Section 01
What it's used for
Approved for a rare light disorder
Scenesse, the approved implant form of melanotan I, reduces painful skin reactions to light and allows more sun exposure in people living with erythropoietic protoporphyria (EPP), a rare inherited blood disorder.
▸Clinical wording
Scenesse implant reduces phototoxicity episodes and allows increased sun exposure in EPP patients.
Sun-damage prevention research
Melanotan I is being studied as a way to prevent UV-related skin damage, and researchers are exploring whether boosting melanin this way could also help prevent skin cancer, though this remains a research question.
▸Clinical wording
Studied for prevention of UV-induced skin damage and potentially skin cancer prevention through melanin-based photoprotection.
Combined with UVB for vitiligo
Researchers combining afamelanotide (melanotan I) with narrow-band UVB light therapy have observed enhanced skin repigmentation in vitiligo, a condition where patches of skin lose their natural color over time.
▸Clinical wording
Research combining afamelanotide with narrow-band UVB therapy shows enhanced repigmentation.
Section 02
Mechanism of Action
How the pigment switch is thrown
- Frozen-sample imaging shows the peptide sitting in a U-shaped pocket of the pigment-cell receptor.
- One of its side chains pushes a molecular toggle that opens the receptor's inner signalling face.
- A messenger cascade then turns on a master gene switch for the pigment-making enzymes.
▸Clinical wording
MC1R engagement and the Gs-cAMP-PKA-CREB-MITF cascade
Melanotan I (afamelanotide) is [Nle4, D-Phe7]-alpha-MSH. Cryo-EM structures of the human MC1R-Gs complex bound to afamelanotide place the ligand in a U-shaped orthosteric pocket, with the conserved His-Phe-Arg-Trp motif making the principal contacts; insertion of Phe7 shifts F257(6.51) and F280(7.35) against the toggle-switch residue W254(6.48) and opens the Gs interface (Ma 2021). In melanocytes the downstream chain described in pharmacology reviews runs from Gs to adenylyl cyclase to cAMP, PKA phosphorylation of CREB, and CREB-driven induction of MITF, which transcribes tyrosinase and the tyrosinase-related proteins (Mun 2023).
Calcium as a required helper
- A calcium ion sits in the receptor pocket, held by both the receptor and the peptide.
- Adding calcium in the dish shifted the response about tenfold for this peptide and far more for the natural hormone.
- The peptide covers more of the receptor surface than a partial activator and switches it on fully.
▸Clinical wording
Calcium-dependent recognition and full-agonist efficacy
The same structural work identifies a calcium ion in the MC1R pocket coordinated by E94(2.60), D117(3.25) and D121(3.29) together with the ligand backbone; adding 0.5 mM Ca2+ shifted cAMP dose-response curves about 10-fold for afamelanotide and roughly 500-fold for alpha-MSH, so calcium behaves as a co-factor for melanocortin recognition rather than a bystander. Afamelanotide buries about 1986 square angstroms of receptor interface and acts as a full agonist, against about 1790 for the partial agonist SHU9119. The structures also revealed a Gbeta contact with helix 8 whose mutation weakens Gs coupling (Ma 2021).
Two swaps that resist breakdown
- Two building blocks were swapped so blood enzymes could not chop the molecule apart.
- It kept nearly all activity after three days in serum and let go of the receptor more slowly.
- In frog-skin and melanoma-cell assays it was many times more potent than the natural hormone.
- It is not selective: it activates all four melanocortin receptors at very low concentrations.
▸Clinical wording
Nle4 and D-Phe7 substitutions and melanocortin receptor breadth
The two substitutions were introduced to resist proteolysis. [Nle4, D-Phe7]-alpha-MSH resisted degradation by serum enzymes, produced prolonged skin darkening in frog-skin bioassay, and was 26 times as potent as alpha-MSH in the melanoma adenylate cyclase assay (Sawyer 1980). A melanocortin tool-compound review reports retention of nearly all activity after 72 hours in serum and slower dissociation from human MC1R than alpha-MSH (0.08 versus 0.17 per hour), and classes NDP-MSH as a pan-agonist with nanomolar to sub-nanomolar EC50 at MC1R, MC3R, MC4R and MC5R rather than an MC1R-selective ligand (Weirath 2024).
