MEDICAL DISCLAIMER: Educational research guidelines only. Lyophilized peptides are investigational chemical compounds and are NOT approved for human consumption, diagnosis, or therapy. Consult a licensed physician before any research application.
PE-22-28 Dosage Chart, Schedule & Reconstitution Protocol
Quickstart Highlights
PE 22-28 is a seven-amino-acid truncated analogue of spadin, itself a fragment derived from the propeptide of sortilin (NTSR3). Both spadin and PE 22-28 act as selective blockers of the TREK-1 two-pore-domain potassium channel, a target identified by Mazella, Heurteaux and colleagues as a critical brake on serotonergic neurotransmission in dorsal raphe and prefrontal cortex (PMID: 20436484). TREK-1 knockout mice display a depression-resistant phenotype, and pharmacological blockade of TREK-1 by spadin or PE 22-28 produces rapid antidepressant-like effects in forced swim, tail suspension, and chronic mild stress paradigms with onset within four days rather than the two to four weeks typical of SSRIs (PMID: 25556916). Researchers study PE 22-28 for rapid-onset antidepressant mechanisms and as a tool compound for TREK-1 channel pharmacology.
Reconstitute: Add 3 mL bacteriostatic water → 3.33 mg/mL concentration.
Easy measuring: At 3.33 mg/mL, 1 unit = 0.01 mL = 0.0333 mg (33 mcg) on a U-100 insulin syringe.
Storage: Lyophilized frozen; reconstituted refrigerated; replace vials every 4 weeks.
Half-life: PE 22-28 was engineered specifically to extend the very short plasma half-life of native spadin; reported plasma exposure in rodents is on the order of several hours, supporting daily subcutaneous dosing in research models.
Route: Subcutaneous or intraperitoneal injection in published rodent work; no validated human delivery route or human pharmacokinetic dataset has yet been reported in peer-reviewed literature.
Status: Investigational research peptide only; not FDA, EMA, or MHRA approved and not entered into registered human clinical trials. All published efficacy data are preclinical.
Quick Protocol Navigation
Reconstitution Instruction & Mixing Step-by-Step
Lyophilized powder must be reconstituted carefully. Agitating peptide chains can shear disulfide bonds and render the peptide biologically inert.
Draw 3.0 mL bacteriostatic water with a sterile syringe.
Inject slowly down the vial wall; avoid foaming.
Gently swirl/roll until dissolved (do not shake).
Inject slowly; wait a few seconds before withdrawing the needle to prevent leakage.
Interactive PE-22-28 Syringe Calculator
Currently visualizing the 10 mg vial reconstituted with 3 mL bacteriostatic water. Adjust the target dose to dynamically render syringe units.
Reconstitution Calculation: 10mg dry powder in 3mL water yields 3.33 mg/mL. To evaluate a 250mcg dose, pull to 7.5 units (8 syringe ticks).
U-100 Syringe Representation
7.5 Units (8 Ticks)
Educational reference visual. Assumes standard U-100 insulin syringe where 1.0 mL volume = 100 units.
Titration & Dose Escalation Schedules
| Week | Daily Dose (µg) | Units (per injection) (mL) |
|---|---|---|
| Weeks 1–2 | 50 µg | 1.5 units (0.015 mL) |
| Weeks 3–4 | 100 µg | 3 units (0.03 mL) |
| Weeks 5–8 | 100 µg | 3 units (0.03 mL) |
| Weeks 9–12 (Optional) | 150 µg | 4.5 units (0.045 mL) |
| Weeks 13–16 (Optional) | 200 µg | 6 units (0.06 mL) |
Administration guidelines: Refer to guidelines | 3 mL Reconstitution
Research Supplies Quantity Planner
Scientific mathematical planning of syringes, bacteriostatic water and dry vials needed for extended research blocks using the 10 mg vial.
Peptide Vials (PE-22-28, 10 mg each):
- check8 weeks ≈ 2 vials
- check12 weeks ≈ 3 vials
- check16 weeks ≈ 4 vials
Insulin Syringes (U-100):
- checkPer week: 7 syringes (1/day)
- check8 weeks: 56 syringes
- check12 weeks: 84 syringes
- check16 weeks: 112 syringes
Bacteriostatic Water (10 mL bottles): Use ~3.0 mL per vial for reconstitution.
- check8 weeks (2 vials): 6 mL → 1 × 10 mL bottle
- check12 weeks (3 vials): 9 mL → 1 × 10 mL bottle
- check16 weeks (4 vials): 12 mL → 2 × 10 mL bottles
Alcohol Swabs: One for the vial stopper + one for the injection site each day.
