MELANOTAN 1
Melanotan I (afamelanotide) is a synthetic tridecapeptide analog of alpha-MSH with selective MC1R agonist activity, FDA-approved as Scenesse for erythropoietic protoporphyria (EPP). It stimulates eumelanin production for photoprotection without requiring UV exposure.
Melanotan I, known by its generic name afamelanotide and brand name Scenesse, is a synthetic tridecapeptide analog of alpha-melanocyte stimulating hormone (alpha-MSH). It is a selective MC1R agonist that stimulates eumelanin production in melanocytes, providing photoprotection independent of UV exposure.
Overview
Afamelanotide was developed at the University of Arizona by Victor Hruby, Mac Hadley, and Robert Dorr in the 1980s as part of a research program investigating melanocortin analogs for sunless tanning. The peptide, designated [Nle4, D-Phe7]-alpha-MSH, incorporates two key amino acid substitutions compared to native alpha-MSH: norleucine at position 4 (replacing methionine) and D-phenylalanine at position 7 (replacing L-phenylalanine). These modifications confer significantly greater metabolic stability by resisting enzymatic degradation from aminopeptidases and serum proteases, extending biological activity from minutes to hours.
Clinuvel Pharmaceuticals developed afamelanotide as a controlled-release subcutaneous implant for clinical use. The 16 mg implant releases the peptide over approximately 10 days, providing sustained MC1R stimulation without the need for repeated injections. This formulation proved critical for achieving the prolonged photoprotection required in EPP patients.
Mechanism of Action
Afamelanotide acts as a potent and selective agonist at the melanocortin 1 receptor (MC1R), the primary melanocortin receptor expressed on melanocytes. Its mechanism of action involves:
- MC1R activation: Binding to MC1R on epidermal melanocytes triggers Gs-coupled adenylyl cyclase activation, increasing intracellular cAMP levels (Mountjoy et al., 1992)
- MITF induction: cAMP-mediated PKA activation phosphorylates CREB, driving transcription of microphthalmic-associated transcription factor (MITF), the master regulator of melanocyte differentiation and melanogenesis
- Eumelanin switching: MITF upregulates tyrosinase, TYRP1, and DCT, shifting melanin synthesis from pheomelanin (red/yellow, phototoxic) toward eumelanin (brown/black, photoprotective) (Abdel-Malek et al., 2006)
- DNA repair enhancement: MC1R signaling also promotes nucleotide excision repair of UV-induced cyclobutane pyrimidine dimers (CPDs), providing photoprotection beyond pigmentation (Swope et al., 2014)
Unlike Melanotan II, afamelanotide exhibits high selectivity for MC1R over MC3R, MC4R, and MC5R, which minimizes off-target effects on appetite, sexual function, and cardiovascular regulation.
Reconstitution Calculator
MELANOTAN 1
Melanotan I, known by its generic name afamelanotide and brand name Scenesse, is
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Research
Polymorphous Light Eruption
Haylett et al. (2017) investigated afamelanotide in patients with severe polymorphous light eruption (PMLE), a common photodermatosis. In a Phase II study, afamelanotide implants reduced the severity of PMLE provocation responses and increased the minimal erythema dose, suggesting potential utility in photosensitivity disorders beyond EPP.
Erythropoietic Protoporphyria (EPP)
EPP is a rare inherited disorder caused by deficiency of ferrochelatase, leading to accumulation of free protoporphyrin IX in erythrocytes and skin. Exposure to visible light triggers severe phototoxic reactions with burning pain, erythema, and edema. Langendonk et al. (2015) conducted a pivotal Phase III randomized, double-blind, placebo-controlled trial in 94 EPP patients across European centers. Patients receiving the 16 mg afamelanotide implant every 60 days showed significantly increased duration of direct sunlight exposure without pain (median 69.4 hours vs. 40.8 hours for placebo, p=0.005) over a 180-day treatment period.
Skin Cancer Prevention
Research by Abdel-Malek et al. (2006) demonstrated that MC1R agonism with afamelanotide reduces UV-induced DNA damage in melanocytes and enhances DNA repair capacity. The dual mechanism of increased eumelanin (UV absorption) and enhanced nucleotide excision repair positions afamelanotide as a potential chemopreventive agent for melanoma and non-melanoma skin cancers, particularly in high-risk populations with MC1R variants (red hair phenotype).
Photoprotection in Fair-Skinned Populations
Barnetson et al. (2006) demonstrated in a randomized controlled trial that afamelanotide (0.16 mg/kg subcutaneous injection) combined with low-dose UV exposure in Fitzpatrick skin type I-II subjects produced significantly greater melanization than UV alone. Eumelanin content increased approximately 2-fold compared to UV-only controls. The study established that afamelanotide-induced melanization is predominantly eumelanin-based, conferring genuine UV-absorbing photoprotection rather than cosmetic darkening alone.
