Side-by-side · Research reference

HexarelinvsPE 22-28

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

APhase 1HUMAN-REVIEWED19/45 cited

BAnimal-StrongHUMAN-REVIEWED16/47 cited

Hexarelin

Hexapeptide GHRP · Cardio-tropic

100–200 mcgPer doseSmith 1996

Phase 1Evidence levelGhigo 1997

~70 minHalf-lifeSemenistaya 2010

SQ · Multiple sites · 1–3×/day

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

01Mechanism of Action

Parameter

Hexarelin

PE 22-28

Primary target

Ghrelin receptor (GHS-R1a) + cardiac CD36Smith 1996 Ghigo 1997

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

Pathway

GHS-R1a → Gαq → Ca²⁺ → GH release. CD36 engagement → direct cardio-tropic actionGhigo 1997

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

Downstream effect

Strong GH pulse + IGF-1 elevation; cardio-protective effects in animal MI modelsGhigo 1997

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

Feedback intact?

Yes initially; tachyphylaxis with chronic useGhigo 1997

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

Origin

Synthetic hexapeptide His-D-2-Methyl-Trp-Ala-Trp-D-Phe-Lys-NH₂Smith 1996

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

Antibody development

—

Not reported in animal studies

02Dosage Protocols

Parameter

Hexarelin

PE 22-28

Standard dose

100–200 mcg per injectionSmith 1996

—

Frequency

1–2× per day max (tachyphylaxis with chronic 3× daily)

Once daily

Sustained antidepressant effect over 7+ days.

Lower / starter dose

50 mcg per dose

—

Evidence basis

Phase 1 / Phase 2 trialsSmith 1996 Ghigo 1997

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

Duration

4–8 weeks on / 4–8 weeks off (tachyphylaxis mitigation)

—

Reconstitution

Bacteriostatic water

—

Timing

Pre-sleep + fasted preferred

—

Half-life

~70 minSemenistaya 2010

—

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.

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.

04Side Effects & Safety

Parameter

Hexarelin

PE 22-28

Cortisol elevation

Modest at high dosesGhigo 1997

—

Prolactin elevation

Modest at high dosesGhigo 1997

—

Hunger

Strong appetite increase via ghrelin agonism

—

Tachyphylaxis

Receptor desensitisation with chronic dosingGhigo 1997

—

Cardiac effects

Direct cardio-tropic; potential benefit in MI but unstudied in humansGhigo 1997

—

IGF-1 elevation

Strong; monitor with chronic high-dose use

—

Cancer risk

Contraindicated in active malignancy (GH/IGF-1 axis)

—

Pregnancy / OB

Avoid

—

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

Absolute Contraindications

Hexarelin

·Active malignancy
·Pregnancy / breastfeeding
·Disrupted hypothalamic-pituitary axis

PE 22-28

·Human use — no clinical safety data available

Relative Contraindications

Hexarelin

·Untreated diabetes
·Severe hyperprolactinemia

PE 22-28

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

05Administration Protocol

Parameter

Hexarelin

PE 22-28

1. Reconstitution

Add 2 mL bacteriostatic water to 5 mg vial → 2.5 mg/mL = 250 mcg per 0.1 mL.

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

2. Injection site

SQ — abdomen or thigh. Rotate sites.

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

3. Timing

Pre-sleep + fasted preferred. Cycle on/off to avoid tachyphylaxis.

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

4. Storage

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

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

5. Needle

29–31G, 4–8 mm insulin syringe.

—

06Stack Synergy

Hexarelin

+ CJC-1295 (no DAC)

Strong

View CJC-1295 (no DAC) →

Hexarelin (GHRP) + CJC-1295-no-DAC (GHRH analogue) is the higher-amplitude variant of the standard GHRH+GHRP stack. Hexarelin produces a stronger pulse than ipamorelin but with cortisol + prolactin signal — choose this stack for maximum GH amplitude when side-effect tolerance is acceptable. Cycle aggressively.

Hexarelin: 100 mcg SQ · pre-sleep
CJC-1295 (no DAC): 100 mcg SQ · same injection
Primary benefit: Maximum GH pulse amplitude (with side-effect signal)

Smith 1996 Teichman 2006

PE 22-28

— no documented stacks