- checkPer week: 14 swabs (2/day)
- check8 weeks: 112 swabs → recommend 2 × 100-count boxes
- check12 weeks: 168 swabs → recommend 2 × 100-count boxes
- check16 weeks: 224 swabs → recommend 3 × 100-count boxes
Mechanism of Action (MOA)
TREK-1 (KCNK2) is a two-pore-domain potassium leak channel concentrated in mood-regulating brain regions including the prefrontal cortex, hippocampus, raphe nucleus, and dorsal striatum. Genetic deletion of TREK-1 in mice produces a depression-resistant phenotype with enhanced serotonergic tone, while pharmacologic openers of TREK-1 produce pro-depressant effects. This identified TREK-1 as a novel antidepressant drug target distinct from monoamine transporters. Mazella and colleagues discovered that the propeptide fragment of sortilin, processed by furin cleavage, yields a 44-amino-acid peptide they named spadin (sortilin-derived peptide for the activation of depression-related sodium influx, later corrected to potassium channel blockade) [1]. Subsequent optimization identified the minimal active sequence within spadin and led to the development of PE-22-28, a heptapeptide with IC50 values in the picomolar range for TREK-1 blockade and dramatically improved metabolic stability compared to spadin [2]. PE-22-28 is a competitive blocker of the TREK-1 channel pore, reducing potassium efflux through this leak channel and thereby depolarizing TREK-1-expressing neurons in mood circuits. The downstream effect is enhanced firing of serotonergic and noradrenergic neurons in raphe and locus coeruleus, increased synaptic monoamine availability in forebrain targets, and engagement of BDNF-CREB plasticity programs in hippocampus. Because TREK-1 blockade increases neuronal excitability selectively in regions enriched in this channel, the antidepressant effect is targeted and does not require chronic dosing to manifest, in contrast to SSRIs which require 2–6 weeks for therapeutic onset. Preclinical studies show measurable antidepressant-like effects in forced swim test, tail suspension, and chronic mild stress models within hours to days of single PE-22-28 dosing, with effects maintained over chronic administration. The peptide is administered subcutaneously or intranasally in rodent studies at 100–500 mcg/kg; intranasal delivery exploits olfactory-pathway transit to the brain and may produce higher central concentrations per administered dose. Plasma half-life of PE-22-28 in rodents is several hours (compared to under 1 hour for spadin), and pharmacodynamic effects on TREK-1 blockade and antidepressant behavior persist up to 23 hours per dose, supporting once-daily dosing in research protocols. PE-22-28 does not cross-react significantly with related two-pore domain channels (TASK, TRAAK, TREK-2) at therapeutic concentrations, and does not block voltage-gated potassium channels, providing a relatively selective pharmacologic profile. Importantly, PE-22-28 is not pro-convulsant despite increasing neuronal excitability — possibly because TREK-1 expression is regional and the net effect on global network excitability is modest. Human pharmacokinetic and pharmacodynamic data are entirely absent. Research-community dosing in human use is extrapolated from rodent allometric scaling and typically falls in the range of 100–500 mcg subcutaneously per day, but there is no evidence base supporting any specific clinical regimen.
Clinical Trial Efficacy Highlights
- starMazella and colleagues showed in PLoS Biology 2010 that spadin, the parent peptide of PE-22-28, produces robust antidepressant-like effects in mice in the forced swim test, tail suspension test, and chronic mild stress model, with action emerging within hours rather than the weeks required for SSRIs [1].
- starDjillani and colleagues demonstrated that PE-22-28 shows IC50 of approximately 0.12 nM for TREK-1 channel blockade versus 40–60 nM for spadin, representing a >300-fold gain in potency, with action duration extended from 7 hours (spadin) to 23 hours (PE-22-28) [2].
- starIn chronic mild stress models in mice, PE-22-28 reversed depression-like behavioral phenotypes including anhedonia (sucrose preference), behavioral despair (forced swim), and social avoidance, with effects comparable to fluoxetine but with faster onset of action.
- starHippocampal neurogenesis was increased by PE-22-28 administration in mouse models, paralleling the well-known neurogenic effects of chronic SSRI treatment but achieved more rapidly with TREK-1 blockade.
- starPE-22-28 increased BDNF expression in mouse hippocampus and prefrontal cortex, consistent with engagement of the same downstream neuroplasticity programs activated by conventional antidepressants but through a non-monoaminergic upstream mechanism.
- starNo pro-convulsant activity was observed in PE-22-28-treated mice despite TREK-1 blockade increasing neuronal excitability, distinguishing this drug class from non-selective potassium channel blockers that lower seizure threshold.
- starCardiac safety in rodent studies showed no significant arrhythmia or QT prolongation at therapeutic doses, consistent with TREK-1 selectivity and low expression of this channel in cardiac conduction tissue.
- starNo human clinical trials of PE-22-28 have been published in indexed databases; all efficacy claims rest on preclinical rodent models, and translation to human depression treatment is unproven [3].
Side Effects & Tolerability Profile
Clinical subjects transiently report mild side effects. Slowly escalating the titration dose represents the single most effective intervention to limit side effects.
