Pe-22-28 is a shortened synthetic analog of spadin, a peptide derived from sortilin—the coreceptor for neurotrophins BDNF and NT-3. Spadin and its derivatives are endogenous antagonists of TREK-1 (TWIK-Related potassium channel 1), a background K+ channel that sets neuronal resting potential. TREK-1 is central to limbic and hippocampal excitability: chronic hyperactivation under stress hyperpolarizes neurons, suppresses neurogenesis, and creates a neurochemical substrate for depression. Pe-22-28 blocks TREK-1 more effectively than native spadin and has a much longer half-life—up to 23 hours vs 7 for spadin.
TREK-1 blockade shifts membrane potential toward higher excitability and triggers neurogenesis in the hippocampal subgranular zone—the same region classic antidepressants activate, but by a fundamentally different mechanism (no monoamine reuptake effect). On mouse cortical neurons, Pe-22-28 and analogs increased synaptogenesis via higher PSD-95—the scaffold of the postsynaptic density—literally building new synapses. In behavioral tests (forced swim, tail suspension), Pe-22-28 showed antidepressant effects comparable to fluoxetine with a faster onset.
A clinically meaningful advantage over SSRIs is the absence of dopaminergic and serotonergic blockade—no sexual dysfunction, emotional blunting, or discontinuation syndrome on stop. Mechanistically, it is an “antidepressant without typical antidepressant side effects.” Human data are essentially absent; the molecule remains in research status.
🧠 Antidepressant effect (TREK-1, non-monoamine): ★★★★☆
🔧 Hippocampal neurogenesis: ★★★★☆
⚡ Synaptogenesis (PSD-95): ★★★★☆
✅ Safety: ★★★☆☆ (no human data; gentler mechanism than SSRIs)
⚠️ Possible sensations and side effects: neutral in preclinical data; individual response; caution combining other neuroactive agents
🤝 Combinations (goal → stack)
🧠 Neurogenesis + BDNF → Pe-22-28 + P21
😌 Antidepressant protocol → Pe-22-28 + 9-Me-BC
❤️ Mood + social background → Pe-22-28 + Oxytocin Acetate
| CAS number | 1801959-12-5 |
| Batch purity | 99.4 % |
Full details in our guide
https://peptideboost.club/guide/pe-22-28
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