Side-by-side · Research reference

PE 22-28vsRetatrutide

Side-by-side comparison across mechanism, dosage, evidence, side effects, administration, and stack synergies. Citations on every claim where available.

AAnimal-StrongHUMAN-REVIEWED16/47 cited

BPhase 2HUMAN-REVIEWED10/41 cited

PE 22-28

TREK-1 Antagonist · Pre-Clinical

0.12 nMTREK-1 IC50Djillani 2017

7 AAPeptide lengthDjillani 2017

AnimalEvidence stage

IP · SQ · Once Daily (animal models)Djillani 2017 Pietri 2019

Retatrutide

Triple-receptor agonist · Phase 3

1–12 mgWeekly doseJastreboff 2023

24.2%Body-weight ↓Jastreboff 2023

~6 daysHalf-life (est)

SQ · Abdomen · Once weekly

01Mechanism of Action

Parameter

PE 22-28

Retatrutide

Primary target

TREK-1 two-pore-domain potassium channelDjillani 2017 Ma 2020

GLP-1R + GIPR + Glucagon receptor (triple agonism)Jastreboff 2023

Pathway

TREK-1 channel blockade → Neuronal membrane depolarisation → Enhanced hippocampal excitability → Increased neuroplasticity

Triple-receptor activation → ↑insulin (GLP-1+GIP), ↓gastric emptying, ↑lipid handling, ↑energy expenditure (glucagon component)Jastreboff 2023

Downstream effect

Antidepressant-like activity in forced swim test and tail suspension test; reduced A1-like reactive astrocyte activation; neuroprotection via NF-κB pathway modulationDjillani 2017 Cong 2023 Wu 2021

Maximal weight loss across class. Glucagon component drives lipolysis and energy expenditure beyond GLP-1+GIP aloneJastreboff 2023

Feedback intact?

N/A — direct ion channel blockade; not receptor-mediated endocrine axis

—

Origin

Synthetic truncation of spadin (PE 12-28), itself derived from the sortilin propeptide C-terminus. Residues 22-28: Val-Val-Arg-Gly-Trp-Leu-Arg.Djillani 2017 Mazella 2018

Synthetic peptide engineered for balanced affinity at three incretin / glucagon receptorsJastreboff 2023

Antibody development

Not reported in animal studies

—

02Dosage Protocols

Parameter

PE 22-28

Retatrutide

Animal dose (antidepressant)

0.3–3 µg/kg IP

Effective in forced swim test, tail suspension test, CUMS models.

—

Animal dose (neuroprotection)

0.03 µg/kg IPPietri 2019

Low-dose TREK-1 activation post-stroke for 7 days, then high-dose blockade.

—

Frequency

Once daily

Sustained antidepressant effect over 7+ days.

Once weekly

Onset (animal)

Within hours (acute); full effect 4–7 days

—

Duration (animal)

7–28 days testedQi 2018 Pietri 2019

—

Comparison to fluoxetine

PE 22-28 outperforms fluoxetine in CUMS-sensitive rats by day 7

Chronic administration shows superior long-term efficacy.

—

Human equivalent (extrapolated)

Not established — no clinical trials

Allometric scaling from rodent data unavailable.

—

Evidence basis

Multiple rodent RCTs; behavioral + electrophysiology endpointsDjillani 2017 Qi 2018 Wu 2021

Phase 2 trial; Phase 3 ongoingJastreboff 2023

Standard dose

—

12 mg / week (max efficacy)Jastreboff 2023

Phase 2 trial dose. Phase 3 dosing TBD.

Titration schedule

—

2 mg → 4 mg → 8 mg → 12 mg over 16 weeks

Duration

—

Indefinite for chronic indication (presumed)

Reconstitution

—

Investigational; not commercially available

Timing

—

Any time of day

Half-life

—

~6 days (estimated from class)

04Side Effects & Safety

Parameter

PE 22-28

Retatrutide

Toxicity (animal)

No adverse effects reported at therapeutic doses

—

Cardiovascular (theoretical)

TREK-1 expressed in cardiac tissue; arrhythmia risk unclear

—

Weight change

Not reported in animal studies

—

Neurological

No seizures or behavioral abnormalities noted

—

Long-term safety

Unknown — longest animal study 28 days

—

GI symptoms

—

Nausea, vomiting, diarrhea (very common, dose-dependent)Jastreboff 2023

Heart rate

—

↑ resting HR (3–7 bpm at 12 mg)Jastreboff 2023

Glucose handling

—

Glycemic improvement; rare hyperglycemia from glucagon component

Pancreatitis risk

—

Class warning

Thyroid C-cell tumours

—

Class warning (presumed)

Pregnancy / OB

—

Avoid (insufficient data)

Absolute Contraindications

PE 22-28

·Human use — no clinical safety data available

Retatrutide

·MTC personal or family history (presumed class effect)
·Pregnancy / breastfeeding

Relative Contraindications

PE 22-28

·Cardiac arrhythmia or channelopathy (theoretical TREK-1 cardiac role)

Retatrutide

·Severe gastroparesis
·History of pancreatitis
·Severe cardiovascular disease (HR signal)

05Administration Protocol

Parameter

PE 22-28

Retatrutide

1. Animal protocol (IP)

Dissolved in sterile saline or vehicle. Intraperitoneal injection, 0.3–3 µg/kg body weight. Once daily administration in rodent behavioral studies.

Investigational peptide. Research vials reconstituted with bacteriostatic water per label.

2. Stability

Shorter peptide length (7 AA) confers improved plasma stability vs 17-AA spadin. Exact storage conditions not detailed in published protocols.Djillani 2017

SQ — abdomen, thigh, or upper arm. Rotate weekly.

3. BBB penetration

Enhanced CNS bioavailability vs full spadin, likely due to smaller size. Mechanism (passive diffusion vs active transport) not fully characterized.

Once weekly, same day.

4. Human formulation

Not established — peptide synthesis methods for research use only. No pharmaceutical-grade formulation available.

Refrigerate 2–8 °C. Light-protected.

5. Needle

—

27–31G, 4–8 mm insulin syringe.