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PE-22-287 residuesGVSWGLREach bubble = one amino acid. Size = residue mass. Color = chemical class.Also known as: PE 22-28, PE22-28, shortened spadin
An IC50 of 0.12 nanomolar makes PE-22-28 roughly 300 times more potent than spadin at blocking TREK-1 potassium channels in the brain. This synthetic heptapeptide (seven amino acids, derived from the sortilin propeptide) produced antidepressant-like effects in mice within four days of treatment. That speed matters because conventional SSRIs typically need three to six weeks. All current data comes from rodent models; zero human clinical trials have been published. Researchers and self-experimenters use PE-22-28 at doses of 100 to 400 mcg daily, often intranasal, for mood support and cognitive exploration.
Four days. That is how quickly PE-22-28 produced antidepressant-like responses in mouse behavioral models, according to Djillani and colleagues [1]. PE-22-28 (also written PE 22-28) is a synthetic heptapeptide derived from spadin, itself a fragment of the sortilin propeptide. Its target is TREK-1 (TWIK-related potassium channel 1), a two-pore domain K+ channel distributed across mood-regulating brain circuits. The IC50 against TREK-1 sits at 0.12 nM, which makes PE-22-28 about 300 times more potent than spadin. The mechanism is straightforward in concept. TREK-1 normally dampens neuronal firing by hyperpolarizing cell membranes. Block that channel and excitability increases in serotonergic and dopaminergic circuits. BDNF expression rises. Hippocampal neurogenesis follows. Functional duration in mice clocks in at roughly 23 hours per dose, compared to about 7 hours for spadin [1]. Community use sits around 100 to 400 mcg daily, administered subcutaneously or intranasally. The intranasal route is strongly preferred for assumed direct CNS access. Cycling follows a 4 weeks on, 4 weeks off pattern borrowed from convention rather than clinical evidence. Anecdotal reports across roughly 20 to 50 Reddit and forum threads describe mood lift and reduced anhedonia within a week. The user base is small, and every reported benefit should be treated as preliminary. No Phase 1 trial, no IND filing, no human pharmacokinetic profile exists as of April 2026.
TREK-1 belongs to the K2P (two-pore domain) family of potassium channels. In mood-regulating brain regions, TREK-1 keeps neurons in a hyperpolarized state, effectively putting the brakes on excitability. PE-22-28 blocks that brake with an IC50 of 0.12 nM. When TREK-1 activity drops, neuronal firing increases across serotonergic and dopaminergic circuits. Serotonin and dopamine transmission both rise as downstream consequences, not through direct transporter or receptor binding. This is what separates PE-22-28 from SSRIs or SNRIs mechanistically; it sits upstream of monoamine signaling. The downstream cascade triggers BDNF (brain-derived neurotrophic factor) expression and promotes hippocampal neurogenesis and synaptogenesis. Djillani's group confirmed that sub-chronic dosing produced measurable antidepressant-like behavior in mice by day four [1]. Spadin's parent compound mapped the same pathway earlier (Mazella et al.)[2]. One detail the community figured out before the researchers published on it: PE-22-28 appears selective for TREK-1 over other K2P channels (TREK-2, TRAAK, TASK, TRESK). That selectivity matters because broad K2P inhibition would carry wider off-target risk, particularly in cardiac tissue where multiple K2P subtypes are present.
TREK-1 blockade produces rapid antidepressant-like and neurogenic effects in rodent models within 4 days; IC50 0.12 nM; zero human trial data exists
Djillani et al. 2017: PE-22-28 IC50 0.12 nM vs TREK-1, functional duration ~23h (vs ~7h spadin), sub-chronic antidepressant-like effects in mice (PMID 28955242)
All efficacy and safety data from rodent models only; no Phase 1 IND or registered human trial found as of April 2026; 23h "half-life" is functional behavioral duration, not plasma half-life; BSA conversion yields HEDs far above community use range
Mood lift and reduced anhedonia reported within days; intranasal route strongly preferred; very small user base limits confidence
Science and community agree on rapid-onset mood effects and the TREK-1 mechanism. Community doses (100–400 mcg) are well below all BSA-corrected HEDs from animal data, which is appropriately conservative given no human safety data. Intranasal preference is community-driven: no published human PK comparison of intranasal vs SC exists. Community protocol length (4 weeks) is unsupported by any clinical data.
