PE-22-28
TREK-1 (KCNK2) channel blocker · shortened, stabilized spadin analog · fast-acting mood research peptide
PE-22-28 is a shortened version of spadin, a natural peptide. People run it for a fast mood lift that skips serotonin reuptake. It blocks the TREK-1 potassium channel about 300 times more potently than spadin, and in mice it acted faster than classic antidepressants.
At a glance
- Dose
- 100–250 mcg a day
- How often
- Once a day
- How
- A small injection under the skin (belly fat)
- When
- Daytime, leaning morning
- Cycle
- 4–8 weeks on, then a 2–4 week break
The 30-second versionEverything on this page, fast
Mood support · Fast-acting · Neurogenesis · Non-SSRI route
A spadin-derived mood peptide studied for a fast-acting lift through a new route. It blocks the TREK-1 potassium channel about 300 times more potently than its parent spadin. In mouse models that brightened mood and sparked the birth of new neurons, without touching serotonin reuptake the way an SSRI (selective serotonin reuptake inhibitor) does.
The basics
- A shortened, sturdier version of spadin, a peptide your own body makes from the receptor sortilin.
- The peptide people reach for as a non-SSRI route to brighter mood.
Why people use it
- A fast route to brighter mood. Studied for low mood and reported to act quicker than classic antidepressants.
- A different mechanism from SSRIs. It blocks the TREK-1 channel instead of acting on serotonin reuptake.
- Encourages the birth of new neurons. It nudges the brain's own neuroplasticity machinery.
- Extremely potent on its target. Roughly 300 times stronger on TREK-1 than the natural peptide it comes from.
Stacks well with
- Selank adds calm, a mood-plus-anxiety pairing on two different levers.
- Semax adds cognitive drive and a neurotrophic push alongside the mood angle.
Good to know
- Dose it in the daytime, leaning morning. It's mood-active and a bit alerting.
- Run it in cycles, 4–8 weeks on and 2–4 weeks off.
- Start at the low end. TREK-1 has roles all over the body.
What it does
PE-22-28 is built around one mood lever, TREK-1 blockade. Here is what people run it for.
- Fast-acting mood supportBlocking TREK-1 produced an antidepressant-like effect in mouse studies, reportedly faster than classic antidepressants.
- A different route than an SSRIIt raises serotonin-neuron firing without acting on the serotonin transporter that SSRIs target.
- Encourages new-neuron formationIn mice it promoted neurogenesis, new-neuron formation in the hippocampus, alongside the mood effect.
- Extremely potent on its targetIt blocks TREK-1 roughly 300 times more potently than spadin, the natural peptide it comes from.
- Stacks with calm and focus peptidesPeople pair it with Selank for added calm or Semax for cognitive drive, each on a different mechanism.
How it works
Blocks TREK-1 hard. PE-22-28 blocks TREK-1, a potassium channel encoded by the gene KCNK2. In lab tests on human TREK-1 it reached half-maximal block at around 0.12 nM (nanomolar). That is roughly 300 times more potent than spadin, its parent peptide.
Why TREK-1 matters for mood. TREK-1 sits in mood-regulating brain regions. Mice that lack it resist depression-like behavior, much like mice on antidepressants.
A route around reuptake. Blocking TREK-1 raises the firing of serotonin neurons in the dorsal raphe and switches on signals tied to new-neuron formation. It gets there without acting on the serotonin transporter the way SSRIs (selective serotonin reuptake inhibitors) do. The proposed payoff is a faster onset than the weeks-long wait on standard antidepressants.
How to dose it
Most people run PE-22-28 as a small injection under the skin, once a day, in cycles.
Dose tiersMost people run 100 to 250 mcg once daily, as a small injection under the skin.
- Route:
- Subcutaneous (SC) injection, into the fat under the skin. All published work used injection. Taken by mouth, digestion would break it down first.
- Range:
- People most often run 100 to 250 mcg once daily by SC injection.
- Where it comes from:
- The studies dosed mice by injection and tested human TREK-1 in cell dishes. The daily range comes from common peptide practice.
How to injectAn injection into belly, love-handle or thigh fat, rotated between doses.
- Injection site:
- Abdomen (a couple of inches clear of the navel), love handles or outer thigh. Rotate sites to avoid irritation and lipohypertrophy (fatty lumps under the skin).
- Measuring the dose:
- Draw it on a U-100 insulin syringe. The Mixing the vial card gives the units, and the calculator covers any vial.
- Time of day:
- Daytime, leaning morning, loosely aligned with the body's cortisol peak. See Best time to take it below.
- Food window:
- Inject with or without food. Meals do not affect absorption.
Cycle and breaksPeople pulse it in cycles of daily use rather than running it nonstop.
- Standard cycle:
- 4 to 8 weeks of daily use, then reassess.
- Washout:
- A 2 to 4 week break. Take stock of your mood during it, ideally with a validated mood scale.
- Keep cycles short:
- People err on the shorter side rather than running it continuously.
