Side-by-side · Research reference

PE 22-28vsSS-31

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 3HUMAN-REVIEWED9/43 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

SS-31

Cardiolipin-binding · Mitochondrial protective

40 mgDaily doseSzeto 2014

Phase 3Evidence levelSzilagyi 2009 Szeto 2014

~3 hrHalf-life

SQ · Abdomen · Once daily

01Mechanism of Action

Parameter

PE 22-28

SS-31

Primary target

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

Cardiolipin in inner mitochondrial membraneSzeto 2014

Pathway

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

Cardiolipin binding → cristae stabilisation → ETC integrity → reduced ROS + preserved ATP synthesisSzeto 2014 Szilagyi 2009

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

Mitochondrial bioenergetic preservation; cardio-, neuro-, and reno-protective effects in animal + clinical studiesSzeto 2014

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 tetrapeptide D-Arg-Dmt-Lys-Phe-NH₂; cell-permeable, mitochondrial-selectiveSzeto 2014

Antibody development

Not reported in animal studies

—

02Dosage Protocols

Parameter

PE 22-28

SS-31

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 daily

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

Multiple Phase 3 trials (Barth, AMD, ischemia-reperfusion)Szeto 2014 Szilagyi 2009

Standard dose

—

40 mg / day SQ (clinical trials)Szeto 2014

Anecdotal community range 5-10 mg/day. Phase 3 trials use 40 mg.

Lower / starter dose

—

5 mg / day (anecdotal)

Duration

—

Indefinite for mitochondrial disease; cycled for healthspan use

Reconstitution

—

Bacteriostatic water

Timing

—

Morning fasted preferred; pre-workout for exercise-induced mitochondrial stress

Half-life

—

~3 h plasma; tissue uptake longer

04Side Effects & Safety

Parameter

PE 22-28

SS-31

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

Phase 3 data over 24+ months; no major safety signalsSzeto 2014

Injection site reaction

—

Erythema, mild pruritus

GI symptoms

—

Nausea (uncommon)

Headache

—

Reported in some Phase 3 trials

Cardiovascular

—

Cardio-protective in studies; no signal of harm

Pregnancy / OB

—

Avoid — insufficient data

Absolute Contraindications

PE 22-28

·Human use — no clinical safety data available

SS-31

·Pregnancy / breastfeeding
·Hypersensitivity to peptide

Relative Contraindications

PE 22-28

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

SS-31

·None established

05Administration Protocol

Parameter

PE 22-28

SS-31

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.

Add bacteriostatic water per label. Light-protected handling.

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 or thigh. Rotate sites.

3. BBB penetration

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

Morning fasted; pre-workout for exercise-augmented mitochondrial stress.

4. Human formulation

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

Lyophilised: refrigerate, light-protected. Reconstituted: refrigerate ≤30 days.

5. Needle

—

29–31G, 4–8 mm insulin syringe.

06Stack Synergy

PE 22-28

— no documented stacks

SS-31

+ MOTS-c

Moderate

View MOTS-c →

SS-31 and MOTS-c address mitochondrial decline through complementary axes. SS-31 protects existing mitochondrial structure (cardiolipin binding, cristae stabilisation). MOTS-c upregulates AMPK/PGC-1α, triggering biogenesis of new mitochondria. Together they pair preservation with renewal — anecdotally favoured in healthspan and post-cardio-event recovery protocols.

SS-31: 5–10 mg SQ · daily morning
MOTS-c: 5 mg SQ · 2× per week pre-workout
Primary benefit: Mitochondrial preservation + biogenesis