Dark pigment as a light filter
- One enzyme sets the pace of pigment making, and two helpers steer it toward the dark type.
- Dark pigment absorbs ultraviolet light and mops up reactive molecules; the reddish type does the opposite.
- In two randomised placebo-controlled trials in a rare light-sensitivity disease, implants extended pain-free sun exposure.
- The US trial reported a median of 69.4 hours against 40.8 on placebo over six months.
▸Clinical wording
Eumelanin output and ultraviolet screening
MITF targets make tyrosinase rate-limiting for melanin synthesis, with TYRP1 and TYRP2 required for the eumelanin branch. Eumelanin absorbs and scatters ultraviolet light and scavenges reactive oxygen species, whereas pheomelanin is comparatively pro-oxidant and depletes glutathione and NADPH, so the balance between them sets how damaging a given UV dose is (Swope 2018; Mun 2023). In two randomised placebo-controlled trials in erythropoietic protoporphyria, 16 mg afamelanotide implants were followed by longer pain-free direct sun exposure than placebo, a median of 69.4 versus 40.8 hours over six months in the US study (Langendonk 2015).
Repair crews beyond the tanning
- The same receptor signal recruits repair machinery to spots of light damage in the cell's DNA.
- Stimulated pigment cells raise several antioxidant and DNA-repair enzymes in culture.
- Pretreatment with the natural hormone cut ultraviolet-driven damage markers, and only through this receptor.
- In injected volunteers pigment rose in everyone, sunburn cells halved and DNA damage marks fell 59%.
▸Clinical wording
DNA repair and antioxidant responses downstream of MC1R
Beyond pigment, cAMP signalling from MC1R has been tied to nucleotide excision repair: PKA phosphorylates ATR at Ser435, which drives XPA recruitment to sites of nuclear photodamage (Cassidy 2015). Melanocortin-stimulated melanocytes show higher catalase, heme oxygenase-1, GSTPi and PRX1 and induction of the repair enzymes OGG1 and APE-1/Ref-1 (Swope 2018), and alpha-MSH pretreatment lowered UV-induced hydrogen peroxide and 8-oxodG in an MC1R-dependent manner (Song 2009). In volunteers injected with the analogue, melanin density rose in every treated subject, epidermal sunburn cells fell by more than half and basal-layer thymine dimers by 59% (Barnetson 2006).
Section 03
Biological Pathways
- MC1R/Gs/cAMP/CREB/MITF CascadeAfamelanotide binds the MC1R orthosteric pocket via its His-Phe-Arg-Trp motif, activating Gs to raise cAMP; PKA phosphorylates CREB, inducing MITF, which transcribes tyrosinase and the tyrosinase-related proteins.
- Calcium-Dependent Receptor BindingA calcium ion coordinated in the MC1R pocket acts as a co-factor for melanocortin recognition, shifting cAMP dose-response about 10-fold for afamelanotide and 500-fold for alpha-MSH, with full agonist activity.
- Pan-Melanocortin EngagementThe Nle4 and D-Phe7 substitutions resist serum proteolysis, extending activity beyond 72 hours and slowing MC1R dissociation versus alpha-MSH, while also activating MC3R, MC4R and MC5R, not just MC1R-selectively.
- Eumelanin PhotoprotectionMITF-driven tyrosinase, TRP-1, and TRP-2 output favors eumelanin, which absorbs UV and scavenges reactive oxygen species over pro-oxidant pheomelanin, extending pain-free sun exposure in porphyria trials.
- DNA Repair & Antioxidant ResponseMC1R cAMP signaling drives PKA phosphorylation of ATR and XPA recruitment for excision repair, raises catalase, heme oxygenase-1, and OGG1/APE-1 activity, lowering UV sunburn cells and thymine dimers in volunteers.
