PE-22-28 (Mini-Spadin): A TREK-1 Peptide Tested Only in Mice

At a Glance

PE-22-28 is one of the more interesting molecules sold in the nootropic peptide market, and one of the least tested. It comes from a serious line of French research on a potassium channel called TREK-1, which began with a 2006 finding that mice lacking the channel behave as if they were taking an antidepressant [3]. The same group then found a natural peptide that blocks TREK-1, named it spadin, and later trimmed it down to seven amino acids. That seven-residue fragment is PE-22-28.

The science up to the mouse stage is careful and coherent. The step to humans has never been taken. Not one person has received PE-22-28 in a published study, so there is no human dose, no human pharmacokinetics and no human safety record.

My verdict up front: PE-22-28 is a credible drug-development lead and an uncontrolled self-experiment. If the reason for looking at it is depression, and especially depression that has not responded to treatment, the right next step is a psychiatrist, not a vial.

A note on the name: there is no peptide called “PE 22-58”. It is a common typo for PE-22-28.

How It Works

The channel. TREK-1 (gene KCNK2) is a “background” potassium channel. When it is open, potassium leaks out of the neuron and the cell is harder to excite. Serotonin signalling regulates TREK-1, and in 2006 Heurteaux and colleagues showed that mice with the gene deleted had stronger serotonin neurotransmission, a blunted stress-hormone response and resistance to depression in five different behavioural models, resembling mice treated with fluoxetine [3]. Fluoxetine itself is among the antidepressants that also inhibit TREK-1 [4].

The natural blocker. Sortilin (also called neurotensin receptor 3) is made as a precursor. When it matures, a 44-amino-acid propeptide called PE is cut off and released. In 2010 Mazella and colleagues showed that a 17-residue piece of it, PE 12-28, binds TREK-1 with about 10 nM affinity and blocks the channel. They named it spadin [5]. Four days of intravenous spadin produced antidepressant-like behaviour in mice, increased hippocampal CREB phosphorylation and neurogenesis, and raised the firing rate of serotonin neurons, changes that standard antidepressants need about three weeks to produce in rodents [4, 5].

The shortened version. Spadin’s effect faded within about seven hours. Studying how blood breaks spadin down, Djillani and colleagues identified the shortest active stretch, PE 22-28. In cells expressing human TREK-1 it blocked the channel far more potently than spadin, and in mice its effect lasted up to 23 hours [1].

One complication matters for anyone thinking about dosing. In a mouse stroke study, mini-spadin acted on TREK-1 in two directions: very low doses (0.03 µg/kg) increased channel activity, while higher doses (3 µg/kg) inhibited it [2]. A molecule whose effect on its own target flips with dose is hard to dose by guesswork.

What the Evidence Shows

Human trials of PE-22-28 or spadin: none. A ClinicalTrials.gov search for “spadin”, “mini-spadin” and “PE 22-28” in October 2026 returned no registered study.

Human data in this research line (not on the drug):

• Serum levels of the natural sortilin propeptide were lower in people with major depressive disorder than in healthy controls, and antidepressant treatment brought them back towards normal. The samples were small, which the authors flag themselves [6].
• In 45 patients with treatment-resistant depression, propeptide levels did not differ from controls at baseline but rose about a month after electroconvulsive therapy, only in responders, and the rise correlated with symptom improvement [7].

These studies suggest the propeptide might work as a blood marker of treatment response. They say nothing about what happens when a person takes synthetic PE-22-28.

Animal and cell studies (all mouse or cell work, all from the same CNRS group):

• Antidepressant-like behaviour. PE-22-28 and its modified analogs reduced immobility in the forced swim test and shortened latency in the novelty-suppressed feeding test after four days of treatment, with neurogenesis and increased synaptic protein (PSD-95) [1].
• Stroke and post-stroke depression. In mice with focal brain ischaemia, a low-dose-then-higher-dose mini-spadin schedule improved motor and cognitive deficits, protected dopamine neurons and prevented depression-like behaviour [2].
• Pancreatic beta cells. The natural propeptide, spadin and mini-spadin protected beta cells from cytokine-induced death in culture, and mini-spadin promoted beta-cell proliferation [8]. This is cell work only.
• Earlier spadin safety work in mice. Because TREK-1 knockout mice are more vulnerable to seizures and brain ischaemia [9], the group tested spadin for those effects. Spadin did not change pain responses, seizure susceptibility, infarct size, cardiac potassium currents, blood pressure or glucose in mice, including after three weeks of treatment [10]. That is reassuring for spadin in mice. It was not repeated for PE-22-28, and it is not human data.

Reviews. The group’s own reviews summarise the programme and present shortened spadin analogs as candidates for clinical development [4, 11]. As of October 2026 none has reached a human study.

