Side-by-side · Research reference

Melanotan-IIvsPE 22-28

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

APhase 1HUMAN-REVIEWED9/43 cited

BAnimal-StrongHUMAN-REVIEWED16/47 cited

Melanotan-II

MC1R + MC4R agonist · Tanning + sexual response

0.25–1.0 mgPer doseDorr 1996

Phase 1Evidence levelDorr 1996

~1 hrHalf-life

SQ · Abdomen · Loading 5–7 days, then maintenance

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

Melanotan-II

PE 22-28

Primary target

MC1R (skin) + MC3R + MC4R (CNS sexual / appetite)Dorr 1996

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

Pathway

MC1R agonism → melanocyte tyrosinase → eumelanin synthesis. MC4R → autonomic sexual arousal centresDorr 1996 Simerly 2023

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

Downstream effect

Skin darkening, photo-protection, increased sexual desire / spontaneous erectionDorr 1996

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?

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

Origin

Cyclic 7-AA modified α-MSH analog; designed at University of ArizonaDorr 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

Melanotan-II

PE 22-28

Loading phase

0.25–0.5 mg/day SQ × 5–7 daysDorr 1996

Builds up to visible tan.

—

Maintenance

0.5–1.0 mg 1–2×/week

After visible tan develops; supports with UV exposure.

—

Frequency

Daily during loading; 1–2× per week maintenance

Once daily

Sustained antidepressant effect over 7+ days.

Lower / starter dose

0.1 mg / day

Conservative starter — assess tolerability for nausea.

—

Evidence basis

Phase 1 + anecdotalDorr 1996

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

Duration

8–12 weeks per cycle

—

Reconstitution

Bacteriostatic water; protect from light

—

Timing

Evening preferred (24h tan-development cycle)

—

Half-life

~1 hour plasma; effects on melanocytes persist days

—

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

Melanotan-II

PE 22-28

Nausea

Common, especially loading phase

—

Flushing

Common transient

—

Spontaneous erection

Common in men — MC4R cross-effectDorr 1996

—

Increased mole / freckle pigmentation

Existing moles darken; new lesions possible

—

Melanoma risk

Theoretical concern — increased melanocyte activity; CAUTION in melanoma history

—

Appetite suppression

MC4R-mediated; mild

—

Pregnancy / OB

Contraindicated

—

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

Melanotan-II

·History of melanoma or atypical mole syndrome
·Pregnancy / breastfeeding
·Active uncontrolled hypertension

PE 22-28

·Human use — no clinical safety data available

Relative Contraindications

Melanotan-II

·Significant freckling / dysplastic nevus
·Personal or family melanoma history

PE 22-28

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

05Administration Protocol

Parameter

Melanotan-II

PE 22-28

1. Reconstitution

Add 2 mL bacteriostatic water to 10 mg vial → 5 mg/mL = 500 mcg per 0.1 mL. Light-protected.

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. 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

Evening preferred. UV exposure (sunlight or tanning bed) helps develop tan.

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

4. Storage

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

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

5. Needle

29–31G insulin syringe.

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