PE-22-28 — Apex Peptide Reference

01 — Identity

Name & Classification

PE-22-28 is a synthetic peptide fragment derived from Spadin — an endogenous neuropeptide cleaved from the propeptide of the neurotensin receptor 3 (NTSR3/sortilin). PE-22-28 corresponds to residues 22–28 of Spadin, with the sequence Arg-Ser-Ala-Thr-Pro-Leu-Met.

It is classified as a TREK-1 potassium channel blocker and rapid-onset antidepressant peptide. TREK-1 (TWIK-related potassium channel 1) is a background leak potassium channel highly expressed in limbic and cortical neurons. Its overactivity is directly linked to depression, anxiety, and cognitive blunting. By blocking TREK-1, PE-22-28 restores normal neuronal excitability and serotonergic transmission — producing antidepressant effects within hours, not weeks.

Also referenced as: Spadin(22-28) | mini-Spadin

SSRIs

Block serotonin reuptake transporter
Onset: 2–4 weeks

Ketamine

Block NMDA glutamate receptors
Onset: hours

PE-22-28

Block TREK-1 K⁺ channel
Onset: hours — new mechanism

02 — Origin

Research Timeline

2000s

TREK-1 potassium channel identified as a key regulator of neuronal excitability and mood. Mice lacking TREK-1 shown to be resistant to depression in multiple behavioral models — establishing TREK-1 as a legitimate antidepressant target.

2010

Spadin first identified by Dr. Catherine Belzung and colleagues in France as an endogenous TREK-1 blocker. Published in Nature Chemical Biology. Landmark paper linking the sortilin propeptide to mood regulation.

2012–2016

Structure-activity studies identified PE-22-28 as the minimal active fragment of Spadin with equivalent TREK-1 blocking potency but improved metabolic stability. Antidepressant effects in rodent models within 4 hours — vs 2–4 weeks for SSRIs.

2017–2020

Research expanded to neurogenesis: PE-22-28 shown to stimulate hippocampal neurogenesis in the dentate gyrus. BDNF and VEGF upregulation identified as downstream mechanisms — new neuron formation detectable within days.

2020–Present

Growing adoption in research and longevity/nootropic communities. No human clinical trials published. Considered one of the most mechanistically novel antidepressant compounds in the research pipeline.

03 — Research History

Research Background

PE-22-28's mechanism is fundamentally different from every antidepressant currently in clinical use. It blocks the TREK-1 potassium channel, which controls the resting membrane potential of serotonergic neurons in the raphe nuclei. When TREK-1 is overactive, it hyperpolarizes neurons — reducing 5-HT release, causing blunted mood, anhedonia, and cognitive slowing. By blocking TREK-1, PE-22-28 restores normal neuronal firing thresholds and serotonin release dynamics without the delayed downstream receptor adaptation that makes SSRIs take weeks to work.

The hippocampal neurogenesis finding is separately compelling. PE-22-28 directly stimulates adult neurogenesis via BDNF and VEGF upregulation — making it one of the very few compounds with both acute mood effects and long-term structural brain repair potential.

TREK-1 Block

Primary Mechanism

Blocks TREK-1 K⁺ leak channel in serotonergic neurons — restores normal firing threshold and 5-HT release. Rapid onset: effects in hours vs weeks for SSRIs.

Neurogenesis

Structural Brain Repair

Stimulates adult hippocampal neurogenesis in the dentate gyrus via BDNF and VEGF. New neuron formation detectable within days — long-term structural antidepressant effect.

Serotonin

Downstream Effect

Increases synaptic serotonin availability by restoring raphe neuron excitability through a pre-synaptic channel mechanism — not reuptake inhibition.

BDNF / VEGF

Growth Factor Upregulation

Upregulates both BDNF and VEGF in hippocampus. BDNF drives synaptic plasticity; VEGF supports new neuron vascularization and survival in the dentate gyrus.

04 — Key Benefits

Proposed Benefits

Rapid-onset antidepressant effect — hours, not weeks

Novel mechanism: TREK-1 blockade — entirely new antidepressant class

Stimulates hippocampal neurogenesis — structural brain repair

Upregulates BDNF and VEGF in hippocampus

Reduces anxiety and anhedonia in animal models

Improves cognitive function — learning and memory

No sedation, no receptor downregulation in current data

Synergistic with SSRIs — potentiates antidepressant effect

Endogenous origin (Spadin fragment) — favorable tolerability profile

Potential PTSD and treatment-resistant depression application

05 — Reconstitution

Vial + BAC Water

33.3 mcg

per unit — based on 10 mg vial + 300 units (3.0 mL) BAC water

Typical Vial Size

5–10 mg

lyophilized peptide

Reconstitution Solvent

BAC Water

3.0 mL / 300 units standard

Shelf Life (Fridge)

4–6 wk

after reconstitution

REFRIGERATION — REQUIRED

Lyophilized powder: Store at –20°C (freezer) for long-term; 2–8°C (fridge) acceptable up to 3 months. Reconstituted solution: 2–8°C strictly — use within 4–6 weeks. Do NOT freeze reconstituted vial — peptide bond integrity degrades with freeze-thaw cycling. PE-22-28 also available intranasally from some research suppliers for faster CNS onset via the olfactory-limbic pathway (similar to Selank).

