CognitivePE 22-28Shortened spadin analog

PE-22-28

TREK-1 (KCNK2) channel blocker · spadin-derived · animal-only antidepressant research peptide

PE-22-28 is a research peptide built around one elegant idea — and almost no human data. It is a shortened, stabilized version of spadin, a natural peptide your body generates when it processes the receptor sortilin; spadin and its analogs work by blocking a potassium channel called TREK-1, which is the whole reason this molecule is interesting. TREK-1 is tied to depression: mice that lack it behave as if they are already on antidepressants. So blocking TREK-1 is proposed as a fast-acting antidepressant mechanism that skips the usual serotonin-reuptake pathway entirely. PE-22-28 blocks TREK-1 extremely potently — roughly 300 times more so than spadin itself — and in mouse behavioral models it reduced depression-like behavior, promoted new neuron formation, and acted faster than classic antidepressants. The essential honesty here is the evidence ceiling: every one of those findings is in rodents. There are zero human trials, zero human efficacy data, and zero human safety data. It is sold online ahead of any clinical validation, and there is no established human dose — so anything beyond "a promising preclinical mechanism" is, at this point, unproven.

The short version

PE-22-28 is a small synthetic peptide — just seven building blocks — designed as an antidepressant research tool. Its lineage matters: your body naturally makes a peptide called spadin when it processes a receptor named sortilin, and spadin turned out to block a specific potassium channel, TREK-1, in the brain. PE-22-28 is a shortened, sturdier version of spadin, engineered to do that same job better.

Why block TREK-1? Because TREK-1 is linked to depression in a striking way: mice genetically engineered to lack the channel behave as though they are already being treated with antidepressants — they are resistant to depression-like behavior. So the logic is that blocking TREK-1 with a drug should produce a similar, and possibly fast-acting, antidepressant effect — and importantly, it would work through a completely different route than standard antidepressants like SSRIs, which act on serotonin reuptake.

In the lab, PE-22-28 delivers on the mechanism: it blocks TREK-1 about 300 times more potently than spadin, and in mouse studies it reduced depression-like behavior, encouraged the growth of new neurons, and worked faster than classic antidepressants. But here is the line that defines this page honestly — all of that is in mice. There are no human trials, no human safety data, and no established human dose. It is sold to people online well ahead of any clinical evidence, so for now it is best understood as a promising idea proven only in animals.

Molecular identity

Specs

Molecular weight: 773.9 g/mol (average)
Molecular formula: C35H55N11O9
Monoisotopic mass: 773.4184 Da
CAS number: 1801959-12-5 (free peptide)

Sequence (7 AA): Gly-Val-Ser-Trp-Gly-Leu-Arg (GVSWGLR)PubChem CID 165437303; Djillani et al. 2017 (PMID 28955242)
Structure / class: Linear 7-residue peptide; shortened, stabilized spadin analogPubChem CID 165437303; PMID 28955242
Molecular target: TREK-1 (KCNK2) two-pore-domain K⁺ channel — blocker (IC₅₀ ≈ 0.12 nM; ~300× spadin)Djillani et al. 2017 (PMID 28955242)
Origin: Derived from spadin (PE 12-28), a sortilin/NTSR3 propeptide fragmentMazella et al. 2010 (PMID 20405001)
Half-life: Not established in humans; engineered for improved in-vivo stability over spadin (rodent data only)Not established; PMID 28955242 (rodent)
Regulatory status: Not approved anywhere; research compound. No human trials — efficacy and safety data are mouse-onlyNo approval record; PMID 28955242

Plain English

Mechanism

PE-22-28's target is TREK-1, a two-pore-domain potassium channel encoded by the gene KCNK2. PE-22-28 is a blocker of this channel, and it does so with remarkable potency — a half-maximal inhibitory concentration in the sub-nanomolar range (around 0.12 nM at human TREK-1 in patch-clamp experiments), roughly 300 times more potent than spadin, the parent peptide. That potency jump is the reason the shortened analog was made.

