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The Peptide Effect
preclinicalMental Health

PE-22-28

Also known as: Spadin analog, Sortilin-derived peptide, TREK-1 blocker peptide

PE-22-28 is a synthetic heptapeptide derived from the propeptide region of sortilin (the mature sortilin receptor precursor). It functions as a potent antagonist of TREK-1 (TWIK-related potassium channel 1), a two-pore-domain potassium channel strongly implicated in depression. TREK-1 knockout mice display a phenotype completely resistant to depression, and PE-22-28 pharmacologically mimics this effect. The compound represents a fundamentally different approach to antidepressant therapy — targeting an ion channel rather than monoamine neurotransmitter systems.

Key Facts

Mechanism
PE-22-28 blocks TREK-1, a mechanosensitive two-pore-domain potassium (K2P) channel expressed throughout the central nervous system. TREK-1 channels regulate neuronal excitability by maintaining resting membrane potential. When TREK-1 is overactive, it hyperpolarizes neurons, reducing their firing rate and contributing to depression-like phenotypes. PE-22-28 binds to and inhibits this channel, increasing neuronal excitability in serotonergic, noradrenergic, and dopaminergic circuits — particularly in the hippocampus, prefrontal cortex, and dorsal raphe nucleus. Critically, this mechanism is upstream of monoamine neurotransmitter release: by depolarizing neurons that produce serotonin, norepinephrine, and dopamine, PE-22-28 enhances the release of all three simultaneously. It may also promote hippocampal neurogenesis, which is considered essential for sustained antidepressant effects.
Research Status
preclinical
Half-Life
Not well established (estimated short plasma half-life; longer CNS effects)
Molecular Formula
C₃₆H₆₂N₁₀O₁₁
Primary Use
Mental Health
Table of Contents

Benefits

  • Rapid antidepressant-like effects in animal models — onset within days compared to weeks for SSRIspreliminary
  • Anxiolytic properties without sedation or motor impairment in preclinical testingpreliminary
  • Novel mechanism of action — TREK-1 potassium channel blockade, entirely distinct from SSRIs, SNRIs, and MAOIspreliminary
  • May enhance hippocampal neurogenesis — a process linked to sustained antidepressant effects and cognitive improvementpreliminary
  • Modulates multiple monoamine systems simultaneously (serotonin, norepinephrine, dopamine) through upstream ion channel blockadepreliminary

Dosage Protocols

RouteDosage RangeFrequencyNotes
Intranasal spray100–300 mcgOnce dailyMost commonly used route in the research community. Intranasal delivery may provide more direct CNS access via the olfactory pathway. Dosing not clinically established.
Subcutaneous injection100–200 mcgOnce dailyAlternative to intranasal. Used in some preclinical protocols. Bioavailability and optimal dose for CNS effects via this route are not well characterized.
Intranasal spray (conservative)50–100 mcgOnce dailyLower starting dose for users titrating up. Given the lack of human clinical data, conservative dosing is prudent.

Medical disclaimer

Dosage information is provided for educational reference only. Always follow your prescriber's instructions and consult a qualified healthcare provider before starting any peptide protocol.

Side Effects

  • Injection site irritation — redness, mild pain, or swelling at subcutaneous injection sitecommon
  • Headache — reported anecdotally, especially during initial usecommon
  • Nasal irritation — burning or dryness when using intranasal administrationcommon
  • Unknown long-term safety profile — no published human clinical trials; all safety data from animal modelsserious
  • Theoretical risk of excessive neuronal excitability — TREK-1 channels serve protective roles including neuroprotection during ischemiaserious

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Frequently Asked Questions

What is TREK-1 and how does it relate to depression?
TREK-1 (TWIK-related potassium channel 1) is a two-pore-domain potassium channel that regulates neuronal membrane potential and excitability. In 2006, researchers discovered that mice genetically lacking the TREK-1 channel (KCNK2 knockout mice) displayed a remarkably depression-resistant phenotype — they behaved as if they were permanently on antidepressants. These mice also showed increased serotonin neurotransmission and enhanced neurogenesis in the hippocampus. This discovery identified TREK-1 as a novel molecular target for antidepressant drug development and led to the creation of PE-22-28 and related compounds.
How does PE-22-28 compare to SSRIs like sertraline or fluoxetine?
PE-22-28 and SSRIs work through entirely different mechanisms. SSRIs block the serotonin transporter (SERT) to prevent reuptake of serotonin from the synapse, increasing serotonin signaling. PE-22-28 blocks TREK-1 potassium channels, which increases neuronal excitability upstream of neurotransmitter release, enhancing serotonin, norepinephrine, AND dopamine simultaneously. In animal models, PE-22-28 showed faster onset of action (days vs weeks for SSRIs). However, SSRIs have decades of human clinical data and FDA approval, while PE-22-28 has only preclinical animal data. It is not a replacement for prescribed antidepressants.
What is the current research status of PE-22-28?
PE-22-28 is strictly preclinical as of February 2026. Published research consists of in vitro studies and animal behavioral models (forced swim test, tail suspension test, elevated plus maze). The original spadin peptide (from which PE-22-28 was derived as a more stable analog) was published by the Bhourde lab in France. No pharmaceutical company has announced clinical trials for PE-22-28. The compound is available from research chemical suppliers but is not approved for human use in any jurisdiction.
Is PE-22-28 available and how is it typically sourced?
PE-22-28 is available from several research peptide suppliers that cater to the self-experimentation community. It is typically sold as a lyophilized powder requiring reconstitution with bacteriostatic water, or as pre-made intranasal spray solutions. Quality and purity vary significantly between suppliers. Because there are no regulated pharmaceutical manufacturers, third-party testing (HPLC, mass spectrometry) is essential to verify identity and purity. It is sold labeled "for research use only."
Can PE-22-28 be combined with other mental health peptides like Selank or Semax?
Some users in the research community do combine PE-22-28 with Selank (anxiolytic tuftsin analog) or Semax (nootropic ACTH analog), reasoning that the mechanisms are complementary. PE-22-28 targets ion channels, Selank modulates enkephalin and serotonin metabolism, and Semax enhances BDNF and dopaminergic transmission. However, there is zero clinical data on any of these combinations, and combining multiple compounds that affect neurotransmitter systems increases unpredictability. Anyone considering combinations should proceed with extreme caution and ideally under medical supervision.

References

  1. 1
    Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design(2013)PubMed ↗
  2. 2
    The antidepressant spadin analog PE 22-28 blocks TREK-1 channels and displays adaptative antidepressant properties(2014)PubMed ↗
  3. 3
    Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype(2006)PubMed ↗
  4. 4
    TREK-1, a K+ channel involved in neuroprotection and general anesthesia(2004)PubMed ↗

Last updated: 2026-02-14