Side-by-side · Research reference

HumaninvsMelanotan-II

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

AAnimal-StrongHUMAN-REVIEWED14/52 cited

BPhase 1HUMAN-REVIEWED9/43 cited

Humanin

Mitochondrial-Derived Peptide · Cytoprotective

24-AAPeptide lengthZhu 2022

mtDNAEncoded originZhu 2022 Shahzaib 2026

Bax/BimPrimary targetZhu 2022 Morris 2021

SQ · Experimental

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

01Mechanism of Action

Parameter

Humanin

Melanotan-II

Primary target

Intracellular: Bax, Bim, tBid (pro-apoptotic Bcl-2 family). Extracellular: FPRL1/2 G-protein-coupled receptorsZhu 2022 Lue 2021

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

Pathway

Humanin binds Bax/Bim → inhibits mitochondrial outer membrane permeabilization (MOMP) → blocks cytochrome c release → prevents caspase activation → cell survival

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

Downstream effect

Suppression of apoptosis, mitochondrial stabilization, reduced oxidative stress, preservation of germ cells and neurons under stressZhu 2022 Lue 2021 Velentza 2024

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

Feedback intact?

Not applicable — peptide acts as anti-apoptotic signal, not hormonal axis

—

Origin

Encoded by short open reading frame in mitochondrial 16S rRNA gene (MTRNR2). 24-28 amino acids. 13 homologous variants (MTRNR2L1-L13) identified.Zhu 2022 Shahzaib 2026

Cyclic 7-AA modified α-MSH analog; designed at University of ArizonaDorr 1996

Antibody development

Not reported in animal models

—

02Dosage Protocols

Parameter

Humanin

Melanotan-II

Standard experimental dose (HNG)

4 mg/kg IP (rat)

Most common dose in rodent models.

—

Ex vivo bone culture

1 µg/mL

Protective against venetoclax-induced bone growth retardation.

—

Frequency

Daily (IP)

Daily during loading; 1–2× per week maintenance

Duration

8–12 weeks in animal studies

8–12 weeks per cycle

Evidence basis

Animal models (rat, mouse)Huang 2025 El 2022 Velentza 2024

Phase 1 + anecdotalDorr 1996

Human data

None — no clinical trials reported

—

Analog (HNG)

Gly[14]-humanin — more potent variant

Substitution at position 14 enhances cytoprotective activity.

—

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.

Lower / starter dose

—

0.1 mg / day

Conservative starter — assess tolerability for nausea.

Reconstitution

—

Bacteriostatic water; protect from light

Timing

—

Evening preferred (24h tan-development cycle)

Half-life

—

~1 hour plasma; effects on melanocytes persist days

03Metabolic / Fat Loss Evidence

Parameter

Humanin

Melanotan-II

Direct fat loss evidence

None

—

Mechanism overlap

Mitochondrial health may indirectly influence metabolic efficiency, but no quantified effect

—

04Side Effects & Safety

Parameter

Humanin

Melanotan-II

Animal model safety

Well-tolerated in rat and mouse studies at 4 mg/kg for 8–12 weeks

—

Human safety data

None — no clinical trials

—

Theoretical fibrillation risk

Induces amyloid-like fibrillation of Bax/BID. Long-term sequelae unknown.

—

Injection site reaction

Not reported in animal studies (IP route)

—

Reproductive safety

Protective in POI model (cyclophosphamide-induced), no adverse effects on fertility notedHuang 2025

—

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

Absolute Contraindications

Humanin

·Unknown — no human data

Melanotan-II

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

Relative Contraindications

Humanin

·Active malignancy (theoretical risk of anti-apoptotic effect on tumour cells)

Melanotan-II

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

05Administration Protocol

Parameter

Humanin

Melanotan-II

1. Route (experimental)

Intraperitoneal (IP) in animal models. Subcutaneous route untested. No human protocols exist.

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

2. Reconstitution

Synthetic peptide reconstituted in sterile saline or PBS. No commercial formulation available.

SQ — abdomen. Rotate sites.

3. Timing

Daily administration in animal studies. Optimal timing not characterized.

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

4. Storage

Lyophilised powder: -20 °C. Reconstituted: 4 °C, use within 7 days. Avoid freeze-thaw cycles.

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

5. Human use

No FDA approval, no IND, no clinical trials. Experimental research tool only.

29–31G insulin syringe.

06Stack Synergy

Humanin

+ MOTS-c

Multi-pathway

View MOTS-c →

Both are mitochondrial-derived peptides. MOTS-c enhances metabolic efficiency and insulin sensitivity via AMPK activation, while humanin prevents mitochondrial apoptosis. Combined, they address mitochondrial function (MOTS-c) and survival signaling (humanin), supporting cellular resilience under metabolic and oxidative stress.

Humanin: 4 mg/kg IP · daily (animal model)
MOTS-c: 5 mg/kg IP · daily (animal model)
Frequency: Once daily
Primary benefit: Mitochondrial health, metabolic efficiency, anti-apoptotic signaling

Melanotan-II

— no documented stacks