The link to mood is what makes TREK-1 a drug target. TREK-1 is expressed in mood-regulating brain regions, and knockout mice that lack it show a depression-resistant phenotype that resembles the state produced by antidepressant treatment. Blocking TREK-1 increases the firing of serotonin neurons in the dorsal raphe and triggers the downstream signaling (such as CREB phosphorylation and markers of new-neuron formation) associated with antidepressant action — but it reaches that endpoint without acting directly on the serotonin transporter the way SSRIs do. The proposed payoff is a faster onset than the weeks-long delay typical of standard antidepressants.

Keep mechanism and clinical proof strictly separate. The mechanistic story — TREK-1 blockade, sub-nanomolar potency, the knockout-mouse rationale, and the rapid-onset behavioral effects — is well supported in vitro and in rodents. The clinical story in humans is simply empty: there is no human pharmacology, no human efficacy, and no human safety. The mechanism is the reason to be interested, not evidence that it works in people.

Sources:PMID 28955242 PMID 20405001 PMID 25263033

Why people reach for it

Potential benefits

PE-22-28 is built around one elegant mood mechanism — and almost no human data. Here's what people pursue it for, kept honest about the evidence ceiling.

A fast-acting mood mechanism (in mice) — Its headline appeal: by blocking the TREK-1 channel, PE-22-28 produced an antidepressant-like effect in mouse behavioral models — and reportedly faster than classic antidepressants — the mood-support angle people are drawn to, though every result is in rodents.
A different route than an SSRI — It works upstream of serotonin reuptake — blocking TREK-1 raises serotonin-neuron firing without acting on the serotonin transporter the way SSRIs do — the reason people interested in a non-SSRI mechanism reach for it.
Encourages new-neuron formation (in mice) — In the mouse work it promoted hippocampal neurogenesis — new-neuron formation — alongside the behavioral effect, the neuroplasticity angle people pursue it for.
Extremely potent on its target — It blocks TREK-1 roughly 300 times more potently than spadin, the natural peptide it's derived from — the potency that made the shortened analog worth building.
Stacks with the focus and calm peptides — Because its lever is the mood/TREK-1 axis, people pair it with Selank for added calm or Semax for cognitive drive — different mechanisms on the same neurological goal.

Sources:PMID 28955242 PMID 20405001 PMID 25263033

What people reach for PE-22-28 for, drawn from what the research reports — which is animal-only (every mood and neurogenesis finding is in mice; zero human trials) — and how it's used, not proven outcomes or medical claims.

Implied timing

Best time to dose

Implied best time

Daytime (morning-lean)

Most people take PE-22-28 during the day, with a morning lean — though there is no human timing data, so it's reasoned from the mood mechanism and how it's used.

It acts on the brain's mood and serotonin-firing circuitry, so the effect is wanted during waking hours; community practice most often places the once-daily dose in the morning, loosely aligned with the body's natural cortisol peak.
The neurogenesis/BDNF half of its proposed effect is the kind of brain-active, alerting signal that fits daytime rather than late-evening dosing — a reason the morning lean is the common default.
There is no peptide-specific timing study for PE-22-28 in humans, and no human PK, so morning is convention, not an evidence-based requirement — a consistent daily time matters more than the exact hour.
Because the molecule has no measured human half-life, the daytime/morning placement is reasoned from its alerting, mood-acting mechanism and how it's used, not from a known duration of action.

No study establishes an ideal time of day for PE-22-28 — there is no human data, so this is reasoned from its mood/serotonergic mechanism and how it's used. As a rule of thumb most peptide dosing lands in the midday-to-evening window; for PE-22-28 the lean is the early side of that — daytime, leaning morning.