Vitiligo
Lim et al. (2015) conducted a pilot study combining afamelanotide implants with narrow-band UVB phototherapy in vitiligo patients. The combination produced faster and more extensive repigmentation compared to NB-UVB alone, with superior results in darker skin types. The melanocortin-stimulated melanocyte proliferation and migration from hair follicle reservoirs contributed to repigmentation in depigmented patches.
Safety Profile
The safety profile of afamelanotide has been extensively characterized through clinical trials and post-marketing surveillance in EPP patients:
- Skin darkening: Expected pharmacological effect; diffuse hyperpigmentation occurs within days of implant insertion and gradually fades over 1-2 months. Darkening of pre-existing nevi has been reported and requires dermatological monitoring
- Implant site reactions: Mild reactions (discoloration, pain, induration) reported in ~20% of patients; generally self-resolving within days
- Nausea: Reported in ~5% of patients, significantly less frequent than with non-selective melanocortin agonists (MT-II), consistent with MC1R selectivity and absence of MC4R-mediated emesis
- Headache: Reported in ~10% of patients
- Melanoma monitoring: No melanoma cases attributable to afamelanotide in clinical trials or post-marketing surveillance through 2025. Dermatological screening with dermoscopy is recommended before and during treatment
- Contraindications: Active melanoma, history of melanoma, severe hepatic impairment
Pharmacokinetic Profile
MELANOTAN 1 — Pharmacokinetic Curve
Subcutaneous biodegradable implant (16 mg)Quick Start
- Typical Dose
- 0.5-1mg subcutaneously daily.
- Route
- Subcutaneous biodegradable implant (16 mg)
Molecular Structure
- Weight
- 1646.9 Da
- CAS
- 75921-69-6
Research Indications
Skin Health
Stimulates melanin production for deeper, longer-lasting tan with reduced UV exposure
Increased melanin density reduces UV damage and sunburn susceptibility
Promotes uniform melanin distribution for consistent skin tone
Anti-Aging
Enhanced melanin acts as natural sunscreen, reducing photoaging
Eumelanin stimulation provides cellular antioxidant protection
Achieves tanning with less UV, minimizing cumulative damage
Research Protocols
subcutaneous Injection
Subcutaneous injection is the standard route for Melanotan I administration.
| Goal | Dose | Frequency | Duration |
|---|---|---|---|
| Initial Tanning (Light Skin) | 0.25mg | 2x daily | —(Route: Subcutaneous injection) |
| Maintenance Tanning | 0.5mg | 1x daily | —(Route: Subcutaneous injection) |
| Enhanced Pigmentation | 0.5mg | 2x daily | —(Route: Subcutaneous injection) |
| Photoprotection Only | 0.25mg | 1x daily | —(Route: Subcutaneous injection) |
Reconstitution Guide (mg vial + mL BAC water)
- Allow peptide vial and BAC water to reach room temperature
- Swab tops of both vials with alcohol and allow to dry
- Draw 2ml of bacteriostatic water into syringe
- Inject BAC water slowly down side of peptide vial to avoid foaming
- Gently swirl (do not shake) until powder completely dissolves
- Solution should be clear and colorless when properly reconstituted
- Draw desired dose using a fresh insulin syringe
- Store reconstituted solution refrigerated at 2–8°C for up to 4 weeks
intranasal Injection
Intranasal delivery provides lower bioavailability (~20-30%) but convenient needle-free administration.
| Goal | Dose | Frequency | Duration |
|---|---|---|---|
| Nasal Administration (alternative) | 0.5mg | 2–3x daily | —(Route: Intranasal spray) |
Interactions
Peptide Interactions
Both target melanocortin receptors; overlapping mechanisms — combining not advised due to additive effects. MT-I has better MC1R selectivity.
Natural carotenoid adds photoprotection; no known adverse interactions.
What to Expect
What to Expect
Possible mild nausea, facial flushing, reduced appetite
Initial skin darkening; increased pigmentation of moles and freckles
Noticeable tanning with minimal UV exposure; enhanced tanning response
Peak tanning effects; maintained pigmentation with reduced injection frequency
Safety Profile
Common Side Effects
- Nausea:: Common, especially initially.
- Facial Flushing:: Temporary redness after injection.
- Mole Darkening:: Existing moles may darken.
- Safer Profile:: Fewer side effects than MT-2.
