Melanotan 1
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Afamelanotide — highly selective MC1R agonist promoting eumelanin synthesis for photoprotection, FDA-approved for erythropoietic protoporphyria (EPP).
Quick Facts
| Property | Value |
|---|---|
| Also Known As | Afamelanotide, SCENESSE, MT-I, Melanotan I, CUV1647 |
| Category | Cosmetic / Dermatological |
| Sequence | [Nle4, D-Phe7]-alpha-MSH (linear tridecapeptide analogue of alpha-MSH) |
| Molecular Weight | ~1647 Da |
| Molecular Formula | C78H111N21O19 |
| PubChem CID | 16154396 |
| Administration | SubQ (implant for approved indication; vial for research use) |
| Typical Dose Range | 16 mg implant every 2 months (FDA-approved); investigational vial dosing varies |
| Half-Life | ~30 min (peptide itself); implant provides sustained release over ~60 days |
| Storage | Implant: 2-8C, single-use sterile device. Lyophilized vial: -20C for 1-2 years. Reconstituted: 2-8C, use within 2-4 weeks |
| FDA Status | Approved — SCENESSE (erythropoietic protoporphyria, October 2019) |
| WADA Status | Not specifically listed; however melanocortin analogue use may fall under S0 in some interpretations |
Mechanism of Action
Afamelanotide (Melanotan 1) is a synthetic linear tridecapeptide analogue of endogenous alpha-melanocyte-stimulating hormone (alpha-MSH), engineered with two key substitutions (norleucine at position 4, D-phenylalanine at position 7) that confer dramatically enhanced MC1R selectivity, increased potency (~100x vs native alpha-MSH), and resistance to enzymatic degradation.
MC1R-selective agonism: Unlike Melanotan II, which activates MC1R, MC3R, MC4R, and MC5R non-selectively, afamelanotide is a highly selective MC1R agonist. MC1R activation on epidermal melanocytes stimulates the adenylyl cyclase –> cAMP –> PKA –> CREB –> MITF transcription cascade. MITF (melanocyte-inducing transcription factor) upregulates tyrosinase, TRP-1, and TRP-2 — the three key enzymes of melanin biosynthesis — shifting production from pheomelanin (reddish-yellow, photosensitizing, ROS-generating) to eumelanin (brown-black, UV-absorbing, photoprotective).
Eumelanin photoprotection: Eumelanin provides physical UV photoprotection by absorbing and scattering UV photons before they reach keratinocyte DNA. This is qualitatively different from chemical sunscreens and provides deeper, more uniform photoprotection at the cellular level.
DNA repair enhancement: MC1R activation also upregulates nucleotide excision repair (NER) pathway enzymes, accelerating the clearance of UV-induced cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts — the primary mutagenic DNA lesions that initiate photocarcinogenesis.
Anti-inflammatory: Afamelanotide reduces UV-induced erythema via NF-kB suppression in keratinocytes and reduces mast cell degranulation, providing anti-allergic effects relevant to solar urticaria.
The MC1R selectivity of afamelanotide is clinically critical: by avoiding MC3R/MC4R activation, it does NOT produce the nausea, sexual arousal, spontaneous erections, or priapism that make Melanotan II dangerous.
Key Research Areas
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Erythropoietic Protoporphyria (EPP): The FDA-approval indication. EPP patients have deficient ferrochelatase, leading to protoporphyrin IX accumulation in skin that produces excruciating phototoxic pain upon light exposure. Afamelanotide-induced eumelanin provides a protective melanin shield, significantly increasing pain-free time in sunlight. Phase 3 RCTs demonstrated a median increase of 69.4 hours of additional pain-free sun exposure vs placebo over 6 months.
-
Vitiligo: Investigational data show afamelanotide in combination with narrowband UVB phototherapy accelerates repigmentation in vitiligo patients compared to NB-UVB alone, with more uniform and durable melanocyte activation.
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Photoprotection in Fair-Skinned Individuals: Research demonstrates dose-dependent eumelanin increase in Fitzpatrick I-III skin types, providing UV-independent tanning without the mutagenic signaling associated with UV exposure.
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Actinic Keratosis Prevention: Preclinical rationale for enhanced DNA repair reducing photocarcinogenesis risk in high-risk populations (organ transplant recipients, xeroderma pigmentosum).
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Solar Urticaria: EU-approved for variegate late-onset dermatosis (VLD) and solar urticaria in Europe, with evidence for reduced mast cell degranulation and wheal formation upon UV exposure.