Mixing the vialA 10 mg vial plus 2 mL bacteriostatic water gives 5,000 mcg per mL.
- Mixing:
- 10 mg vial + 2 mL bacteriostatic water = 5,000 mcg per mL, drawn on a 100-unit (1 mL) insulin syringe.
- Units at 5,000 mcg per mL:
- 100 mcg takes 2 syringe units, 150 mcg takes 3 units, 200 mcg takes 4 units, 250 mcg takes 5 units, 500 mcg takes 10 units.
- Why 2 mL:
- The calculator defaults to 2 mL, so doses stay small and the units stay easy to read.
Sources:PMID 28955242PMID 20405001
Best time to take it
Implied best time
Daytime (morning-lean)
Most people take it once a day in the daytime, leaning toward the morning.
- It acts on mood and serotonin-firing circuits, so the effect is wanted in waking hours. The morning slot loosely tracks the body's cortisol peak.
- Its neurogenesis and BDNF (brain-derived neurotrophic factor) side is a brain-active, alerting signal that fits daytime better than late evening.
- A consistent daily time matters more than the exact hour.
Sources:PMID 28955242
What to stack it with
PE-22-28 pulls one lever, TREK-1. The best partners add a different angle, calm or cognitive, rather than doubling that one.
PE-22-28 + SelankA mood-plus-calm pairing that adds a separate anti-anxiety mechanism.
- Why it works:
- Selank is a seven-amino-acid peptide derived from tuftsin, studied in rodents and some human research for calming effects. It works through a different mechanism than TREK-1 blockade.
- The protocol:
- PE-22-28 100–250 mcg SC once daily + Selank 250–500 mcg SC once daily. Intranasal is Selank's primary route.
- Outcome:
- Reached for when mood and anxiety are both goals, two different mechanisms on one aim.
PE-22-28 + SemaxAdds a brain-growth-factor and focus lever to the fast mood angle.
- Why it works:
- Semax is an analog of ACTH(4-7), a fragment of adrenocorticotropic hormone, studied in Russian and some international research for BDNF upregulation, cognition and neuroprotection. It feeds PE-22-28's new-neuron side.
- The protocol:
- PE-22-28 100–250 mcg SC once daily + Semax 300–600 mcg SC or intranasal once daily. Intranasal is Semax's primary route.
- Outcome:
- Reached for in nootropic (focus and cognition) stacks where clarity and mood are both goals.
Support nutrients
People often add nutrients and habits that feed the same serotonin and new-neuron pathways.
Feed the serotonin pathwayTryptophan or 5-HTP (5-hydroxytryptophan) and B6 feed serotonin, and omega-3 fats modulate TREK-1 itself.
- Tryptophan or 5-HTP:
- The raw material for serotonin. L-tryptophan 500–1,000 mg in the evening with a small carbohydrate, or 5-HTP 50–100 mg at bedtime. Not with prescription antidepressants.
- Vitamin B6 (P5P form):
- Pyridoxal-5-phosphate, the ready-to-use B6 form serotonin synthesis runs on. 25–50 mg P5P daily with food.
- Omega-3 DHA/EPA:
- TREK-1 responds to DHA and EPA (docosahexaenoic and eicosapentaenoic acid), and DHA builds the membranes of new neurons. ~2–3 g combined EPA/DHA daily from fish or algae oil.
Habits that grow new neuronsExercise, sleep and morning light drive the same new-neuron biology PE-22-28 moved in mice.
- Exercise (aerobic):
- The best-evidenced non-drug driver of hippocampal BDNF and neurogenesis. 3–5 sessions/week of 30–45 min sustained cardio (zone 2 heart rate).
- Sleep (7–9 hours):
- Ongoing short sleep suppresses BDNF and new-neuron growth, and no supplement makes up for a steady sleep deficit. Fix sleep timing and consistency first.
- Morning light exposure:
- 10–20 minutes of outdoor morning light (or a 10,000 lux light box) within the first hour of waking. It sets the body clock and supports mood.
Little to offsetPE-22-28 has no known nutrient drain, so this list is short.
- Magnesium glycinate:
- General mood and sleep support, often low under stress or heavy caffeine. 300–400 mg at bedtime.
- No known depletion targets:
- Its TREK-1 mechanism drains no known nutrient.
Dose calculator
Reconstitution calculator
Calculated for a 1 mL U-100 insulin syringe (100 units/mL).
Units per dose
3 units
Draw this many units on a U-100 syringe
Each unit holds 50 mcg
- Volume per dose
- 0.03 mL
- Doses per vial
- 66
- Concentration
- 5 mg/mL
One vial lasts
- Daily
- 66 days
- Every other day
- 133 days
- 5×/week
- 93 days
Research use only. Not for human consumption. Outputs are reference values based on research literature. Verify all measurements independently.
Side effects and what to watch
What the research found. In rodents, spadin analogs acted as relatively selective TREK-1 blockers and seemed to lack some side effects of classic antidepressants.