06 — Dosage

Dosage Reference

Based on 10 mg vial reconstituted with 3.0 mL BAC water = 33.3 mcg/unit

Dose	Units to Draw	Context
100–200 mcg SC	3–6 u	Low / Intro
200–500 mcg SC	6–15 u	Common
500 mcg – 1 mg SC	15–30 u	Standard
1–2 mg SC	30–60 u	High

No established human dose. HED extrapolation suggests 200 mcg – 1 mg/day for most individuals. Start at 200–250 mcg and titrate slowly over 1–2 weeks. PE-22-28 is derived from an endogenous peptide sequence — tolerability profile expected to be favorable, but individual CNS sensitivity varies significantly.

07 — Monitoring

Biomarkers, Lab Tests & Ranges

Monitor before starting and at 4–6 week intervals. PE-22-28 targets hippocampal neurogenesis, serotonergic function, and BDNF signaling.

▸ Neuroplasticity & Growth Factors

Biomarker	Lab Test	Clinical Range	Optimal Range
BDNFPrimary neurogenesis marker	Serum BDNF (fasting AM)	~10,000–30,000 pg/mL	Upper half of reference range; expect increase on PE-22-28
VEGFHippocampal vascularization	Serum VEGF	62–707 pg/mL	Mid-to-upper range; trending up indicates neurogenic activity
NGFNerve growth factor	Serum NGF (specialty labs)	~15–100 pg/mL	Upper half of range; supports neuronal survival and plasticity

▸ Serotonin System & Mood Markers

Biomarker	Lab Test	Clinical Range	Optimal Range
Whole Blood Serotonin	Whole Blood Serotonin	50–200 ng/mL	100–180 ng/mL
Urine 5-HIAASerotonin metabolite / turnover	24-hr Urine 5-HIAA	2–9 mg/24h	Mid-range; very low = poor serotonin turnover
TryptophanSerotonin precursor pool	Plasma Tryptophan (fasting)	45–74 µmol/L	55–74 µmol/L; adequate substrate for serotonin synthesis
Cortisol (AM)HPA axis / depression marker	AM Serum Cortisol	6–23 µg/dL	10–18 µg/dL; elevated AM cortisol is a key depression/anxiety biomarker

▸ Cognitive & Stress Markers

Biomarker	Lab Test	Clinical Range	Optimal Range
hsCRPNeuroinflammation proxy	High-sensitivity CRP	<3.0 mg/L	<0.5 mg/L; inflammation drives TREK-1 upregulation and depression
IL-6	Serum IL-6	<7.0 pg/mL	<1.5 pg/mL
DHEA-SNeuroprotective adrenal hormone	Serum DHEA-Sulfate	Age/sex dependent	Upper 25th percentile for age/sex; low DHEA-S linked to depression

▸ Safety Panel

Biomarker	Lab Test	Clinical Range	Optimal Range
AST / ALT	CMP	AST 10–40 / ALT 7–56 U/L	AST <26 / ALT <26 U/L
CBC	Complete Blood Count	Standard ranges	Mid-range; WBC 4.5–6.0
Thyroid (TSH)Rule out hypothyroidism as depression driver	TSH + Free T3 / T4	TSH 0.4–4.0 mIU/L	TSH 1.0–2.5 mIU/L; rule out hypothyroidism before peptide use

⚠ Research Status Warning

PE-22-28 has no published human clinical trials. All efficacy data derives from rodent models. Derived from an endogenous peptide (Spadin) with expected favorable tolerability, but this has not been confirmed in humans. If currently taking SSRIs — PE-22-28 may be synergistic but this interaction has not been clinically evaluated. Do not discontinue psychiatric medications without physician guidance. Monitor BDNF as the primary objective biomarker of neurogenic response.

08 — Cycle Protocol

Cycle Length, Frequency & Timing

Acute / On-Demand Use

Single Dose

Given its rapid-onset mechanism, PE-22-28 can be used acutely for same-day mood, focus, or cognitive enhancement — unlike SSRIs which require weeks of continuous use.

Neurogenesis Protocol

4–8 Weeks

For hippocampal neurogenesis and lasting structural antidepressant effects — new dentate gyrus neurons take 3–4 weeks to mature and integrate into circuits.

PE-22-28 shares the dual use pattern of Selank — both acutely effective and cumulatively therapeutic. The neurogenesis benefit specifically requires sustained use: new neurons take 3–4 weeks to mature and functionally integrate into memory and mood circuits. A 4-week minimum for structural benefit is supported by animal data.

Frequency & Timing

Variable	Recommendation	Why
Daily dosing (cycle)	Once Daily	Once daily maintains continuous TREK-1 modulation and neurogenic signaling. No evidence twice-daily provides meaningfully superior outcomes.
Morning (AM)	✓ Preferred for Cognition	AM dosing aligns with peak hippocampal neuroplasticity windows — learning and memory consolidation more active in the morning.
Evening (PM)	~ Acceptable if Targeting Sleep	Pre-bed dosing leverages serotonergic effects for sleep onset and mood regulation overnight. No sedation risk — PE-22-28 does not cause drowsiness.
Fasted vs Fed	~ Either Acceptable	CNS mechanism is not insulin or glucose-dependent. Food intake does not meaningfully affect efficacy.
Intranasal option	✓ Faster CNS Onset	Like Selank, intranasal delivery bypasses the BBB via the olfactory-limbic pathway — faster onset (~15–20 min vs 30–45 min SC) for acute mood and cognitive effects.
SSRI combination	⚠ Potentially Synergistic — Discuss with Prescriber	Animal data suggests PE-22-28 potentiates SSRI antidepressant effects. Do not adjust psychiatric medications without physician involvement.

4–8 wk

Cycle Length

Daily

Frequency

Timing

SC or Nasal

Route

Either

Fed State

2–4 wk

Break