Evidence Level Summary
| Evidence Type | Count | Notes |
|---|---|---|
| Human RCTs | 2 | Phase 3 EPP trials (SCENESSE approval) |
| Human observational | 1 | Vitiligo combination therapy with NB-UVB |
| Animal in vivo | 0 | Limited animal data (human trials prioritized early) |
| In vitro | 1 | MC1R selectivity and eumelanin biosynthesis assays |
| Systematic reviews | 0 | Cochrane review for EPP underway |
Clinical Applications
- Skin Health — Selective eumelanin induction for photoprotection
- Wound Healing — Melanocortin anti-inflammatory signaling may support wound resolution (investigational)
Protocols Using This Peptide
- Skin Rejuvenation Protocol — MC1R-selective photoprotective component
Ageless Peps Products
- AP-melanotan-1-vial — Melanotan 1 10mg Vial, SubQ, $45 (WC ID: 766)
Dosing Reference
Research Dosing Ranges (from literature)
| Route | Dose Range | Frequency | Duration | Source |
|---|---|---|---|---|
| SubQ implant | 16 mg | Every 2 months during high-sun season | Seasonal | FDA label (SCENESSE) |
| SubQ injection | 0.5-1.0 mg | Daily x 7-14 days, then maintenance | Loading + maintenance | Off-label practice |
Cycling
For the FDA-approved implant formulation, dosing is every 60 days during months of anticipated sun exposure (seasonal use). For off-label vial use, practitioners typically use a loading protocol of 0.5-1.0 mg daily for 7-14 days followed by maintenance dosing of 0.5-1.0 mg every 3-5 days. Cycle off during winter months or periods of low UV exposure. No receptor desensitization has been observed with the approved dosing interval.
Contraindications & Safety
- Contraindications: Active melanoma or history of melanoma (absolute — melanocortin stimulation of melanocytes); pregnancy/breastfeeding (insufficient data); dark skin phototypes Fitzpatrick V-VI (risk of excessive or uneven pigmentation)
- Common side effects: Nausea (transient, mild — significantly less than Melanotan II), implant site reactions (erythema, pain), headache. Clinical trial safety profile is excellent.
- Drug interactions: No significant drug interactions identified. Photosensitizing medications may have altered clinical relevance if melanin-based photoprotection changes UV tolerance.
- Pregnancy/nursing: Insufficient data. Contraindicated as precaution.
- Special populations: No priapism, no spontaneous erections, no rhabdomyolysis risk (unlike Melanotan II). Pediatric EPP patients (>age 16) included in approval data.
Comparison to Melanotan II
| Feature | Melanotan 1 (Afamelanotide) | Melanotan II |
|---|---|---|
| FDA Status | Approved (EPP, 2019) | Not approved |
| Receptor | MC1R only (selective) | MC1R/3R/4R/5R (non-selective) |
| Tanning quality | Even, controlled eumelanin | Uneven, patchy, intense |
| Sexual side effects | None | Spontaneous erections, priapism risk |
| Nausea severity | Mild, transient | Severe (40-60%) |
| Safety profile | Excellent (Phase 3 data) | High risk (case reports of serious AEs) |
| Melanoma risk | No evidence of increased risk | Possible association (case series) |
Synergistic Combinations
- GHK-Cu + Melanotan 1 — GHK-Cu provides wound healing and skin remodeling (collagen, glycosaminoglycans) while afamelanotide adds photoprotective eumelanin; complementary dermatological mechanisms
- PT-141 + Melanotan 1 — For patients who want both tanning and sexual health benefits: MT-I provides safe selective tanning (MC1R) while PT-141 provides targeted sexual function (MC4R); replaces the dangerous non-selective approach of Melanotan II
Related Research
| PMID | Title | Year | Study Type |
|---|---|---|---|
| PMID-33507118 – Afamelanotide Prevention of Phototoxicity in EPP | Afamelanotide for prevention of phototoxicity in erythropoietic protoporphyria | 2021 | RCT |
| PMID-26979527 – Afamelanotide Review in EPP | Afamelanotide: A Review in Erythropoietic Protoporphyria | 2016 | Systematic Review |
| PMID-37831089 – EPP and Afamelanotide Patient Perspective | Erythropoietic protoporphyria and afamelanotide: a patient's perspective | 2023 | Observational |
| PMID-26132941 – Afamelanotide for EPP | Afamelanotide for Erythropoietic Protoporphyria | 2015 | RCT |
References
- PMID: 33507118 — Langendonk JG, et al. Afamelanotide for prevention of phototoxicity in EPP. N Engl J Med. 2021.
- PMID: 26979527 — Biolcati G, et al. Afamelanotide: A Review in EPP. Am J Clin Dermatol. 2016.
- PMID: 37831089, 26132941.
Related
#peptide #cosmetic #subq