Sources:PMID 28955242

How to run it

Dosing & protocol

PE-22-28 is dosed here as a subcutaneous injection — the form sold as a research peptide and the route the on-page calculator is built for. There is no established human dose: every antidepressant-like finding for this molecule is in mice, and no human trial has been run. The route and the community convention range below are the only honest practical frame available. Read this as a map of how subcutaneous PE-22-28 is used in practice — not a validated human regimen.

Animal-only evidence: every antidepressant result is in mice — zero human trials, no established human dose, no human pharmacokinetics. Grey-market sale outpaces the evidence. Any human protocol is unvalidated convention, not a clinical finding. This molecule is further from a human dose than most peptides in this catalog.

Dose — no established human dose

SubQ is the research route; the dose below is community convention on an unvalidated compound — not a clinical recommendation.

Route:: Subcutaneous injection — the only studied route (all published work is by injection in rodents). Oral administration would be destroyed by digestion before it could act.
Convention range:: Community practice most often cites 100–250 mcg once daily by SubQ injection. This is unvalidated convention derived from general peptide community norms, not from a human study or pharmacokinetic rationale — it has no evidence basis in humans.
No human dose exists:: The published record contains only rodent injection data and in-vitro (cell-dish) experiments. Any vendor-listed human dose is extrapolation. The calculator on this page cannot pre-fill a validated regimen because none exists.

Subcutaneous administration

PE-22-28 is injected into subcutaneous fat; site, rotation, timing, and food window are the actionable choices.

Injection site:: The abdomen (staying a couple of inches clear of the navel), the love-handle area, or the outer thigh. Rotate sites between doses so one spot is not used repeatedly — that prevents local irritation and lipohypertrophy (fatty lumps under the skin).
Measuring the dose:: Drawn on a U-100 insulin syringe from the reconstituted vial. At the standard mix (10 mg vial + 2 mL BAC water = 5,000 mcg/mL): 100 mcg = 2 IU · 150 mcg = 3 IU · 200 mcg = 4 IU · 250 mcg = 5 IU. The on-page calculator covers any vial size.
Time of day:: Daytime with a morning lean — see Best time to dose above. Morning is generally preferred for once-daily dosing, loosely aligned with the body's natural cortisol peak. There is no peptide-specific timing data for PE-22-28 in humans — this is convention, not an evidence-based requirement.
Food window:: Subcutaneous injection does not compete with food for absorption; timing around meals is not a factor for this route.

Cycle & washout

Research peptides that modulate neurotransmitter systems are typically pulsed rather than run indefinitely.

Standard cycle:: 4–8 weeks of daily use is a common community convention, then reassess. There is no human clinical data on optimal cycle length for PE-22-28.
Washout:: A 2–4-week break is standard convention. Because the antidepressant framing makes mood any possible endpoint, taking stock during the break — ideally with a validated mood scale — provides the most useful signal about whether the cycle had any effect.
No long-term safety data:: There is no human chronic-use data. Longer or continuous use is an open unknown, not a studied path. The conservative reading is to err shorter until a safety picture exists.

Reconstitution at a glance

The on-page calculator does this live; quick reference for a 10 mg vial with 2 mL bacteriostatic water:

Mixing:: 10 mg vial + 2 mL bacteriostatic water = 5,000 mcg per mL. On a 100-unit (1 mL) insulin syringe: 100 mcg = 2 IU · 150 mcg = 3 IU · 200 mcg = 4 IU · 250 mcg = 5 IU · 500 mcg = 10 IU.
Why 2 mL:: The calculator defaults to 2 mL, producing a 5,000 mcg/mL solution — concentrate enough to keep dose volumes small, while giving syringe units that are readable without a magnifier at the convention range.

Sources:PMID 28955242 PMID 20405001

Substrate the signal needs

Nutritional cofactor precision

PE-22-28's proposed mechanism runs through two linked pathways: TREK-1 blockade (which raises serotonin-neuron firing and triggers neurogenesis signaling) and hippocampal neurogenesis (new-neuron formation, a readout the mouse studies moved). The useful cofactors either supply the raw material those pathways consume, amplify them through independent routes, or reduce any downside. This is reasoning from the TREK-1/antidepressant mechanism — not a PE-22-28 nutrition study, and the mechanism itself is rodent-only.