Worth knowing. TREK-1 also has roles in the heart and blood vessels and in pain and neuroprotection pathways. People start at the low end of the range.
Competing? It is not specifically named on the 2026 WADA Prohibited List, but broad categories such as non-approved substances can cover research peptides. Check with your federation.
Sources:PMID 30291907
Common questions
How is PE-22-28 dosed?
Most people run 100 to 250 mcg once daily as a small injection under the skin. A 10 mg vial with 2 mL bacteriostatic water gives 5,000 mcg per mL.
What does it do?
It blocks TREK-1 (gene KCNK2), a potassium channel, about 300 times more potently than its parent peptide spadin. Mice lacking TREK-1 resist depression-like behavior, so blocking it is a proposed fast-acting route to better mood.
How is it different from an SSRI?
SSRIs block serotonin reuptake and typically take weeks to act. PE-22-28 blocks the TREK-1 channel instead, without acting on the serotonin transporter. In animal studies that produced a faster antidepressant-like effect.
Do I need to cycle PE-22-28?
People run it in cycles. The usual pattern is 4 to 8 weeks of daily use, then a 2 to 4 week break to take stock of mood.
What does it stack with?
Selank for calm, at 250 to 500 mcg once daily, or Semax for focus and a BDNF push, at 300 to 600 mcg once daily.
Where does PE-22-28 come from?
It is a shortened, stabilized version of spadin, a natural peptide the body makes from the receptor sortilin (NTSR3). Spadin is known as 'PE 12-28'. PE-22-28 is the shorter fragment (residues 22-28), built for better potency and stability.
Deep dive
Doses used in studies · Molecular identity · References
10From the researchDoses used in studies
These are the published study results for PE-22-28 and its parent spadin, from mouse studies and lab tests on human TREK-1.
| Dose | Route | Model | Outcome | Sources: |
|---|---|---|---|---|
| Sub-chronic course (mouse) | Intraperitoneal / oral gavage | Preclinical, mouse, forced swimming test | Reduced immobility time (an antidepressant-like effect); preclinical only | PMID 28955242 |
| ~4-day treatment (mouse) | Intraperitoneal | Preclinical, mouse, novelty-suppressed feeding + neurogenesis | Reduced latency to feed and induced hippocampal neurogenesis after only ~4 days; faster than classic antidepressants; preclinical only | PMID 28955242 |
| In-vitro exposure | In vitro | Cellular, human TREK-1 (patch-clamp) | Blocked TREK-1 with IC50 ≈ 0.12 nM (~300x more potent than spadin); mechanistic | PMID 28955242 |
| Spadin lineage (mouse) | Intracerebroventricular / intravenous / intraperitoneal | Preclinical, mouse (the parent peptide spadin) | Spadin blocked TREK-1, raised serotonin-neuron firing, and produced antidepressant-like effects; the founding rationale | PMID 20405001 |
11ChemistryMolecular identity
- Molecular weight
- 773.9 g/mol (average)
- Molecular formula
- C35H55N11O9
- Monoisotopic mass
- 773.4184 Da
- CAS number
- 1801959-12-5 (free peptide)
- Sequence (7 AA)
- Gly-Val-Ser-Trp-Gly-Leu-Arg (GVSWGLR)PubChem CID 165437303; Djillani et al. 2017 (PMID 28955242)
- Structure / class
- Linear 7-residue peptide; shortened, stabilized spadin analogPubChem CID 165437303; PMID 28955242
- Molecular target
- TREK-1 (KCNK2) two-pore-domain K⁺ channel; blocker (IC₅₀ ≈ 0.12 nM; ~300× spadin)Djillani et al. 2017 (PMID 28955242)
- Origin
- Derived from spadin (PE 12-28), a sortilin/NTSR3 propeptide fragmentMazella et al. 2010 (PMID 20405001)
- Half-life
- Not established in humans; engineered for improved in-vivo stability over spadin (rodent data only)Not established; PMID 28955242 (rodent)
- Regulatory status
- Not approved anywhere; research compound. No human trials; efficacy and safety data are mouse-onlyNo approval record; PMID 28955242
12Primary sourcesReferences
- PubChem CID 165437303PubChem CID 165437303 (PE 22-28)
- PMID 28955242Djillani et al., Front Pharmacol 2017. Shortened spadin analogs (PE 22-28): better TREK-1 inhibition, stability & antidepressant activity (mouse)
- PMID 20405001Mazella et al., PLoS Biology 2010. Spadin, a sortilin-derived TREK-1-targeting antidepressant concept (rodent)
- PMID 30291907Djillani et al., Pharmacol Ther 2019. Fighting depression with TREK-1 blockers, focus on spadin (review)
- PMID 25263033Borsotto et al., Br J Pharmacol 2015. Targeting TREK-1/TASK-3 channels for depression (review)
Reviewed by Ki Researcher Team · Research use only · Not medical advice · Updated 2026-09-24