Pe-22-28

Overview

PE-22-28 is a synthetic seven-amino-acid peptide engineered from the C-terminal end of spadin (PE 12-28), itself a 17-residue fragment cut from sortilin's propeptide. The founding characterisation came from the Borsotto/Mazella laboratory at CNRS in 2017, which reported that PE-22-28 binds the human TREK-1 (KCNK2) potassium channel with an IC50 of 0.12 nM in patch-clamp assays — roughly 400 times tighter than spadin itself, which sits at 40-60 nM. The peptide preserves spadin's fast antidepressant-like signal in mice while lasting considerably longer in the body, with a behavioural effect of about 23 hours compared to roughly 7 hours for the parent compound.

Editorial verdict

The mechanism is genuinely interesting and well-defined, but that is where the certainty ends. Every claim about how PE-22-28 behaves in people — dosing, onset, duration, side effects — is extrapolated from rodent data. There is no human trial, no pharmacokinetic profile, and no safety record. Treat the marketing language accordingly: this is an unproven research chemical, not a therapy.

How it works

TREK-1 is a two-pore-domain (K2P) potassium channel concentrated in the serotonergic neurons of the dorsal raphe nucleus. Mice lacking TREK-1 resist depression-like behaviour, and blocking the channel pharmacologically recreates that same resistance in normal animals. PE-22-28 functions as a high-affinity, selective TREK-1 blocker. In rodents, downstream effects include greater hippocampal neurogenesis and higher PSD-95 levels in cortical neurons — pointing to both quick changes in neurotransmission and slower structural remodelling.

A separate mouse study (Ye et al., 2015) demonstrated that TREK-1 blockade and 5-HT1A receptor activation reinforce each other to generate antidepressant-like effects. That synergy is exactly why caution is warranted when stacking TREK-1 inhibitors with serotonergic antidepressants such as SSRIs, SNRIs, or MAOIs.

Evidence quality

PE-22-28 remains strictly preclinical. As of the latest literature search, no clinical trial has been registered or completed, and no human efficacy, pharmacokinetic, or safety data has been published. The peptide is offered by research-chemical vendors but is not an approved treatment anywhere in the world.

Who should be cautious

Anyone taking serotonergic antidepressants should regard combination use as risky given the documented 5-HT1A synergy. More broadly, because human safety is entirely unmeasured, self-administration is a leap into the unknown.

Community sentiment

Across 9 community reports, sentiment skews unfavourable: 0% neutral, 67% negative, and 33% positive. The most cited effects are single mentions each of neuroprotection, mood, and cognitive function, while the side effects flagged are worsened brain fog and sedation.

Studies cited (summarised)

• Founding paper: Built from spadin's blood-degradation products, PE-22-28 inhibits human TREK-1 at IC50 0.12 nM (versus 40-60 nM for spadin), cuts immobility in the forced-swim test and latency in novelty-suppressed feeding, drives neurogenesis, and raises PSD-95 within 4 days, with an action lasting up to 23 hours against spadin's roughly 7.
• A study showing TREK-1 blockade yields an antidepressant-like response in rodents that is amplified by 5-HT1A signalling, establishing the rationale — and the caution — around combining it with serotonergic drugs.
• A study showing TREK-1 activation reverses manic-like behaviour, the opposite direction from the PE-22-28/spadin antidepressant data, which helps frame the channel's overall role.

Dosage and availability

No human dose has ever been established or tested; rodent studies used intraperitoneal or intravenous routes. There is no pharmaceutical-grade supply, and purity and identity vary widely between vendors, so any self-administration carries unmeasured risk.