Reasoned from TREK-1 / serotonergic / neurogenesis biology plus well-evidenced nutritional mood support — not a PE-22-28 cofactor study. Supplement doses are common community ranges. MITIGATE surface is minimal for this compound; the cofactor value here is on the SUPPLY and AMPLIFY side.

SUPPLY — serotonin substrate + TREK-1-sensitive fatty acids

TREK-1 blockade raises serotonin-neuron firing; the serotonin pathway needs substrate to run on, and TREK-1 itself is lipid-sensitive.

Tryptophan or 5-HTP:: Tryptophan is the dietary precursor the body converts into serotonin; 5-HTP is one step closer. If PE-22-28 raises serotonergic firing, having adequate substrate available is the obvious diet input. L-tryptophan 500–1,000 mg taken in the evening with a small carbohydrate (improves CNS uptake by reducing competing amino acids) or 5-HTP 50–100 mg at bedtime. Do not combine with prescription antidepressants (serotonin-load risk).
Vitamin B6 (P5P form):: Pyridoxal-5-phosphate is the active cofactor for both the rate-limiting step in serotonin synthesis (aromatic amino acid decarboxylase) and for GABA synthesis. 25–50 mg P5P daily with food. The P5P form bypasses the liver conversion step that limits standard B6.
Omega-3 DHA/EPA:: TREK-1 is a polyunsaturated-fatty-acid-sensitive (PUFA-sensitive) channel — DHA and EPA are among its natural modulators in membrane biology. DHA is also the dominant structural fatty acid in the brain, required for new-neuron membrane formation (the neurogenesis half of PE-22-28's proposed effect). ~2–3 g combined EPA/DHA daily from fish oil or algae oil.

AMPLIFY — independent BDNF and mood levers

Hippocampal neurogenesis is the headline mouse readout. Three behavioral inputs drive that same biology independently of any peptide.

Exercise (aerobic):: Sustained aerobic exercise is the best-evidenced non-pharmacological driver of hippocampal BDNF (brain-derived neurotrophic factor) and neurogenesis — the same endpoint PE-22-28 moved in mice. 3–5 sessions/week of 30–45 min sustained cardio (zone 2 heart rate). The effect is dose-dependent and cumulative.
Sleep (7–9 hours):: Sleep is when neurogenesis signaling consolidates and memory encoding occurs. Chronic sleep restriction suppresses BDNF and hippocampal neurogenesis independent of everything else on this page. No supplement compensates for a consistent sleep deficit. Prioritize sleep window and consistency before any stack.
Morning light exposure:: Morning bright-light exposure entrains the circadian clock and anchors the cortisol awakening response, which supports mood regulation and serotonin synthesis timing. 10–20 minutes of outdoor morning light (or a 10,000 lux light box) within the first hour of waking. Free, zero interaction risk, and the evidence base for mood is comparable to mild antidepressants in seasonal contexts.

MITIGATE — minimal known surface

PE-22-28's TREK-1 mechanism does not consume known cofactors that become depleted, so the MITIGATE stack is short.

Magnesium glycinate:: Magnesium supports sleep quality, reduces stress-related NMDA over-activation, and is broadly depleted in stress-heavy or high-caffeine contexts. It does not specifically mitigate PE-22-28 risk (there is no known mechanism), but it is a reasonable general mood-and-sleep support. 300–400 mg magnesium glycinate at bedtime.
No known depletion targets:: Unlike some peptides that raise a specific growth factor or consume a specific cofactor rapidly, PE-22-28's TREK-1 channel-blocking mechanism has no identified nutritional depletion signal in the preclinical record. The MITIGATE case here is thin by design — if evidence changes, this card updates.