Discontinue If
- Severe nausea, vomiting, or GI distress lasting more than 24 hours
- Rapid or concerning changes in moles, freckles, or pigmented lesions
- Injection site infection: persistent redness, swelling, warmth, or discharge
- Unusual skin reactions: rashes, hives, or severe itching
- Signs of allergic reaction: breathing difficulty, facial swelling, severe dizziness
Quality Indicators
What to look for
- Third-party HPLC purity testing confirming >98% purity
- Lyophilized powder stable at room temperature during shipping; refrigerate on arrival
- Properly reconstituted solution is clear and colorless, particle-free
- High-quality product causes only mild nausea and flushing
Caution
- Nasal sprays or 'tanning injections' marketed by some vendors — stick to research-grade lyophilized powder
- Nasal route provides only ~20–30% absorption vs. injection; milder effects expected
- Nasal solutions degrade faster — prepare smaller batches more frequently
Red flags
- Pre-mixed liquid Melanotan I — peptides degrade rapidly in solution without proper preservation
Frequently Asked Questions
References (21)
- [18]Mountjoy KG, Robbins LS, Mortrud MT, Cone RD The cloning of a family of genes that encode the melanocortin receptors Science (1992)
- [1]In vitro evaluation of Poly(d,l-lactide-co-glycolide) polymer-based implants containing the α-melanocyte stimulating hormone analog, Melanotan-I
→ Study examined release patterns of Melanotan-I from biodegradable PLGA implants, observing three-phase release.
- [2]An unhealthy glow? A review of melanotan use and associated clinical outcomes
→ Literature review on Melanotan I and II effects, identifying minor and serious adverse effects including toxidrome and melanoma.
- [4]In vitro characterization and in vivo release profile of a poly (d,l-lactide-co-glycolide)-based implant delivery system for the α-MSH analog, Melanotan-I
→ Researchers developed biodegradable copolymer implants for sustained Melanotan-I delivery, demonstrating steady release over one month.
- [5]Effect of MELANOTAN®, [Nle4, D-Phe7]-α-MSH, on melanin synthesis in humans with MC1R variant alleles
→ Study found MELANOTAN® significantly increased melanin, especially in those with MC1R genetic variants.
- [6]
- [7]
- [10]
- [11]
- [3]Controlled-Release Delivery System for the α-MSH Analog Melanotan-I Using Poloxamer 407
→ Researchers developed controlled-release formulations using poloxamer 407 with additives for sustained delivery.
- [8]
- [9]
- [14]Lim HW, Grimes PE, Agbai O, et al Afamelanotide and narrowband UV-B phototherapy for the treatment of vitiligo JAMA Dermatol (2015)
- [12]Langendonk JG, Balwani M, Anderson KE, et al Afamelanotide for erythropoietic protoporphyria N Engl J Med (2015)
- [13]Swope VB, Jameson JA, McFarland KL, et al Defining MC1R regulation in human melanocytes by its agonist alpha-melanocortin and antagonists agouti signaling protein and beta-defensin 3 J Invest Dermatol (2014)
- [17]Barnetson RS, Ooi TK, Zhuang L, et al Nle4-D-Phe7-alpha-melanocyte-stimulating hormone significantly increased pigmentation and decreased UV damage in fair-skinned Caucasian volunteers J Invest Dermatol (2006)
- [20]Biolcati et al — Long-term efficacy of afamelanotide for erythropoietic protoporphyria Br J Dermatol (2020)
- [15]Haylett AK, Sherwood V, Sheridan M, et al An open-label pilot study of afamelanotide for prevention of polymorphous light eruption Br J Dermatol (2017)
- [16]Abdel-Malek ZA, Kadekaro AL, Kavanagh RJ, et al Melanocortin 1 receptor and the protective effect of alpha-melanocyte-stimulating hormone Arch Biochem Biophys (2006)
- [19]Swope et al — MC1R signaling and the DNA damage response in human melanocytes Pigment Cell Melanoma Res (2020)
- [21]Minder et al — Real-world experience with afamelanotide in erythropoietic protoporphyria Orphanet J Rare Dis (2022)
Mechano Growth Factor (MGF)
Mechano Growth Factor (MGF) is the C-terminal splice variant of IGF-1 (IGF-1Ec in humans) produced in response to mechanical loading, activating muscle satellite stem cells for local tissue repair with distinct signaling from systemic IGF-1.
Melanotan 2
Melanotan 2 (MT-2) is a synthetic cyclic heptapeptide analog of alpha-MSH that acts as a non-selective melanocortin receptor agonist, studied for effects on skin pigmentation, sexual function, appetite regulation, and metabolic signaling.