- warningPE-22-28 has no documented human safety data; reported side effects are limited to anecdotal reports from research-chemical use, without controlled adverse-event surveillance.
- warningTheoretical risks based on TREK-1 pharmacology include increased neuronal excitability and the possibility of agitation or anxiety, though preclinical data suggest the effect is regional and does not generalize to global hyperexcitability.
- warningMild injection site reactions (redness, irritation) with subcutaneous administration are anecdotally reported.
- warningSleep disruption has been reported anecdotally with evening dosing, possibly reflecting the increased monoaminergic tone produced by TREK-1 blockade.
- warningCardiac arrhythmia risk is theoretically low based on rodent data but has not been formally excluded in humans; ECG monitoring is reasonable in users with pre-existing arrhythmia.
- warningDrug interactions are uncharacterized; concurrent use with SSRIs, SNRIs, or other monoaminergic drugs is theoretically additive and may increase serotonergic effects.
- warningNo tolerance or dependence has been documented in rodent chronic dosing studies, but human data are absent.
- warningReproductive, pregnancy, and lactation safety are entirely unstudied; PE-22-28 should not be used in these populations.
Subcutaneous Injection Technique
Most research peptides require subcutaneous injection into fatty tissue. Never inject directly into a blood vessel or deep muscle tissue unless clinically detailed.
1. Site Selection
Common locations include the abdomen (2 inches from navel), outer upper arms, or thighs.
2. Sanitization
Thoroughly clean the selected site, stopper and vial top using 70% isopropyl alcohol prep swabs.
3. Angle & Push
Pinch the skin and insert the needle at a 45 to 90-degree angle. Depress plunger smoothly.
4. Site Rotation
Rotate injection sites continuously to avoid lipodystrophy or tissue scarring.
Frequently Asked Questions
What is the typical PE-22-28 dosage?expand_more
There is no established human dose. Rodent studies use 100–500 mcg/kg subcutaneously or intranasally, typically once daily. Research-community human use extrapolates to 100–500 mcg subcutaneously per day, but this is not validated by clinical evidence.
How is PE-22-28 administered?expand_more
PE-22-28 is administered subcutaneously or intranasally in preclinical research. Intranasal delivery exploits olfactory pathway access to the brain and may improve CNS exposure per dose. Oral bioavailability has not been characterized but is expected to be poor.
Can PE-22-28 be stacked?expand_more
Combination with SSRIs, SNRIs, or other monoaminergic antidepressants is theoretically additive on serotonergic tone and may carry serotonin syndrome risk. Stacking with cognitive peptides (Semax, Selank) is reported in research-community use without controlled-trial data.
What are the side effects of PE-22-28?expand_more
Human safety data are absent. Theoretical risks include agitation, sleep disruption, and additive serotonergic effects with antidepressants. Preclinical data show no pro-convulsant or cardiac arrhythmia signals at therapeutic doses, but human verification is lacking.
Is PE-22-28 FDA approved?expand_more
No. PE-22-28 has no regulatory approval anywhere in the world and is not registered as a pharmaceutical. It remains a research-only compound with no published human clinical trials and is sold for in vitro and preclinical investigation only.
Academic References & Study Citations
Mazella J, Petrault O, Lucas G, et al. Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design. PLoS Biol. 2010;8(4):e1000355. View Scientific Paper →
Djillani A, Mazella J, Heurteaux C, Borsotto M. Shortened spadin analogs display better TREK-1 inhibition, in vivo stability, and antidepressant activity. Front Pharmacol. 2017;8:643. View Scientific Paper →
Djillani A, Pietri M, Mazella J, Heurteaux C, Borsotto M. Fighting against depression with TREK-1 blockers: past and future. A focus on spadin. Pharmacol Ther. 2019;194:185-198. View Scientific Paper →
Heurteaux C, Lucas G, Guy N, et al. Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype. Nat Neurosci. 2006;9(9):1134-41. View Scientific Paper →
Borsotto M, Veyssiere J, Moha Ou Maati H, et al. Targeting two-pore domain K(+) channels TREK-1 and TASK-3 for the treatment of depression: a new therapeutic concept. Br J Pharmacol. 2015;172(3):771-84. View Scientific Paper →
Veyssiere J, Moha Ou Maati H, Mazella J, Gaudriault G, Moreno S, Heurteaux C, Borsotto M. Retroinverso analogs of spadin display increased antidepressant effects. Psychopharmacology (Berl). 2015;232(3):561-74. View Scientific Paper →
Moha Ou Maati H, Veyssiere J, Labbal F, et al. Spadin as a new antidepressant: absence of TREK-1-related side effects. Neuropharmacology. 2012;62(1):278-88. View Scientific Paper →
Djillani A, Doukmak E, Borsotto M, Mazella J, Heurteaux C. Sortilin-Derived Peptides Promote Pancreatic Beta-Cell Survival through CREB Signaling Pathway. Pharmacol Res. 2021;167:105539. View Scientific Paper →