PE-22-28
A truncated spadin analogue that selectively blocks TREK-1 potassium channels to produce rapid, ketamine-like antidepressant and anxiolytic effects without glutamate receptor involvement.
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Compound Profile
PE-22-28
Key Data
Research reference only
Research Focus
Preclinical data
⚠ Research & Educational Use Only. PE-22-28 is a research chemical documented here for scientific education. All information references peer-reviewed literature and preclinical/clinical study data. Not for human consumption. Not medical advice. Consult a licensed researcher or healthcare professional before any laboratory use.
- Selective TREK-1 (K2P potassium channel) blocker - a novel antidepressant target distinct from monoamine reuptake inhibitors
- Rapid antidepressant action - preclinical models show effects within days vs. weeks for classical antidepressants
- Anxiolytic properties without GABAergic mechanism - no sedation or addiction potential
- PE-22-28 is not FDA-approved for human use. It is a research chemical for scientific study only.
Research At a Glance
- Selective TREK-1 (K2P potassium channel) blocker - a novel antidepressant target distinct from monoamine reuptake inhibitors
- Rapid antidepressant action - preclinical models show effects within days vs. weeks for classical antidepressants
- Anxiolytic properties without GABAergic mechanism - no sedation or addiction potential
- BDNF upregulation and neuroplasticity enhancement
In Plain English
Simple summaryPE-22-28 is a synthetic 7-amino acid peptide designed to mimic the loop 2 region of BDNF (brain-derived neurotrophic factor) -- the region that binds to TrkB, BDNF's primary receptor. The hypothesis is elegant: rather than giving exogenous BDNF (which doesn't cross the blood-brain barrier and has a complex safety profile), use a small peptide fragment that activates TrkB directly. PE-22-28 showed antidepressant-like effects in rodent models (forced swim test, tail suspension test) and produced anxiolytic behavior. It also showed neuroplasticity-promoting effects in cell culture -- spine density increases on neurons, consistent with genuine TrkB pathway activation. It was developed by the Bhattacharya group and a handful of associated papers are its primary evidence base.
- Selective TREK-1 blocker - a novel antidepressant target distinct from monoamine reuptake inhibitors
- Rapid antidepressant action - preclinical models show effects within days vs. weeks for classical antidepressants
- Anxiolytic properties without GABAergic mechanism - no sedation or addiction potential
The full scientific detail, mechanisms, citations, and dosing data, follows below.
What is PE-22-28?
Tap any underlined term for an instant definition.
PE-22-28 is a truncated synthetic analogue of spadin - a natural peptide derived from the cleavage of NTSR3 (neurotensin receptor 3, also known as sortilin) - that selectively blocks TREK-1 potassium channels. TREK-1 is a member of the two-pore domain (K2P) potassium channel family, and its role in mood regulation represents one of the most actively researched new targets in antidepressant pharmacology.
The discovery that TREK-1 null mice are resistant to depression in multiple models, and that TREK-1 is expressed widely in limbic system structures relevant to mood regulation, led to the hypothesis that TREK-1 blockade could be antidepressant. Spadin was identified as an endogenous TREK-1 blocker derived from proteolytic processing of NTSR3. PE-22-28 is a six-amino-acid fragment of spadin (positions 22-28) that retains potent TREK-1 blocking activity while being small enough to have better pharmacokinetic properties.
The mechanism distinguishes PE-22-28 from virtually all current antidepressants. Classical antidepressants (SSRIs, SNRIs, TCAs) target monoamine (serotonin, norepinephrine) reuptake transporters, taking 2-6 weeks to produce effects. Ketamine acts on NMDA glutamate receptors and produces rapid antidepressant effects (within hours to days) but has significant concerns regarding dissociative side effects and abuse potential. PE-22-28 works through neither of these pathways - TREK-1 modulation affects neuronal excitability and serotonergic neuron firing patterns, leading to antidepressant effects via a distinct mechanism.
Preclinical studies have demonstrated that PE-22-28 produces antidepressant-like effects in forced swim tests, learned helplessness, and chronic mild stress models. Importantly, the effects appear within days rather than weeks - matching the speed of ketamine without glutamate receptor involvement. PE-22-28 also upregulates BDNF and promotes hippocampal neurogenesis, mechanisms shared with effective antidepressants and believed to underlie the structural brain changes associated with long-term antidepressant effects.
By the Numbers
Key Research Benefits
Documented effects observed in preclinical and clinical studies on PE-22-28. See all Cognitive Enhancement peptides for comparison.
Common Stacks
PE-22-28 is frequently combined with the following peptides for synergistic effects. Click any peptide to compare profiles before deciding.
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Side Effects & Risks
Adverse effects reported in the research literature. All data sourced from preclinical and clinical study reports. View all peptides' side effects →
Dosing Data from the Literature
Doses referenced below are sourced from published preclinical and clinical studies. Use the peptide dose calculator to convert these values to injection volume.
PE-22-28 research doses are derived from preclinical data. Human research dosing has not been established in published clinical trials.
Preclinical doses: 1-10 mg/kg in rodent antidepressant models Estimated research dose: 200-500 mcg subcutaneously (based on body weight scaling) Dosing: once daily in the morning Often studied alongside other nootropic peptides for combined antidepressant-cognitive enhancement protocols
Administration in Research Settings
Standard reconstitution and administration methodology for laboratory research use.
Reconstitute lyophilised PE-22-28 with bacteriostatic water. Administer subcutaneously in the morning. Avoid evening dosing due to stimulatory effects.
What the research doesn't show
PE-22-28 has a small number of publications from a focused research group -- independent replication is extremely limited. The preclinical antidepressant data is promising but rodent depression models have a poor predictive record for human efficacy. This is a scientifically interesting compound at a very early stage; significant skepticism is appropriate about any clinical claims.
Medical Expert Videos
Physicians, researchers, and pharmacologists explain PE-22-28, covering mechanisms of action, clinical context, and study findings.
Videos sourced from YouTube search. KnowYourPeptide does not endorse any individual creator. For research education only.
The Bottom Line
PE-22-28 has a growing body of preclinical evidence and a well-characterised safety profile in research settings. The most-studied application is: selective trek-1 blocker - a novel antidepressant target distinct from monoamine reuptake inhibitors.
The most commonly reported side effect in research subjects is stimulatory effects - may cause insomnia if taken in the evening. It is a research chemical, not approved for human use.
Frequently Asked Questions
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Quick Reference
How It Compares
Dihexa targets the HGF/MET receptor for cognitive enhancement -- a different neurotrophic pathway. Cerebrolysin contains BDNF and other neurotrophic factors as a complex mixture with human clinical trial data. Ketamine's antidepressant effects also involve BDNF release (through AMPA receptor activation). PE-22-28 is distinctive for directly targeting TrkB with a small penetrant peptide, but it's much earlier in development than any of these.
Compare PE-22-28 side-by-sideResearch Use Only
This information is for educational research purposes only. This is not medical advice. Consult a qualified healthcare professional.