in people," and the potency figures describe channel binding, not clinical benefit.

Mechanism

TREK-1 blockade — a different antidepressant target

How PE-22-28 Works

TREK-1 potassium-channel blockade: PE-22-28 selectively inhibits TREK-1 (TWIK-related K⁺ channel 1), a two-pore-domain potassium channel enriched in the hippocampus and cortex. TREK-1 sets neuronal excitability; blocking it raises excitability and serotonergic tone in mood circuits. Mice lacking TREK-1 are resistant to depression, so pharmacological blockade mimics a "depression-resistant" state.

Spadin lineage and potency: PE-22-28 is residues 22–28 of spadin, itself cleaved from the sortilin propeptide. Engineering from spadin's degradation products gave PE-22-28 an IC50 of ~0.12 nM — roughly 300-fold more potent than spadin — and specificity for TREK-1 over related channels (TREK-2, TRAAK, TASK-1).

Neurogenesis and synaptogenesis: In rodents, PE-22-28 stimulated adult hippocampal neurogenesis within about four days and raised synaptic markers such as PSD-95. New-neuron formation on that timescale parallels the onset of antidepressant response — a structural correlate, not just a functional one.

Speed as the selling point: The whole rationale is onset speed. SSRIs take weeks; TREK-1 blockade produced antidepressant-like effects rapidly in rodent paradigms, and related work has probed TREK-1 in stroke recovery and post-stroke depression. All of this is preclinical — the human translation is the open question.

Because TREK-1 is expressed in tissues beyond the brain — including cardiovascular and gastrointestinal systems — systemic blockade raises the possibility of off-target effects that short rodent behavioural studies are not designed to detect. This is theoretical rather than observed, precisely because no human data exists.

Safety — The Preclinical-Only Reality

Risks & the empty human record

Unknown

No human safety data — there is no established dose, no human pharmacokinetics, and no monitoring framework. Any use is self-experimentation with an unstudied compound.

Unknown

Off-target TREK-1 effects — TREK-1 is expressed in cardiovascular, gastrointestinal and immune tissue. Systemic blockade could affect these systems in ways short rodent studies would not reveal.

Unknown

Interaction with antidepressants — the mechanism overlaps serotonergic signalling. Combining PE-22-28 with SSRIs, SNRIs or other mood medications is completely uncharacterised and could be hazardous.

Moderate

Unverified research-vial identity — sold research-use-only; product identity, purity and dose in grey-market vials are not verified against any pharmaceutical standard.