Section 04
Dosage Information
Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2| Route / system | Context | Range studied | Limitation |
|---|---|---|---|
| Subcutaneous implant | FDA/EMA label (SCENESSE), a rare sunlight disease | One 16 mg implant under the skin at the hip every 2 months, placed by a trained clinician; measurable in blood for about four days | A slow-release rod, not a shot: the 16 mg does not convert into a per-injection dose. The label also orders a full skin check twice a year. |
| Subcutaneous injection — research doses | 1997 tanning and blood-level study, 3 men | 0.08–0.21 mg/kg a shot — about 6–19 mg for a 70–90 kg adult; ten doses over two weeks, five days a week; tan showed three weeks later | Three volunteers, no control group, a half-life of one to two hours — nothing like the implant's steady release. Not the product or the route later approved. |
| Subcutaneous — self-administration | Grey-market vials labelled Melanotan-1 | 500–1000 µg a day for one to two weeks, then 500–1000 µg once or twice weekly — roughly 6–14 µg/kg for a 70–90 kg adult | Circulating practice, not a finding. These vials are not the licensed implant, and case reports link unregulated use to darkening moles and new abnormal ones. |
Results
Syringe Fill Level (100u syringe)
Set positive values for: Recommended dose per kg.
Research Use Only. This information is for educational and research purposes only. Not intended for medical advice or self-medication.
Section 05
Protocols
No protocols featuring this peptide yet. Browse All Protocols
Section 06
Stability & Storage
Storing the product
Melanotan I is available as the approved subcutaneous implant Scenesse (16 mg), which provides sustained release for about 60 days after insertion, and as a research-grade powder kept at -20°C. The Nle/D-Phe substitutions make it more stable than native α-MSH.
After opening
Once the powder container is opened, contents are kept sealed, cold, and away from moisture to limit degradation; overall stability after opening depends on the batch and how it is handled rather than a fixed timeframe.
Section 07
Side Effects & Precautions
Nausea (most common), skin darkening (expected/desired), headache, nasopharyngitis. Implant site reactions. Mole darkening — dermatological monitoring recommended.
Section 08
Regulatory Status
FDA / United States
Approved (2019), narrow indication
Approved on 8 October 2019 as a 16 mg subcutaneous implant to increase pain-free light exposure in adults with a history of phototoxic reactions from erythropoietic protoporphyria (EPP) — not for tanning or cosmetic use.
European Union
Approved (2014); dosing widened in 2025
EMA approved Scenesse for the same EPP indication in 2014; in September 2025 the CHMP removed the previous cap of four implants a year, clearing year-round dosing (one implant every two months) and aligning the EU label with the US.
Australia
Approved (2020)
The TGA registered Scenesse in October 2020 for the same EPP indication after a nine-month dossier review — the first approved EPP treatment available in the country.
WADA
Not on the Prohibited List
Because afamelanotide is an approved medicine, it does not fall under WADA's S0 catch-all for non-approved substances, and it is not separately named under S2 either.
Unapproved online "Melanotan"
A different, unregulated market
Injectable tanning products sold online as "Melanotan" are not the approved Scenesse implant; the FDA has issued warning letters over such sales, including to Melanocorp Inc. in 2007, for lacking any evidence of safety or effectiveness.
Approval here covers one implant, one indication, in three jurisdictions — it says nothing about unrelated products marketed for tanning under a similar name. Regulatory status differs by country and changes over time; check the current label and indication before relying on any of this.