| Level | Dose / Injection | Frequency |
|---|---|---|
| Beginner | 100mcg | Daily |
| Moderate | 200mcg | Daily |
| Aggressive | 400mcg | Daily |
Start with a 5 mg vial and 2 mL of bacteriostatic water. That gives you 2,500 mcg per mL, or 25 mcg per unit on a U-100 insulin syringe. For 100 mcg you'll pull 4 units; for 200 mcg, pull 8 units; for 400 mcg, pull 16 units. If you're going intranasal, swap BAC water for bacteriostatic saline. Regular BAC water burns. Get a nasal spray atomizer that delivers a consistent spray volume so you can calculate dose per pump. With a 10 mg vial at 2 mL reconstitution, the math doubles: 5,000 mcg per mL, so 50 mcg per unit. A 200 mcg dose is then 4 units; 400 mcg is 8 units. The 10 mg vial at 200 mcg daily lasts about 50 days, which means one vial covers your entire 4-week cycle with room to spare. Vendor quality matters more than usual here. PE-22-28 is niche, few vendors carry it, and Peptide Sciences closed in March 2026. Request a CoA with HPLC purity above 98% and mass spec confirmation. Store lyophilized powder at minus 20 degrees Celsius; reconstituted solution at 2 to 8 degrees Celsius, use within 30 days.
Cycling recommendations are extrapolated from community protocols: no human clinical data supports a specific schedule. The 4-on/4-off pattern is commonly used to prevent potential receptor desensitization.
TREK-1 channel desensitization is the theoretical basis for the 4-week on / 4-week off pattern. No human data validates this; 4/4 is derived by community convention analogized from other CNS-active peptide cycles. The off-period also provides a safety monitoring window given the absence of long-term human safety data.
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Expected: Based on rodent data: mood improvement and anhedonia reduction within 4–7 days. Human outcomes undocumented.
Monitor: Monitor resting heart rate at baseline and weekly. Discontinue if palpitations or notable mood volatility occur.
Inject 2 mL bacteriostatic water (or bacteriostatic saline for intranasal use) slowly down the side of the vial. Let the powder dissolve; do not shake.
With a 5 mg vial and 2 mL BAC water: 100 mcg = 4 units, 200 mcg = 8 units, 400 mcg = 16 units on a U-100 insulin syringe.
For subcutaneous injection: use a 29 to 31 gauge, half-inch insulin syringe. Draw the calculated units from the vial. Pinch skin on your abdomen or thigh. Insert at a 45-degree angle. Inject slowly. Rotate sites each day.
For intranasal delivery: draw the calculated dose into a nasal spray device or atomizer. Tilt your head slightly forward. Spray into one nostril while gently inhaling. Alternate nostrils daily if using split doses.
Administer once daily in the morning, preferably on an empty stomach. Morning dosing aligns with the 23-hour functional duration and avoids potential CNS stimulation near bedtime.
Track resting heart rate at baseline and weekly throughout the cycle. Stop immediately if you notice palpitations or irregular rhythm.
Store the reconstituted vial upright at 2 to 8 degrees Celsius. Use within 30 days. Do not freeze reconstituted solution.
Same dose range (100–400 mcg); no published human bioavailability comparison to intranasal
Rotate injection sites (abdomen, thigh). Blood-brain barrier passage is indirect vs. intranasal; functional duration ~23h still expected based on lipophilicity and CNS distribution data.
Same dose range; 400 mcg intranasal is the single most-cited community/clinician dose; some vendors sell pre-made 20 mg spray format
Requires nasal spray device or atomizer. Reconstitute in bacteriostatic saline rather than BAC water for nasal use. No published human PK comparison to SC route.