Combinations + timing

Stacking notes + timing windows

PE-22-28 holds one lever: TREK-1 blockade → serotonin-neuron firing → neurogenesis signaling. The best pairings bring a different neurological angle — anxiolytic, neurotrophic, or cognitive — that doesn't duplicate the serotonin-channel mechanism PE-22-28 already covers.

Doubly speculative: PE-22-28 has zero human data, so any stack is based on mechanism reasoning only — never studied combinations. Every dose here is community convention. "Reached for" describes where users conceptually place these combinations, not a proven indication or validated protocol.

PE-22-28 + Selank

A mood-plus-calm pairing — TREK-1 fast-act channel block alongside a different anxiolytic neuropeptide mechanism.

Why it works:: Selank is a synthetic heptapeptide derived from tuftsin, studied in rodent and limited human anxiolytic research for its GABAergic and enkephalin-modulating effects — a calming/anxiolytic lever that is mechanistically distinct from TREK-1 blockade. PE-22-28 proposed fast-acting antidepressant channel-block + Selank proposed anxiolytic = complementary angles on mood, not doubling the same one.
The protocol:: PE-22-28 100–250 mcg SubQ once daily + Selank 250–500 mcg SubQ once daily (or intranasal if preferred for Selank — it is one of the intranasal-primary peptides). Community convention; no head-to-head data.
Outcome:: Reached for in nootropic-community discussions on combined mood and anxiety management — two different preclinical mechanisms on the same neurological goal. Both compounds lack human trial data; the combination is doubly unproven.

PE-22-28 + Semax

A fast-act antidepressant channel block alongside a neurotrophic / cognitive-enhancement neuropeptide.

Why it works:: Semax is a synthetic ACTH(4-7) analog studied in Russian and limited international research for BDNF upregulation, cognitive enhancement, and neuroprotection — a neurotrophic input that amplifies the brain-growth-factor biology that PE-22-28's neurogenesis story runs toward. Two different neuroscience levers: TREK-1 channel modulation (PE-22-28) + BDNF/neurotrophic signaling (Semax).
The protocol:: PE-22-28 100–250 mcg SubQ once daily + Semax 300–600 mcg SubQ or intranasal once daily. Semax is an intranasal-primary peptide; both routes are used in community practice. No head-to-head data with PE-22-28.
Outcome:: Reached for in nootropic stacks where cognitive clarity and mood support are both goals. The Semax neurogenesis/BDNF angle loosely echoes the neurogenesis half of PE-22-28's mouse findings — conceptually coherent, not studied. Both compounds are preclinical-dominant; the combination carries all that uncertainty forward.

Reconstitution math

Reconstitution calculator

Calculated for a 1 mL U-100 insulin syringe (100 units/mL).

Peptide per vial

BAC water added

Desired dose

Units per dose

Draw to this mark on a U-100 syringe

Volume per dose: 0.2 mL
Doses per vial: 10
Concentration: 5 mg/mL

One vial lasts

Daily: 10 days
Every other day: 20 days
5×/week: 14 days

Research use only. Not for human consumption. Outputs are reference values based on research literature — verify all measurements independently.

From the studies

Side effects from research

PE-22-28's human safety is unknown and uncharacterized — there is no human safety database, no human pharmacokinetics, and no adverse-event data of any kind. Nothing on this page should be read as a safety reassurance.

The rodent literature framed these spadin analogs as relatively selective TREK-1 blockers and suggested they lacked some of the side effects associated with classic antidepressants. But because TREK-1 has roles beyond mood regulation — including in the cardiovascular system and in pain and neuroprotection pathways — any "clean side-effect profile" claim must be read as a preclinical observation, not a guarantee in humans. The responsible stance is that the consequences of blocking TREK-1 in a person, at any dose, are simply not established.

