PE-22-28

PE-22-28 is a synthetic 7-amino-acid peptide (sequence GVSWGLR) and a shortened analog of spadin. Spadin (PE 12-28) is a natural 17-amino-acid fragment released when the receptor sortilin (neurotensin receptor-3) is processed, and it blocks the TREK-1 potassium channel. Researchers found PE-22-28 among spadin's breakdown fragments and showed it is the shortest piece that still blocks TREK-1 - and is actually more potent and more selective than spadin. It has been studied only in cells and mice as a fast-acting antidepressant candidate. It is not related to humanin. [PMID:28955242]

No. As of 2026 there are no published human trials of PE-22-28, no ClinicalTrials.gov registrations, and no human pharmacokinetic, safety or efficacy data. All evidence is preclinical (cell lines and mice), and all human use is self-experimentation with research-chemical vendor material. [PMID:28955242]

Its proposed mechanism is blockade of the TREK-1 (K2P2.1) potassium channel. In mice, removing TREK-1 produces a depression-resistant, pro-serotonergic phenotype, so blocking the channel pharmacologically is thought to be antidepressant. PE-22-28 inhibits TREK-1 with an IC50 near 0.12 nM (more potent than spadin), and in rodents a few days of dosing increases hippocampal neurogenesis, cortical synaptogenesis and BDNF - a rapid-onset pattern unlike the multi-week lag of SSRIs. This is a plausible, preclinically supported mechanism, but human efficacy has not been demonstrated. [PMID:28955242][PMID:20405001]

There is no clinically validated dose. Effective rodent doses were very low (around 3 micrograms per kilogram, injected). Research-chemical community protocols instead use fixed doses in the range of roughly 250-2000 micrograms per injection, subcutaneously, once daily or every other day - figures that are empirical and not derived from human studies. Because no human pharmacokinetic data exist, all of these numbers should be treated as unvalidated. [PMID:28955242]

In rodents, the antidepressant-type effects and the neurogenesis that accompanies them developed over about 4 days of dosing rather than after a single dose, and the parent peptide's behavioral effect was relatively short-lived per dose. Community self-reports vary widely - some describe changes within days, others none at all. Any human onset timing is anecdotal, since there are no controlled human data. [PMID:28955242]

Unknown. There are no long-term safety data in humans and no extended toxicology studies. The preclinical appeal is that PE-22-28 was selective for TREK-1 and did not affect the cardiac hERG channel or several related potassium channels, and spadin analogs showed no obvious effects on pain, seizures or heart function in short rodent studies - but chronic TREK-1 blockade in humans has never been evaluated. Conservative community practice is to cycle rather than dose continuously. [PMID:28955242]

Not without talking to the prescriber first. PE-22-28's proposed mechanism (TREK-1 blockade with downstream serotonergic and neurogenic effects) overlaps conceptually with how antidepressants act, so combining it with SSRIs, SNRIs, tricyclics, MAOIs, lithium, or ketamine could have additive or unpredictable effects that have never been studied. Do not stop or replace a prescribed medication with PE-22-28, and keep regular psychiatric follow-up. [PMID:28955242]

No side effects are documented in humans because no trials have been done. In practice the most concrete risks are those of any injected research peptide: injection-site reactions and flu-like symptoms from endotoxin/pyrogen contamination or from impure or mislabeled material. Paradoxical worsening of mood or anxiety is possible with any centrally acting compound, especially in people with bipolar or psychotic vulnerability. [PMID:28955242]

It has only been studied as an antidepressant candidate in rodents; there are no controlled data for anxiety. TREK-1 does have roles in mood and neuronal excitability, so an effect on anxiety is conceivable, but community reports are mixed and unverified. Significant anxiety disorders should be treated with evidence-based care rather than an unvalidated peptide. [PMID:28955242]

That is a personal risk decision, and the honest answer is that the evidence is thin: promising, mechanistically coherent rodent data from a single research group, no human trials, and an unregulated supply chain of variable quality. For anyone with more than mild, subclinical mood complaints - and certainly for moderate-to-severe or unstable depression - established care (therapy, approved medication, sleep, exercise) is the appropriate path, and PE-22-28 is not a substitute. Anyone who does experiment should use tested material, keep expectations realistic, and be prepared to conclude it does nothing. [PMID:28955242]