Cognition & Mood
PE-22-28
aka pe 22-28 · pe22-28 · mini-spadin · spadin analog · trek-1 inhibitor peptide
Grade
An experimental brain peptide that blocks the TREK-1 potassium channel to act like a fast antidepressant in mice, with zero human testing to date.
- Class
- Synthetic heptapeptide (7 amino acids), a shortened analogue of spadin
- Evidence
- Grade D · Animal data only
- Sport / WADA
- Not specifically named on the WADA Prohibited List. It is not an established performance-enhancing agent and there is no human evidence in a sport context; as a novel, non-approved CNS peptide its status would be uncertain, and athletes should treat any such compound with caution.
- Last reviewed
- 2026-06
Grade D · Animal data only
Why this grade
Antidepressant and pro-neurogenic effects have been shown only in mice and in vitro; no registered or completed human trials exist, so there is no human evidence at all.
What is it?
PE-22-28 is a tiny lab-made protein fragment designed to behave like a quick-acting antidepressant. Your brain cells have lots of little gates that control how excitable they are, and one of these gates is called TREK-1. When TREK-1 is open, certain mood-related signals get dampened. PE-22-28 jams that gate shut, which in mice seems to lift their mood faster than ordinary antidepressants and even helps the brain grow new cells. The catch: every bit of this evidence comes from mice and cells in dishes. No human has ever been tested with it in a proper trial, so nobody actually knows if it works in people or whether it is safe. It is sold online as a 'research chemical', not a medicine.
Think of TREK-1 as a pressure-release valve on a brain cell. PE-22-28 is a custom-made plug engineered to seal that valve far more tightly than the body's own version. In mice the sealed valve lifts mood quickly — but so far the only patients who have ever tried this plug have whiskers and tails.
How is it meant to work?
PE-22-28 selectively inhibits TREK-1 (KCNK2), a two-pore-domain background potassium channel that helps set neuronal resting potential and excitability. By blocking TREK-1, it is thought to increase serotonergic signalling and neuronal excitability in mood-relevant circuits, mimicking the depression-resistant state seen in TREK-1 knockout mice. In rodents this is associated with enhanced hippocampal neurogenesis, CREB phosphorylation and synaptic markers, suggesting a rapid-onset antidepressant mechanism distinct from SSRIs. It is derived from spadin, the body's natural TREK-1-blocking fragment of the sortilin propeptide, but engineered to be more potent and longer-lasting.
What's it studied for?
Research contexts. Not proven uses, and not recommendations.
Does the human evidence stack up?
There is none. Every published finding on PE-22-28 comes from mouse behavioural models and in-vitro electrophysiology. No human pharmacokinetic, efficacy or safety study has been completed, and no clinical trial of PE-22-28 (or its parent spadin) appears to be registered. Claims that it is a fast-acting antidepressant or memory aid in people are extrapolations from rodent data, not human results.
What could go wrong?
- !No human safety data whatsoever — unknown dosing, toxicity, immunogenicity or long-term effects in people.
- !Sold as an unlicensed 'research chemical'; grey-market products have no guarantee of identity, purity or sterility.
- !TREK-1 is expressed widely (brain, heart, smooth muscle, pain pathways), so off-target effects on cardiovascular function and pain are plausible but uncharacterised in humans.
- !Marketing routinely overstates the evidence, presenting mouse antidepressant findings as if proven in people.
- !Self-experimentation with an injectable, untested CNS-active peptide for a serious condition like depression carries real risk and may delay evidence-based treatment.
Is it legal in the UK?
PE-22-28 is not a licensed medicine in the UK and has no MHRA marketing authorisation. It exists only as an unlicensed, investigational peptide typically sold 'for research use only'. Marketing or supplying it for human use would bring it within the Human Medicines Regulations 2012 as an unlicensed medicinal product, and any human therapeutic claims would be unlawful. There is no approved route for a person to obtain or use it legitimately as a treatment.
Key trials
- · None
No registered or completed human clinical trials of PE-22-28
As of this review, no PE-22-28 (or spadin) trial appears registered on ClinicalTrials.gov or other registries. All evidence is preclinical.
Sources
- 01Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant Activity — Djillani A, Pietri M, Moreno S, Heurteaux C, Mazella J, Borsotto M, Frontiers in Pharmacology (2017)
The defining paper: introduces PE-22-28 as a shortened spadin analogue, reports ~0.12 nM TREK-1 IC50, improved stability (~23 h) and antidepressant-like effects in mice. Animal/in-vitro only.
- 02Spadin, a Sortilin-Derived Peptide, Targeting Rodent TREK-1 Channels: A New Concept in the Antidepressant Drug Design — Mazella J, Petrault O, Lucas G, et al., PLoS Biology (2010)
Original discovery of spadin (the parent of PE-22-28) as a natural TREK-1 blocker with antidepressant effects in mice; establishes the TREK-1 mechanism.
- 03PE-22-28 and spadin TREK-1 antidepressant peptide research (PubMed search), PubMed (2026)
Search link to track the (preclinical) literature on PE-22-28 and spadin; no human trials indexed as of this review.
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