PE-22-28

TREK-1 knockout mice are resistant to depression, which made the channel an attractive antidepressant target. Spadin, a natural fragment of the sortilin propeptide, blocks it, and PE-22-28 is a shortened analogue with roughly 300-fold better potency, an IC50 in the sub-nanomolar range and a duration of action reported out to about 23 hours. Blocking TREK-1 depolarises and increases the firing rate of dorsal raphe serotonergic neurons, elevates hippocampal BDNF and synaptic protein expression, and produces antidepressant-like behaviour in the forced swim and novelty-suppressed feeding tests after roughly four days of dosing - much faster than the several weeks fluoxetine needs in the same models. Everything above is rodent.

Targets: TREK-1 (KCNK2) potassium channel, Dorsal raphe serotonergic neurons, BDNF / synaptogenesis

• · No human dose exists. Rodent studies dosed around 100 mcg/kg; grey-market protocols land at 200-500 mcg daily, which is broadly in that neighbourhood for an adult but has never been validated.
• · Chosen to favour CNS exposure. No comparative bioavailability data exists for this peptide by either route.

Work out your exact syringe units →

• commonInjection-site irritation
• uncommonHeadache
• uncommonAnxiety or agitation— Increasing serotonergic firing is not uniformly calming.
• rareUnknown cardiovascular effects— TREK-1 is expressed in cardiac and smooth muscle. Nobody has characterised what systemic blockade does in a person.

• Pregnancy and breastfeeding - no data.
• Serious cardiac arrhythmia - TREK-1 contributes to cardiac electrophysiology and the consequences of blocking it in humans are unstudied.
• Do not use it to replace an antidepressant you are currently stabilised on; there is no human evidence it substitutes for one.

• synergyselank — Different mood mechanisms, no known conflict; frequently stacked.
• synergysemax — Commonly paired for a mood-plus-drive combination. No data.

• · Track mood with a structured scale such as the PHQ-9 rather than by impression.
• · If you have any cardiac history, having a baseline ECG is a reasonable precaution given the channel target.

Not approved anywhere; research chemical only.

• Djillani et al. 2017, shortened spadin analogs display better TREK-1 inhibition, in vivo stability and antidepressant activity, Frontiers in Pharmacology (preclinical)
• Djillani et al. 2019, fighting against depression with TREK-1 blockers: past and future, Pharmacology & Therapeutics (review)

The target here is unusually well validated for something in this class, and the potency numbers are real and published. TREK-1 is a two-pore domain potassium channel; TREK-1 knockout mice are resistant to depression across standard paradigms, which is what made the channel an antidepressant target in the first place. Spadin, a natural fragment of the sortilin propeptide, blocks it with an IC50 of 40 nM. PE 22-28 blocks it at 0.1 nM - a genuine 400-fold potency improvement, published with the comparison series in the same paper (0.1 nM for PE 22-28, 0.12 nM for the G/A analogue, 1.2 nM biotinylated, 40 nM spadin). Blocking TREK-1 depolarises dorsal raphe serotonergic neurons and increases their firing rate, which raises hippocampal BDNF and synaptic protein expression and produces antidepressant-like behaviour in forced swim and novelty-suppressed feeding after roughly four days of dosing - against several weeks for fluoxetine in the same models. That speed is the entire interest of the compound. Two things to hold alongside it. First, all of that is mouse behaviour, and forced swim immobility is a much weaker proxy for human depression than the enthusiasm around rapid-onset antidepressants usually admits. Second, TREK-1 is not a brain-specific channel - it is expressed in cardiac and vascular smooth muscle, and what systemic blockade does to human cardiac electrophysiology is entirely uncharacterised. Neither spadin nor PE 22-28 has ever been given to a person.

The first problem is expectation calibration. The rapid-onset antidepressant claim comes from mouse forced-swim and novelty-suppressed-feeding assays after four days of dosing, and human reports of a same-day mood lift are not supported by anything published - if you feel something within hours, that is not the mechanism the literature describes. The second is the cardiac blind spot: users treat this as a mood peptide and think about it in psychiatric terms, when the actual uncharacterised risk is a sub-nanomolar blocker of a channel expressed in heart and vasculature being given systemically to a human for the first time. The third is the serotonergic stacking question above. The fourth is a dosing subtlety specific to this compound: unlike most things in this class, the common human protocols are not far below the rodent equivalent - 200-500 mcg for an adult is in the same neighbourhood as 3-4 mcg/kg, so the usual reassurance that grey-market doses are homeopathic compared to animal studies does not apply here. Fifth, and worth stating plainly, using an unstudied research peptide to self-treat depression is a decision with a real downside beyond the pharmacology.

1. 200 mcgDays 1-7 — Once daily subcutaneous or intranasal. The cautious start here is not about tolerability, which is unknown, but about the cardiac channel expression - a slow approach gives you time to notice a cardiovascular effect before you are at full dose.
2. 350 mcgWeeks 2-4 — Middle of the anecdotal range. Rodent antidepressant-like effects appeared after about four days of dosing, so if nothing has shifted by the end of week two at this dose, the compound is probably not doing anything for you.
3. 500 mcgWeeks 3-4, ceiling — Top of the anecdotal range. Worth knowing the published acute rodent dose was 3-4 mcg/kg intraperitoneally, which for a 75 kg adult would be roughly 225-300 mcg - so the common human protocols sit near or above the direct rodent equivalent rather than below it, unusually for this class. Stop at four weeks.

• TREK-1 (KCNK2) two-pore domain potassium channel — IC50 0.1 nM, published alongside 0.12 nM for the G/A analogue, 1.2 nM for the biotinylated form and 40 nM for spadin - a roughly 400-fold improvement over the parent

  Channel blockade depolarises and increases the firing rate of dorsal raphe serotonergic neurons. This is a genuinely well-quantified interaction, which is rare in this class.