Complementary mood stack: PE-22-28 targets TREK-1 (monoaminergic), Selank modulates GABA-A/BDNF/serotonin via different receptor systems; anxiolytic + mood support pairing
PE-22-28 100–200 mcg + Selank 250–500 mcg intranasal, both AM
Cognitive/neurogenic stack: Semax boosts BDNF and NGF independently; combined neurogenesis and cognitive enhancement rationale
PE-22-28 200–400 mcg + Semax 100–300 mcg intranasal, both AM
Recovery + mood stack: BPC-157 used post-injury or trauma context; monoaminergic mood support from PE-22-28 alongside BPC-157 systemic healing
PE-22-28 modulates serotonergic signaling via TREK-1 downstream pathways; combining with SERT inhibitors may increase serotonergic tone unpredictably: serotonin excess risk
Do not combineTREK-1 blockade amplifies monoamine signaling; combining with MAOIs risks excessive monoamine accumulation
Do not combineTCAs modulate K+ channels independently; overlap with TREK-1 inhibition creates unpredictable channel pharmacology
Do not combineK+ channel involvement theoretical; no human ECG data for PE-22-28; avoid until cardiac safety established
Pricing updated 2026-04-09
The biggest concern with PE-22-28 is the total absence of human safety data. Zero clinical trials, zero published human pharmacokinetics, zero formal adverse event reporting. Every safety statement here is extrapolated from rodent studies or drawn from a very thin base of community self-reports. TREK-1 is expressed in cardiomyocytes, where it contributes to resting membrane potential. Blocking a potassium channel in the heart carries a theoretical arrhythmia risk. Rodent studies at standard research doses showed no cardiac toxicity, but mice don't predict human cardiac electrophysiology reliably. Anyone with pre-existing arrhythmias, conduction disorders, or concurrent QT-prolonging medications should not use this compound. There is zero human ECG data. Seizure threshold is another concern. TREK-1 blockade increases neuronal excitability by design. That same property that supports the antidepressant mechanism also lowers the threshold for seizure activity. People with a history of seizure disorders should avoid PE-22-28 entirely. Serotonergic interactions deserve serious attention. PE-22-28 modulates serotonin pathways downstream of TREK-1 inhibition. Combining it with SSRIs, SNRIs, or MAO inhibitors creates unpredictable serotonergic tone. This isn't a theoretical footnote; serotonin excess is a medical emergency. If you take any antidepressant, this compound is off the table. Published rodent data reports no significant adverse effects at research doses. That sounds reassuring until you consider that rodent tolerability screening catches gross toxicity, not subtle rhythm disturbances or mood volatility. Community reports are too sparse to build a side-effect profile. At 800 mcg intranasal, a handful of users reported lethargy and what they described as rebound sedation. At 400 mcg and below, reports are generally positive, but the sample size (roughly 20 to 50 total forum discussions) can't rule out rare events. Injection-site reactions (for subcutaneous users) include mild redness and warming at the site. These are typical of subcutaneous peptide administration and not specific to PE-22-28. When to stop: palpitations, irregular heartbeat, agitation, mood swings, or any sign of seizure activity. Seek medical evaluation before considering resumption. Pregnancy and breastfeeding are absolute contraindications given the complete absence of reproductive safety data.
Verify PE-22-28 dosing and safety with a second opinion
Niche product with very limited vendor base. Peptide Sciences (previously a major supplier) shut down March 2026. Few vendors carry PE-22-28; purity certification is rare. No USP standard, no FDA-regulated manufacturing.
| Test | When | Target |
|---|---|---|
| Resting heart rate (wearable or manual) | Baseline before first dose, then weekly throughout cycle | Baseline ±10 bpm; discontinue if sustained elevation or irregularity |
| ECG (12-lead) | Recommended before starting, especially if any cardiac history or concurrent QT-affecting medications | — |
| Mood tracking (subjective daily log) | Daily during cycle | — |
TREK-1 is expressed in cardiomyocytes; K+ channel modulation poses theoretical arrhythmia risk with no human safety data
K+ channel pharmacology; no human ECG data for PE-22-28 exists
Primary endpoint in rodent studies was behavioral; tracking allows personal dose-response assessment and catches mood volatility early
Based on animal data, initial mood and cognitive effects may begin. TREK-1 blockade and downstream serotonin modulation start rapidly. Individual responses in humans are undocumented.
