PE-22-28
Cognitive / AntidepressantAlso known as: Spadin Analog, PE22-28, Sortilin Propeptide Fragment
Mechanism
A small peptide fragment that blocks a specific potassium channel in the brain called TREK-1. Blocking TREK-1 produces antidepressant effects similar to SSRIs, but instead of taking weeks to work, the effect can appear within days in animal studies. It represents a completely new approach to treating depression that bypasses the serotonin system entirely.
Technical detail
Heptapeptide derived from the propeptide domain of sortilin (amino acids 22-28). Potent and selective inhibitor of TREK-1 (TWIK-related potassium channel-1, KCNK2), a two-pore domain potassium channel. TREK-1 knockout mice display a depression-resistant phenotype mimicking SSRI treatment. PE-22-28 blocks TREK-1 with nanomolar affinity, increasing neuronal excitability in hippocampal and cortical circuits. Rapidly elevates 5-HT neurotransmission and promotes hippocampal neurogenesis within 4 days vs. 3 weeks for fluoxetine in murine models. Does not directly bind serotonin receptors or transporters.
Effects
NERVOUS SYSTEM (MOOD/COGNITION): PE 22-28 is a synthetic analog of spadin, itself a fragment of the propeptide of sortilin (the neurotensin receptor 3). PE 22-28 specifically blocks TREK-1 (TWIK-related potassium channel 1), a two-pore-domain potassium channel expressed in limbic brain regions (hippocampus, prefrontal cortex, amygdala) [in vitro, animal]. TREK-1 blockade produces rapid antidepressant effects — within 4 days in mouse models, compared to 2-3 weeks for SSRIs [animal — Mazella et al., 2010; Djillani et al., 2017]. Mechanism: TREK-1 blockade increases neuronal excitability in mood-regulating circuits, enhances serotonergic and noradrenergic neurotransmission, and stimulates hippocampal neurogenesis (similar endpoint to SSRIs but via a different upstream mechanism) [animal]. Increases BDNF expression in hippocampus [animal]. Corticotropic axis modulation — reduces HPA axis hyperactivity associated with chronic stress and depression [animal]. Anxiolytic effects in elevated plus maze and open field tests [animal]. NEUROPLASTICITY: Promotes hippocampal neurogenesis — increased BrdU+ cells in dentate gyrus after 4 days of treatment (SSRIs require 2-3 weeks to produce this effect) [animal]. Increases dendritic arborization and synaptogenesis in hippocampal neurons [animal]. VALIDATION OF TARGET: TREK-1 knockout mice display a depression-resistant phenotype (reduced immobility in forced swim test, increased serotonin neurotransmission) — genetic validation of the target [animal — Heurteaux et al., 2006]. TREK-1 is the first validated K2P channel target for antidepressant drug development [review].
Practitioner Guide
AVAILABILITY STATUS: PE 22-28 is a RESEARCH PEPTIDE — not approved for human use in any jurisdiction. Available from research chemical suppliers (e.g., peptide synthesis companies). Some biohackers/nootropic users have self-experimented, but this is off-label and unapproved. No pharmaceutical development program has been publicly announced. BIOHACKING COMMUNITY INTEREST: The nootropic community is interested in PE 22-28 because: (1) rapid onset antidepressant mechanism (days vs. weeks), (2) novel target (not serotonin reuptake — appeals to SSRI non-responders), (3) preclinical data is compelling, (4) peptide format accessible to experienced self-experimenters. Community-reported protocols (UNVERIFIED, NOT MEDICAL ADVICE): intranasal or subcutaneous administration, doses ranging from 100-500 mcg/day, typically 5 days on/2 days off cycles. COMPARISON TO EXISTING ANTIDEPRESSANTS: Conceptually similar to ketamine/esketamine in offering rapid-onset antidepressant action, but via a completely different mechanism (K2P channel blockade vs. NMDA antagonism). Does not appear to have abuse potential or dissociative effects (advantage over ketamine). STACKING (THEORETICAL): Some biohackers combine with NA-Selank-Amidate (anxiolytic) or Semax derivatives (BDNF enhancement). Theoretical synergy with magnesium (also modulates ion channels) and omega-3 fatty acids (neuroplasticity support). SAFETY CONCERNS: No human safety data. Unknown off-target effects of TREK-1 blockade (TREK-1 is also expressed in the heart and participates in cardiac mechanoelectric coupling — cardiac safety unknown). Unknown drug interactions. Unknown long-term effects on neurogenesis (uncontrolled neurogenesis is theoretically concerning). STORAGE: Lyophilized peptide stable at -20°C. Reconstituted in bacteriostatic water, store at 2-8°C, use within 4-6 weeks. IMPORTANT DISCLAIMER: All dosing information is from community self-reports and animal studies. No human clinical trials have been conducted. This is not a recommendation for use.
Research Summary
TIER 1: No human RCTs. No FDA or EMA regulatory submissions. Entirely preclinical at this stage. TIER 2: Key publications from the Mazella/Bhéreur group (Nice, France): Mazella et al., 2010 — original characterization of spadin as TREK-1 blocker with antidepressant properties. Djillani et al., 2017 — PE 22-28 as optimized spadin analog with improved stability and antidepressant activity in mice (rapid onset, 4 days). Djillani et al., 2018 — review of spadin analogs and TREK-1 as antidepressant target. Heurteaux et al., 2006 — TREK-1 knockout mice display depression-resistant phenotype (foundational genetic validation). Reviews of two-pore-domain potassium channels as CNS drug targets. TIER 3: Nootropic community self-experimentation reports (Reddit, Longecity forums — anecdotal, uncontrolled). Limited case reports. No international clinical data. KEY FINDINGS: The science is compelling but entirely preclinical. TREK-1 is a genetically validated antidepressant target (knockout mice), and PE 22-28 is a potent and selective TREK-1 blocker with rapid antidepressant onset in animals. The speed of onset (4 days vs. 2-3 weeks for SSRIs) and novel mechanism make it genuinely interesting. However, the gap between mouse behavioral models and human depression is vast, and many promising preclinical antidepressants have failed in human trials. GAPS: No human PK/PD data. No safety/toxicology data in humans. Cardiac safety of TREK-1 blockade unstudied. No pharmaceutical development program publicly disclosed. Bioavailability by different routes unknown in humans. ACTIVE TRIALS: None registered on ClinicalTrials.gov as of 2025. Academic research continues at the University of Nice.