Dosing

For informational purposes only — this summarises doses used in research and practice; it is not a prescription or individual medical advice.

No human has received PE-22-28 in a study, so there is no trial, label or practice-protocol basis for any dose. Every row below is community-reported. For scale, the effective mouse dose of about 3 µg/kg [1, 2], converted with the usual body-surface-area factor, works out at roughly 15–20 mcg for a 70 kg adult. Community doses run about 10 to 20 times higher than that, and the stroke study shows that dose can change the direction of the effect [2].

What the community sources themselves stress:

• Lower is reported to be better. Lethargy and heavy sedation are the most common complaint, mostly above roughly 500–600 mcg a day.
• Morning dosing, because people describe the effect as activating at low doses.
• Off-cycle: people usually stop after 4–8 weeks for at least as long. Nothing is known about tolerance or withdrawal in humans.
• Reconstitution and injection technique: see the peptide injection guide. Intranasal use was never studied, even in mice, so whether the peptide is absorbed that way is unknown.

If you take an antidepressant, lithium, or any psychiatric medication: do not add or swap a research peptide without your psychiatrist. Stopping an antidepressant abruptly carries its own risks, and how PE-22-28 interacts with serotonergic drugs in humans has never been studied.

What People Report: What Works and What Doesn’t

Reports on PE-22-28 are few and mostly collected second-hand by peptide-information sites rather than in identifiable, detailed threads. Many users take it with Selank, Semax or other compounds, and the identity of grey-market vials is unverified. This is a map of what people describe, not evidence.

Reported to work

• Lifted mood and motivation, often described within the first few days at 200–400 mcg intranasally (PeptideProtocolWiki; Jay Campbell write-up).
• Some describe clearer focus at lower doses.

Mixed or unclear

• Whether subcutaneous use is stronger than intranasal: some say yes, with more lethargy as the price.
• Whether any effect outlasts the cycle. No one has tracked this systematically.

Reported not to work, or disappointing

• Lethargy, flatness and sedation at higher doses, the opposite of what people were hoping for.
• Non-response, with doubts about what the vial contained.

What a proper trial would need to show: a phase 1 study establishing human safety, pharmacokinetics and the dose range in which PE-22-28 inhibits rather than activates TREK-1, followed by a blinded, placebo-controlled trial in clinically diagnosed depression with standard rating scales, run under psychiatric supervision.

Safety and Side Effects

There are no human safety data for PE-22-28. Everything below is inference from mouse work and from what TREK-1 does.

• Seizures and brain ischaemia. TREK-1 helps protect neurons; knockout mice are more vulnerable to seizures and ischaemic damage [9]. Spadin did not reproduce this in mice [10], but PE-22-28 is a different, far more potent molecule and was not tested the same way. People with epilepsy or a history of stroke have particular reason for caution.
• Dose-dependent direction of effect. Low doses activated TREK-1 and higher doses blocked it in mice [2]. In humans the dose that does either is unknown.
• Psychiatric risk. Any compound with antidepressant-like activity can in principle trigger agitation, insomnia or a switch into hypomania or mania in people with bipolar disorder. Depression that is severe, or comes with thoughts of self-harm, needs urgent professional care, not experimentation.
• Reported effects: lethargy and sedation at higher doses; nasal irritation with sprays.
• Interactions: unknown. Several antidepressants act on TREK-1 themselves [4].
• Who should not experiment: anyone with suicidal thoughts, bipolar disorder, psychosis, epilepsy, recent stroke, pregnancy or breastfeeding, and anyone under 18.
• Product risk: grey-market vials have no pharmaceutical quality control. Identity, content, sterility and endotoxin are unknown unless independently tested.

Where depression belongs. Depression is a medical illness, and it deserves a search for its cause: the brain networks, the immune system, possible infections and the people around the patient. For treatment-resistant depression, targeted TMS is my first choice, with ketamine only as a time-limited addition or short-term relief in a crisis. Electroconvulsive therapy is not an option I consider acceptable (here is why). These decisions belong with a physician who can assess the diagnosis, the risk and the history of what has been tried. If you are in crisis, contact your local emergency number or a crisis line now.

Legal and Regulatory Status

• US: Not FDA-approved and not on FDA’s 503A bulk-substance lists, so a compounding pharmacy has no legal route to prepare it. It is sold as a “research chemical, not for human use”.
• EU / Germany: No marketing authorisation. A product intended to treat depression or alter mood meets the definition of a medicinal product, so selling it for human use without authorisation is not legal.
• Sport: Not approved by any health authority, so it falls under WADA’s S0 (non-approved substances), prohibited at all times.

How PE-22-28 Fits Among the Mood and Cognitive Peptides

Of the three, PE-22-28 has the most elegant preclinical story and the least human information.

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