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PE-22-28

PE-22-28 · GVSWGLR

Animal replicated

Research chemicalSpadin Analog TREK-1 Modulator Nootropic Peptide

RouteInjectableGray-market only

Evidence grade: Animal replicated

Effect demonstrated in multiple animal studies; human data sparse or extrapolated. Grades summarize evidence quality, not whether a compound is appropriate, legal, or risk-free.

At a glance

What it is: GVSWGLR — Spadin Analogue — TREK-1 Potassium Channel Blocker — Nootropic / Antidepressant — Spadin Analog, TREK-1 Modulator, Nootropic Peptide.
Why people use it: Used primarily for cognitive support and sleep and recovery.
What the evidence supports: PE-22-28's safety profile in humans is essentially unknown — no systematic human safety study has been conducted. The preclinical mouse data showed no significant adverse effects at antidepressant doses in behavioral studies. The TREK-1 KO mice do not show increased mortality or gross pathology — removing the channel entirely does not produce severe systemic effects. This suggests that pharmacological blockade of TREK-1 with PE-22-28 is unlikely to cause severe acute systemic toxicity at typical doses. The important caveats: TREK-1 KO mice do show increased sensitivity to cerebral ischemia — the depression-resistance comes with a vulnerability to ischemic injury. Whether this translates to any clinical concern with pharmacological TREK-1 blockade at the doses used by the community is not established but represents a theoretical consideration for anyone with known cerebrovascular disease. Standard precautions: no SSRI/MAOI combination without physician awareness; depression treatment context should involve physician oversight; quality COA verification; liver enzyme monitoring not specifically required based on mechanism but general peptide safety monitoring applies.

If you only read one thing

PE-22-28 represents the most mechanistically novel antidepressant compound in this reference. Blocking a potassium channel to increase serotonergic neuron excitability — rather than blocking the reuptake transporter to prevent serotonin clearance — is a genuinely different pharmacological approach to depression. The mouse data shows 4-day antidepressant onset with neurogenesis induction, outperforming SSRIs in speed. The compound is more potent than its parent spadin by 333-fold. And the entire published evidence base — every mouse study, every patch-clamp experiment, every neurogenesis measurement — comes from one research group in Valbonne, France. No independent laboratory has replicated the core antidepressant findings with PE-22-28 specifically. No human has ever been enrolled in a PE-22-28 clinical trial. The community uses it for depression and cognitive enhancement based on mouse behavioral data from a single institution. This is not a critique of the science — the Heurteaux/Borsotto work is published in peer-reviewed journals and is mechanistically coherent. It is an accurate description of the evidence stage.

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Route / form

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Evidence fit

Route-specific

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Route caveat

Protocol not standardized

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Protocol anchor

Full dosing section

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Typical dose snapshot

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Evidence varies by use case

Evidence reality check

Evidence snapshot

PE-22-28's safety profile in humans is essentially unknown — no systematic human safety study has been conducted. The preclinical mouse data showed no significant adverse effects at antidepressant doses in behavioral studies. The TREK-1 KO mice do not show increased mortality or gross pathology — removing the channel entirely does not produce severe systemic effects. This suggests that pharmacological blockade of TREK-1 with PE-22-28 is unlikely to cause severe acute systemic toxicity at typical doses. The important caveats: TREK-1 KO mice do show increased sensitivity to cerebral ischemia — the depression-resistance comes with a vulnerability to ischemic injury. Whether this translates to any clinical concern with pharmacological TREK-1 blockade at the doses used by the community is not established but represents a theoretical consideration for anyone with known cerebrovascular disease. Standard precautions: no SSRI/MAOI combination without physician awareness; depression treatment context should involve physician oversight; quality COA verification; liver enzyme monitoring not specifically required based on mechanism but general peptide safety monitoring applies.

From the chapter quick-reference block.

Risk posture

No major flags listed

Review route-specific cautions before use.

Categories

Cognition & Mood Sleep & Recovery

Properties

Not injectable

Half-life

The limitation: spadin's half-life in vivo was approximately 7 hours, limiting its duration of action.

Evidence

CAnimal replicated

Why the Mechanism Is Novel

SSRIs (fluoxetine, sertraline, etc.) block the serotonin reuptake transporter (SERT), increasing serotonin in the synapse by preventing its removal. They do not affect serotonin production or the excitability of the serotonergic neurons that produce it. PE-22-28 works upstream: by blocking TREK-1, it makes the dorsal raphe neurons that produce serotonin more excitable — increasing serotonin production and release at the source rather than blocking reuptake. This is mechanistically different from every approved antidepressant. Additionally, PE-22-28 promotes hippocampal neurogenesis — the process of growing new neurons — which appears to be a shared final common pathway for antidepressant efficacy across multiple mechanism classes.

The Speed Advantage

4 days of treatment with spadin (the parent compound) was shown to correspond to 21-28 days of treatment with SSRIs in mouse behavioral models. PE-22-28 retains this rapid onset with superior potency (IC50 0.12 nM vs 40-60 nM for spadin). SSRIs typically require 2-4 weeks before clinical antidepressant effect — one of the most significant limitations of current antidepressant pharmacotherapy. The mechanism explains the speed: TREK-1 blockade immediately increases dorsal raphe excitability and serotonin output; neurogenesis induction follows within days. In contrast, SSRI neurogenesis induction (via elevated synaptic serotonin) takes weeks to produce the downstream neurogenic effects that may mediate their full antidepressant benefit.

Practical Details

Community administration: SubQ injection (50-300 mcg per injection, once daily) or intranasal (1 mg nasal drops in saline). Sequence: GVSWGLR. MW ~730 Da. All current evidence is preclinical (mouse/rat behavioral models). No dose-response in humans. No human pharmacokinetic data. Research chemical access only. Primary applications in community: depression, mood enhancement, cognitive performance, nootropic stacking with Selank or Semax.

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