PE-22-28
PE 22-28; mini-spadin; shortened spadin analog (residues 22-28 of the sortilin propeptide); CAS 1801959-12-5
PE-22-28 is a synthetic heptapeptide analog of spadin that potently and selectively inhibits the TREK-1 two-pore domain potassium channel (IC50 0.12 nM), demonstrating rapid antidepressant-like effects, neurogenesis, and synaptogenesis in preclinical mouse models (PMID 28955242; PMC5601071).
Last updated: 2026-03-13
Safety Summary
All side effect data for PE-22-28 comes from either preclinical animal studies or uncontrolled anecdotal community reports. No formal Phase I-III clinical trial safety data exist, and no precise incidence rates or graded severity distributions have been documented in the public literature. Preclinical mouse studies (PMC5601071) reported no toxicity or dose-limiting adverse effects. Community anecdotal reports indicate a dose-dependent side effect profile: lower doses (100-400 mcg) are generally well-tolerated with cognitive/mood benefits, while higher doses (500+ mcg) increase the risk of sedation/lethargy. Tolerance development over weeks of continuous use is commonly reported, with many users recommending periodic washouts (2-8 weeks off) to restore effect. No serious adverse events have been reported in FAERS or EudraVigilance public databases. No GLP repeated-dose toxicology, carcinogenicity, reproductive/developmental, or immunogenicity studies have been conducted. Long-term safety in humans is entirely unknown. No clinical withdrawal syndrome has been documented, though this absence of evidence does not constitute evidence of absence given the lack of controlled study.
Known Side Effects
common
common
uncommon
uncommon
rare
rare
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rare
Who Should NOT Use This
No reproductive, embryo-fetal development, or teratogenicity data exist for PE-22-28 in any species. No pregnancy-exposure registry data or human outcomes are available. Avoid use due to complete absence of safety data.
Standard peptide precaution. No specific immunogenicity studies have been conducted for PE-22-28 but general peptide immunogenicity concerns apply.
Theoretical concern: TREK-1 blockade increases neuronal excitability, which could theoretically lower seizure threshold. Not observed in preclinical models but no formal seizure-liability studies have been conducted.
TREK-1 is expressed in cardiac tissue and modulation could theoretically affect cardiomyocyte excitability and remodeling pathways (calcineurin/NFAT). No direct measurements of blood pressure or heart rate after PE-22-28 exist in peer-reviewed literature.
No formal drug interaction studies exist. PE-22-28 is cleared by peptidases rather than CYP450 enzymes, reducing expected pharmacokinetic interactions, but serotonergic synergy with SSRIs/SNRIs is a theoretical concern that has not been studied.
Listed as a precaution in vendor/clinical summary sources. No specific data support or refute use in psychotic disorders; prudent clinical caution given the neuroactive mechanism.
Talk to Your Doctor
Before considering PE-22-28, discuss it with your healthcare provider. Ask about potential interactions with your current medications, whether it is appropriate for your health conditions, and what monitoring may be needed.
Sources: [1-3]
Evidence Assessment
PE-22-28 has exclusively preclinical evidence. All efficacy and safety data come from in vitro (patch-clamp on hTREK-1/HEK cells) and in vivo mouse models (FST, NSF behavioral tests, BrdU neurogenesis assays) from a single primary research group (Djillani et al., 2017; PMC5601071). No human clinical trials have been registered on ClinicalTrials.gov, EU CTR, WHO ICTRP, or Health Canada databases. No IND application has been publicly identified. No pharmaceutical companies have announced development programs. The evidence base consists of one primary peer-reviewed publication plus reviews and vendor/community summaries.
1Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant ActivityPMID 28955242
Djillani A, Pietri M, Mazella J, Heurteaux C, Borsotto M - Frontiers in Pharmacology (2017) - Preclinical (in vitro electrophysiology + in vivo mouse behavioral studies) - Mouse models (multiple groups; exact N per group specified in paper)
PE-22-28 (GVSWGLR) identified as minimal active fragment of spadin with IC50 0.12 nM at TREK-1 (>300-fold more potent than spadin). Reduced FST immobility to ~91.8s vs ~140s saline (p<0.0001). Increased hippocampal neurogenesis (BrdU+ cells ~doubled in 4 days). Enhanced PSD-95 synaptogenesis marker. In vivo functional duration ~23h vs ~7h for spadin. Selective for TREK-1 over TREK-2, TRAAK, TRESK, TASK-1.
Limitations: Single research group; preclinical only (mouse models); short study durations (acute to 4-day subchronic); no human data; translation to humans unknown; standard behavioral models (FST/NSF) have known translational limitations.
2Role of TREK-1 in Health and Disease, Focus on the Central Nervous SystemPMID 31031627
Moha ou Maati H, et al. - Frontiers in Pharmacology (2019) - Review - N/A (review article)
Comprehensive review of TREK-1 channel biology and its role in depression, neuroprotection, pain, and cardiac function. Discusses spadin and PE-22-28 analogs as TREK-1 blockers with antidepressant potential. Provides context for TREK-1 as a validated therapeutic target.
Limitations: Review article, not primary data. Covers TREK-1 broadly, not PE-22-28 specifically.
3Fighting against depression with TREK-1 blockers: Past and future. A focus on spadin
Moha ou Maati H, et al. - Pharmacology & Therapeutics (2019) - Review - N/A (review article)
Reviews the development of spadin and its shortened analogs including PE-22-28 as TREK-1 blockers for depression treatment. Discusses the rationale for TREK-1 as an antidepressant target and structure-activity relationships of spadin analogs.
Limitations: Review article. Does not present new primary data on PE-22-28.