Section 09
Research Studies
- [1]Structural mechanism of calcium-mediated hormone recognition and Gβ interaction by the human melanocortin-1 receptorMa S, Chen Y, Dai A, Yin W, Guo J, Yang D, Zhou F, Jiang Y, Wang MW, Xu HE. · Cell Research · 2021
- [2]Melanocortin 1 Receptor (MC1R): Pharmacological and Therapeutic AspectsMun Y, Kim W, Shin D. · International Journal of Molecular Sciences · 2023
- [3]4-Norleucine, 7-D-phenylalanine-alpha-melanocyte-stimulating hormone: a highly potent alpha-melanotropin with ultralong biological activitySawyer TK, Sanfilippo PJ, Hruby VJ, Engel MH, Heward CB, Burnett JB, Hadley ME. · Proceedings of the National Academy of Sciences · 1980
- [4]Recommended Tool Compounds for the Melanocortin Receptor (MCR) G Protein-Coupled Receptors (GPCRs)Weirath NA, Haskell-Luevano C. · ACS Pharmacology & Translational Science · 2024
- [5]MC1R: Front and Center in the Bright Side of Dark Eumelanin and DNA RepairSwope VB, Abdel-Malek ZA. · International Journal of Molecular Sciences · 2018
- [6]Beyond Red Hair and Sunburns: Uncovering the Molecular Mechanisms of MC1R Signaling and Repair of UV-Induced DNA DamageCassidy PB, Abdel-Malek ZA, Leachman SA. · Journal of Investigative Dermatology · 2015
- [7]α-MSH activates immediate defense responses to UV-induced oxidative stress in human melanocytesSong X, Mosby N, Yang J, Xu A, Abdel-Malek Z, Kadekaro AL. · Pigment Cell & Melanoma Research · 2009
- [8][Nle4-D-Phe7]-α-Melanocyte-Stimulating Hormone Significantly Increased Pigmentation and Decreased UV Damage in Fair-Skinned Caucasian VolunteersBarnetson RStC, Ooi TKT, Zhuang L, Halliday GM, Reid CM, Walker PC, Humphrey SM, Kleinig MJ. · Journal of Investigative Dermatology · 2006
- [9]Afamelanotide for Erythropoietic ProtoporphyriaLangendonk JG, Balwani M, Anderson KE, Bonkovsky HL, Anstey AV, Bissell DM, et al. · New England Journal of Medicine · 2015
Section 10
Frequently Asked Questions
As afamelanotide (brand name Scenesse), it's EMA-approved since 2014 for erythropoietic protoporphyria, a rare disease causing extreme UV sensitivity — it reduces phototoxic reactions and lets patients tolerate more sun exposure. It is not FDA-approved, though it holds FDA breakthrough therapy designation, and it is prescription-only where it is approved.
Clinically, afamelanotide is reported to produce minimal sexual or appetite effects compared with Melanotan II's broader impact on those systems. That sits oddly next to the receptor-binding data, though: structural studies describe the same molecule as a broad-acting agonist across multiple melanocortin receptors rather than one selective for skin pigmentation alone, so why the clinical effects differ so much isn't fully resolved by the mechanism data.
Yes — that's the basis of its approved use. It drives melanin production through the MC1R signaling pathway independent of UV light, which is why it helps patients who can't tolerate sun exposure at all. In an early study, visible tanning appeared roughly three weeks after starting a two-week injection course, with no stated UV requirement.
The approved product is a 16 mg implant placed under the skin every two months by a clinician — not a per-injection dose at all. A small 1997 study without a control group used 0.08 to 0.21 mg/kg per injection over two weeks in three men. Doses of 500 to 1,000 µg a day circulating outside any trial are unregulated self-administration, not a studied regimen.
Nausea is the most commonly reported effect, along with headache and nasopharyngitis; skin darkening is the intended effect rather than a side effect. Implant-site reactions occur with the approved product, and mole darkening is reported closely enough that dermatological monitoring is recommended for anyone using it.
Mole darkening is a documented reason dermatological monitoring is recommended with this drug, and case reports describe unregulated (non-implant) use being linked to darkening moles and new abnormal ones appearing. The sourced material doesn't report a specific melanoma-risk finding for Melanotan I the way it does for Melanotan II, but that absence reflects what has been studied, not a demonstration of safety.
The approved implant releases its dose over about 60 days once placed and doesn't need separate storage by the patient. Research-grade powder is kept at −20°C; once a container is opened, keeping it sealed, cold, and away from moisture limits degradation, though exact stability after opening depends on the specific batch.