PE-22-28

PE-22-28 is a synthetic peptide made of seven amino acids. It is considered a potent TREK-1 channel blocker in depression research - but it has only been tested in animal and cell models. There are no human studies, no clinical trials, and no approval anywhere in the world.

What is PE-22-28?

PE-22-28 (sometimes called "Mini-Spadin") is a short peptide made of seven amino acids. It is a shortened, optimized derivative of Spadin. Spadin itself is a naturally occurring peptide of 17 amino acids that is released in the body when the protein sortilin matures. The name "PE 22-28" refers to positions 22 to 28 in the sortilin propeptide [1].

Spadin became interesting because it blocks the TREK-1 channel - a potassium channel in the brain that has been linked to depression. Mice that genetically lack this channel show depression-resistant behavior [3]. PE-22-28 was developed to overcome Spadin's weaknesses: it blocks TREK-1 about 300 times more strongly (IC50 of 0.12 nM compared to 40-60 nM for Spadin) and lasts much longer, around 23 hours, compared to Spadin (about 7 hours) [1].

How is PE-22-28 used?

In scientific research, PE-22-28 has only been tested in mice - either intraperitoneally (into the abdominal cavity) at 3.2-4.0 µg/kg or by oral gavage (through a tube into the stomach) at 1.0 mg/kg. It was given either as a single dose or daily over four days [1]. There are no human studies and therefore no validated form, dose, or frequency for humans.

On the gray market, PE-22-28 is typically sold as a lyophilized powder in 5-mg vials and is used both subcutaneously (under the skin) and intranasally (through the nose). Commonly cited doses range from 500 µg to 1 mg daily over 4-8 weeks. This practice is completely unsubstantiated - it comes from forums and shop recommendations, not from studies. There is no data at all on the safety, pharmacokinetics, or efficacy of PE-22-28 in humans via any route of administration.

From vial to use: Reconstitution and calculation

Since there is no validated human dose, I can only document the gray market practice here - explicitly as unsubstantiated user practice and not as a recommendation.

Typically, a 5-mg vial is reconstituted with 2 ml of bacteriostatic water (BAC water). This gives a concentration of 2.5 mg/ml, or 2500 µg per ml. With a standard insulin syringe with 100 units (1 ml), one marking (1 "tick") equals 25 µg. For a gray market dose of 500 µg, that would be 20 units on the syringe; for 250 µg, it would be 10 units.

For intranasal use, a higher concentration is preferred: Reconstituting with 1 ml of BAC water gives you 5 mg/ml. A typical spray from a nasal sprayer delivers about 100 µl, so 500 µg per spray. These numbers are also purely user experience values with no scientific basis. If you want to learn more about mixing and storing peptides in general, you'll find step-by-step guides under Guides.

How does PE-22-28 work?

The mechanism of action of PE-22-28 is fundamentally different from all common antidepressants. Instead of directly changing serotonin or norepinephrine levels, PE-22-28 blocks the TREK-1 channel - a so-called two-pore potassium channel that is expressed in large parts of the brain and regulates the excitability of nerve cells [1, 2].

When TREK-1 is blocked, neurons become more excitable - which can paradoxically have an antidepressant effect. The blockade leads to increased serotonergic neurotransmission and also promotes neurogenesis (the formation of new nerve cells) and synaptogenesis (the formation of new synapses) in the hippocampus, a brain region that is often damaged in depression [2, 3].

Spadin, the precursor of PE-22-28, showed an antidepressant effect in mouse models after just four days - compared to 3-4 weeks for classic antidepressants like fluoxetine [2]. PE-22-28 is said to produce this effect even more potently and for a longer duration. Additionally, Spadin interacts with prefrontal 5-HT4 and mGluR2 receptors, suggesting additional pathways beyond pure TREK-1 blockade [4].

What do the studies show?

All the evidence on PE-22-28 comes from a single research group in the south of France (around Jean Mazella and Catherine Heurteaux). No independent group has replicated the results so far [1, 2].

The IC50 of PE-22-28 at the human TREK-1 channel is 0.12 nM - that is an extremely high binding affinity, measured on human HEK cells using the patch-clamp technique [1]. In vivo, PE-22-28 showed comparable antidepressant effects at about 25 times lower doses than Spadin [1].

Are there risks or side effects?

There is no safety data for PE-22-28 in humans. The available data comes exclusively from mouse models. For the precursor Spadin, one mouse study reported the absence of typical TREK-1-related side effects - but again, only in an animal model [4].

Since PE-22-28 has entered the gray market without ever being tested in humans, all potential risks in humans are unknown. This includes: unknown bioavailability (how much of it actually reaches the blood) with subcutaneous or intranasal administration, unknown long-term effects on TREK-1 regulation, unknown interactions with other medications (especially antidepressants), and unknown effects on pregnancy or pre-existing conditions.

What is still unknown?

• No human studies: PE-22-28 has never been given to a human - there is no data on pharmacokinetics, safety, or efficacy in humans.
• No clinical trials: No studies are registered (ClinicalTrials.gov, EudraCT) that investigate PE-22-28 in humans.
• Single-source evidence: All data comes from one research group. No independent replication.
• No bioavailability data: It is unknown whether subcutaneous or intranasal administration in humans even reaches effective levels. The studies used i.p. and oral administration in mice.
• No long-term data: The longest animal testing lasted four days. There is no data on longer use.

Related peptides and further links

PE-22-28 shares thematic overlaps with other neuroactive peptides that also circulate on the gray market. If you're interested in the scientific status of peptides that affect the central nervous system, it's also worth looking at DSIP (Delta Sleep-Inducing Peptide) - another peptide with limited, but at least existing, human evidence. You can also find an overview of all peptides in the Peptide Library at Peptigraph.