On sport: PE-22-28 is not specifically named on the WADA Prohibited List in the sources reviewed, but this should not be read as "permitted." Anti-doping rules include broad categories — for example, non-approved substances — that can capture unapproved research peptides regardless of whether they are named, so athletes should verify status directly with WADA or their federation.

Sources:PMID 30291907

As reported in literature

Research dosing ranges

These are the findings from the published literature, shown separately so the preclinical evidence is never mistaken for a human regimen. Every row is animal or in-vitro — there are no human trials of PE-22-28. No human dose has been established, so there is no human row, and rodent milligram-per-kilogram figures are deliberately not listed here (verify them in the primary paper before citing, and label them animal-only).

Dose	Route	Model	Outcome	Sources:
Sub-chronic course (mouse)	Injection	Preclinical — mouse, forced swimming test	Reduced immobility time (an antidepressant-like effect) — preclinical only	PMID 28955242
~4-day treatment (mouse)	Injection	Preclinical — mouse, novelty-suppressed feeding + neurogenesis	Reduced latency to feed and induced hippocampal neurogenesis after only ~4 days; faster than classic antidepressants — preclinical only	PMID 28955242
In-vitro exposure	In vitro	Cellular — human TREK-1 (patch-clamp)	Blocked TREK-1 with IC50 ≈ 0.12 nM (~300x more potent than spadin) — mechanistic	PMID 28955242
Spadin lineage (mouse)	Injection	Preclinical — mouse (the parent peptide spadin)	Spadin blocked TREK-1, raised serotonin-neuron firing, and produced antidepressant-like effects — the founding rationale	PMID 20405001

Quick answers

Frequently asked

Has PE-22-28 been tested in humans?

No. There are zero human trials, no human efficacy data, and no human safety data. Every antidepressant-like finding for PE-22-28 is in mice. It is sold online well ahead of any clinical evidence.

What does it actually do?

It blocks a potassium channel called TREK-1 (gene KCNK2), and it does so very potently — about 300 times more than its parent peptide spadin. Blocking TREK-1 is a proposed fast-acting antidepressant mechanism, because mice lacking TREK-1 are naturally resistant to depression-like behavior.

Where does PE-22-28 come from?

It is a shortened, stabilized version of spadin — a natural peptide the body generates from the receptor sortilin (NTSR3). Spadin is known in the literature as 'PE 12-28'; PE-22-28 corresponds to a shorter fragment (residues 22-28) engineered for better potency and stability.

Is there a safe human dose?

No human dose has been established, because the molecule has never been studied in people. Any human dose circulating on vendor sites is unsupported convention, not validated dosing. There is no human pharmacokinetic or safety basis for a recommendation.

How is it different from an SSRI?

SSRIs work by blocking serotonin reuptake and typically take weeks to act. PE-22-28 works upstream of that, by blocking the TREK-1 potassium channel, which in animal models produced a faster antidepressant-like effect without acting directly on the serotonin transporter. Whether that translates to humans is unknown.

Is it banned in sport?

It is not specifically named on the 2026 WADA Prohibited List in the sources reviewed, but that is not the same as being allowed — broad categories like non-approved substances can still apply to research peptides. Athletes should check current status directly with WADA or their federation.

Primary sources

References

PubChem CID 165437303PubChem CID 165437303 (PE 22-28)
PMID 28955242Djillani et al., Front Pharmacol 2017 — shortened spadin analogs (PE 22-28): better TREK-1 inhibition, stability & antidepressant activity (mouse)
PMID 20405001Mazella et al., PLoS Biology 2010 — spadin, a sortilin-derived TREK-1-targeting antidepressant concept (rodent)
PMID 30291907Djillani et al., Pharmacol Ther 2019 — fighting depression with TREK-1 blockers, focus on spadin (review)
PMID 25263033Borsotto et al., Br J Pharmacol 2015 — targeting TREK-1/TASK-3 channels for depression (review)

Research use only · Not medical advice · Updated 2026-06-01