• Dorsal raphe serotonergic neurons — Downstream consequence of channel blockade

  Increased serotonergic tone without acting on transporters or receptors directly - which is why the onset is days rather than the weeks an SSRI needs for receptor adaptation.

• Hippocampal BDNF and synaptic protein expression — Downstream

  Elevated BDNF and synaptic protein expression with rapid synaptogenesis in hippocampus and prefrontal cortex. The structural correlate of the fast behavioural effect.

• Cardiac and vascular smooth muscle TREK-1 — Same channel, same affinity - there is no tissue selectivity in the molecule

  Uncharacterised. TREK-1 contributes to cardiac electrophysiology and vascular tone, and nobody has measured what blocking it systemically does in a human.

Rodent antidepressant-like effects appeared after roughly four days of daily dosing - the headline finding, against several weeks for fluoxetine in the same paradigms. In-vivo activity from a single dose was reported to last up to about 23 hours, against roughly 7 hours for spadin, which supports once-daily dosing. There is no human timeline of any kind. Anecdotal use runs 2-4 weeks; the rodent studies used 4-day acute and short sub-chronic protocols, so anything past a month is completely uncharted.

The commonly run pairings - with Selank for a different anxiolytic mechanism, or with Semax for mood plus drive - have no data and no obvious conflict. The combination that deserves actual thought is with a serotonergic drug. PE 22-28 increases dorsal raphe serotonergic firing rate; SSRIs, SNRIs, MAOIs, triptans, tramadol and high-dose tryptophan all raise serotonergic tone by other routes. There is no documented serotonin syndrome case with this compound because there are no documented human cases of anything with this compound, but increasing the firing rate of serotonergic neurons while blocking reuptake is a mechanistically coherent way to get into trouble, and nobody has characterised the interaction. Do not use it to replace an antidepressant you are stabilised on, and be deliberate about combining it with one. The other stack to think about is anything else with cardiac electrophysiological effects, given the channel target.

Against an SSRI, which is the comparison people are actually making: SSRIs have decades of replicated human trials, known effect sizes, known adverse effects and known discontinuation syndromes. PE 22-28 has mouse behaviour. The attraction is the four-day onset against the SSRI's several weeks, and that is a real and interesting preclinical finding that has never been tested in a person. Against ketamine or esketamine, the other rapid-onset antidepressant mechanism: those have genuine human trials and regulatory approval, and the honest comparison is that PE 22-28 occupies the same conceptual space with none of the evidence. Against Selank: Selank has a comparative human trial in generalised anxiety and works on arousal; PE 22-28 is aimed at depression and has no human data. Against spadin, its parent: 400-fold more potent at the channel, roughly three times the duration, and neither has ever been given to a human. Against the rest of this class, PE 22-28 stands out for having genuinely well-quantified target pharmacology - a published IC50 series, a validated knockout-mouse rationale, a clear structure-activity story - and no human exposure whatsoever. It is the best-characterised molecule here at the receptor and among the least characterised in a person.

$30–$90/month. A 5 mg vial typically runs 50-90 USD. At 350 mcg daily that is roughly two weeks, so 60-120 USD per month at mid-range dosing, or 30-50 USD at the 200 mcg end. Availability is inconsistent and this is a genuinely obscure research peptide, so identity and purity risk is higher than for the mainstream compounds in this class.

• ?Neither PE 22-28 nor spadin has ever been administered to a human. There is no clinical data of any kind.
• ?I could not confirm the amino acid sequence against the primary literature and have deliberately left the sequence fields blank rather than reproduce the Core record's Gly-Val-Ser-Trp-Gly-Leu-Arg unverified.
• ?No pharmacokinetic parameters exist in any species - no tmax, half-life, bioavailability, volume of distribution, clearance or protein binding. The 23-hour figure is duration of behavioural activity, not a half-life.
• ?The Core record states rodent studies dosed around 100 mcg/kg; the primary paper reports 3-4 mcg/kg intraperitoneally for acute studies and 1 mg/kg by gavage. That discrepancy is unresolved and matters for dose scaling.
• ?The cardiovascular consequences of systemic TREK-1 blockade in humans are entirely uncharacterised. This is the most substantive unknown about the compound.
• ?Whether the intranasal route achieves useful CNS exposure has never been tested for this peptide.
• ?The interaction with serotonergic drugs is mechanistically plausible and completely unstudied.
• ?The molecular weight of 773.9 Da in the Core record I did not verify against a primary characterisation.
• ?All efficacy evidence comes from a single research group in Nice. There is no independent replication.

• Shortened 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 · PMID 28955242

  The primary PE 22-28 paper. Source of the IC50 series (0.1 nM for PE 22-28 against 40 nM for spadin), the 3-4 mcg/kg intraperitoneal and 1 mg/kg oral gavage dosing, and the 23-hour versus 7-hour duration comparison. Every number quoted about this compound comes from here.

• Fighting against depression with TREK-1 blockers: Past and future. A focus on spadin Djillani A, Pietri M, Mazella J, Heurteaux C, Borsotto M, Pharmacology & Therapeutics, 2019 · PMID 30291907

  The review that situates the whole TREK-1 antidepressant programme, including the knockout-mouse rationale and where the development stands. The honest place to start if you want to know how far this target has actually got.

• First evidence of protective effects on stroke recovery and post-stroke depression induced by sortilin-derived peptides Pietri M, Djillani A, Mazella J, Borsotto M, Heurteaux C, Neuropharmacology, 2019 · PMID 31325429

  Extends the sortilin-derived peptide work to stroke recovery and post-stroke depression in rodents. Useful for seeing the breadth of what the same group has claimed and the fact that it remains entirely preclinical.