In rodent models, measurable antidepressant effects and early neurogenesis are observed by day 4. Anecdotal reports suggest improved mood stability and mental clarity.
Continued hippocampal neurogenesis and BDNF elevation expected based on preclinical data. End of standard 4-week cycle.
Neurogenesis-driven benefits may persist beyond the active dosing period. Allow a washout period equal to the on-cycle length before resuming. Long-term effects in humans are unknown.
Days 1 to 3: TREK-1 channel blockade begins with each dose. Downstream serotonin and dopamine signaling starts shifting, but neurogenesis markers won't show up yet. Some community users report mood elevation and mental clarity within 24 to 48 hours, though this isn't consistent across the small user base. Side effects at standard doses are minimal; subcutaneous users occasionally note mild stimulation or warmth at the injection site. Days 4 to 7: This is the benchmark window from rodent research. Djillani's group [1] showed measurable antidepressant-like effects and early hippocampal neurogenesis by day four. Community reports line up reasonably well here, with improved mood stability, reduced anhedonia, and clearer cognition most commonly described in this range. Cardiac monitoring should continue throughout. Weeks 2 to 4: Continued BDNF elevation and hippocampal neurogenesis are expected based on sub-chronic rodent data. No human timeline has been established. Community users report sustained mood and cognitive benefit through the end of the standard 4-week cycle. No cumulative toxicity appeared in rodent studies, but human long-term data simply doesn't exist. Post-cycle (weeks 5 to 8 off): Neurogenesis-driven changes to BDNF may outlast the active dosing period in animal models. Receptor resensitization is expected during the off-cycle. Some users report mood benefits persisting one to two weeks after stopping. Most describe returning to baseline by weeks three to four of the off period. Long-term consequences of repeated cycles are completely unknown.
TREK-1 channel inhibition begins with each dose. Downstream serotonergic/dopaminergic tone begins increasing. Neurogenesis markers not yet measurable.
Occasional mood elevation and increased mental clarity reported anecdotally within 24–48 hours. Not reliably reproducible across users.
Rodent models show measurable antidepressant effects and early hippocampal neurogenesis by day 4 (PMID 28955242). BDNF upregulation expected.
Improved mood stability, reduced anhedonia, and clearer cognition reported in this window. Most users who report benefits note onset in this range.
Continued BDNF elevation and hippocampal neurogenesis based on sub-chronic rodent data. No human timeline established.
Sustained mood benefit and cognitive enhancement reported. End of standard 4-week cycle.
Neurogenesis-driven BDNF changes may persist beyond active dosing in animal models. Receptor resensitization expected during off-cycle.
Some users report mood benefits persisting 1–2 weeks post-cycle. Most return to baseline by week 3–4 off.
Source: Functional duration ~23h in mice (vs. ~7h for spadin); Djillani et al. 2017, PMID 28955242. No human PK data available.
Loading the interactive decay curve.
PE-22-28 is classified as a research chemical. It is not approved by the FDA, EMA, or any national regulatory agency for human use. No IND (Investigational New Drug) application has been filed as of April 2026. In the United States, PE-22-28 can be legally purchased "for research purposes only" and is not scheduled under the Controlled Substances Act. It is not available through compounding pharmacies; sourcing is limited to research peptide vendors, and the vendor base is particularly thin for this compound. WADA status has not been explicitly addressed for PE-22-28. Athletes subject to anti-doping testing should assume risk, as novel performance-modifying peptides can be flagged under the S0 (non-approved substances) category. This content is provided for educational and informational purposes only. It does not constitute medical advice, diagnosis, or treatment recommendations. Consult a qualified healthcare provider before using any research compound. All dosing information is derived from preclinical animal studies and unverified community reports.
Peptide Schedule Research TeamReviewed Apr 20265 Citations
