What are Melanotan I and II?
Compound Spotlight
Melanotan I and Melanotan II came out of the same University of Arizona research program and share a parent hormone, but they ended up in very different places. One became an approved prescription drug for a rare light-sensitivity disorder. The other was never approved anywhere, and today appears mostly in regulatory warnings.
Quick summary
- Both are synthetic analogs of alpha-melanocyte-stimulating hormone (alpha-MSH), designed at the University of Arizona to resist enzymatic breakdown.
- Melanotan I is afamelanotide: a linear 13-amino-acid peptide, [Nle4, D-Phe7]-alpha-MSH.
- Melanotan II is a cyclic 7-residue fragment analog that binds several melanocortin receptor subtypes (MC1, MC3, MC4 and MC5 in cell-based assays).
- Afamelanotide is approved as Scenesse for erythropoietic protoporphyria: in the EU since December 2014 and in the US since October 2019.
- Melanotan II has no marketing approval. Bremelanotide (PT-141), an approved drug, differs from it by a single C-terminal group.
- Regulators including the UK MHRA have warned about unlicensed melanotan products sold online.
Where they come from
Alpha-MSH is a 13-amino-acid hormone that acts on melanocortin receptors. Researchers at the University of Arizona, including Hadley, Hruby and Dorr, set out to build analogs that were more potent, longer acting and more resistant to enzymes than the natural hormone. One of them replaced methionine at position 4 with norleucine and phenylalanine at position 7 with its D-isomer. That molecule, [Nle4, D-Phe7]-alpha-MSH, is Melanotan I, now called afamelanotide.
Melanotan II followed. It is a shortened, ring-closed analog covering positions 4 to 10 of alpha-MSH: Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH2, with a lactam bridge closing the ring. A 2006 history of the program by Hadley and Dorr describes Melanotan I as tested clinically for skin pigmentation and Melanotan II for male erectile dysfunction.
Melanocortin receptor pharmacology
There are five melanocortin receptors, MC1R through MC5R, and they do different jobs. MC1R on melanocytes is the receptor most closely tied to pigmentation. MC3R and MC4R are expressed mainly in the central nervous system, and a melanocortin agonist acting at them produced erections and activated hypothalamic neurons in rats.
Which receptors a compound reaches largely determines what it does. Afamelanotide is characterized in its US labeling as an MC1R agonist, and its approved use rests on MC1R-driven melanin production in skin. Melanotan II is different: in binding studies on cells expressing human receptors, it bound MC1, MC3, MC4 and MC5, and the cyclic lactam analogs as a class showed higher overall affinity for melanocortin receptors than the comparison peptides. That breadth explains why its observed effects in people extend well beyond pigmentation.
What was studied with Melanotan II
In a 1996 pilot phase I study of three healthy men, investigators recorded increased pigmentation in two subjects, along with nausea, fatigue and a stretching-and-yawning response. The stretching and yawning coincided with the onset of intermittent spontaneous erections over the following one to five hours.
That unplanned finding redirected the program. A 1998 double-blind, placebo-controlled crossover study in ten men with psychogenic erectile dysfunction reported erections in eight of ten men after Melanotan II, measured by RigiScan monitoring. Nausea, stretching and yawning, and reduced appetite were reported more often than with placebo.
Melanotan II itself was not taken further as a drug. Its development continued through bremelanotide (PT-141), which has the same cyclic sequence but a free carboxylic acid at the C-terminus where Melanotan II has an amide. Bremelanotide is often described as a metabolite of Melanotan II; the program histories we reviewed describe it as an analog. Our PT-141 article covers its later development and approval.
Afamelanotide and erythropoietic protoporphyria
Erythropoietic protoporphyria (EPP) is a rare inherited disorder in which light exposure causes acute phototoxic reactions and severe pain. The rationale for afamelanotide in EPP is MC1R activation and the resulting increase in skin melanin.
Two multicenter, randomized, placebo-controlled trials were published together in the New England Journal of Medicine in 2015, with 74 patients in the European Union and 94 in the United States. The primary endpoint was hours of direct sunlight exposure without pain. In the US trial, median pain-free time over six months was 69.4 hours with afamelanotide versus 40.8 hours with placebo; in the EU trial the medians were 6.0 versus 0.8 hours, and phototoxic reactions were fewer (77 versus 146).
The European Commission authorised Scenesse on 22 December 2014 under “exceptional circumstances”, a route used when complete data cannot be obtained, often because a disease is rare. The FDA approved it on 8 October 2019 to increase pain-free light exposure in adults with a history of phototoxic reactions from EPP. Both approvals are limited to EPP.
What the evidence supports
The two compounds have very different evidence bases. Afamelanotide has randomized controlled trial data in a defined rare disease and two regulatory approvals for that indication. Melanotan II has small early-phase human studies from the 1990s, receptor-binding work and animal research, and no completed drug development program.
There is also a body of literature on unlicensed use. A 2010 commentary in the British Journal of Dermatology noted that the UK Medicines and Healthcare products Regulatory Agency had raised concerns about needle sharing and the possible impurity of products labeled as melanotan sold through the internet, tanning salons and gyms. A 2017 review summarized case reports of changes in existing moles and newly appearing nevi in people using unregulated melanotans, including four reports of melanoma, while noting that conclusive causal evidence is lacking. The same review states that several national health authorities have issued safety warnings about Melanotan I and II.
Frequently asked questions
Is Melanotan I the same as afamelanotide?
Yes, by structure: both names refer to [Nle4, D-Phe7]-alpha-MSH. The approved product, Scenesse, is a specific pharmaceutical formulation of afamelanotide. Research material sold as Melanotan I is not that approved medicine.
How are Melanotan II and PT-141 related?
They share the same seven-residue cyclic structure and differ only at the C-terminal end: an amide in Melanotan II, a carboxylic acid in bremelanotide. Bremelanotide was developed by Palatin Technologies and approved by the FDA as Vyleesi; Melanotan II was not approved.
Why does Melanotan II have effects beyond pigmentation?
Because it binds several melanocortin receptor subtypes, including MC3R and MC4R in the brain. Afamelanotide’s approved use is built on MC1R activity in skin.
How do I know what is actually in the vial?
Every lot we sell has a published Certificate of Analysis from an independent, third-party lab confirming identity and purity. Lot numbers on the vial should match the COA you are referencing. With these two compounds this matters more than usual, since the regulator warnings above concern products of unknown content.
References
- Dorr RT, et al. Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study. Life Sci. 1996;58(20):1777–1784.
- Schiöth HB, et al. Selectivity of cyclic [D-Nal7] and [D-Phe7] substituted MSH analogues for the melanocortin receptor subtypes. Peptides. 1997;18(7):1009–1013.
- Wessells H, et al. Synthetic melanotropic peptide initiates erections in men with psychogenic erectile dysfunction: double-blind, placebo controlled crossover study. J Urol. 1998;160(2):389–393.
- Hadley ME, Dorr RT. Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization. Peptides. 2006;27(4):921–930.
- Molinoff PB, et al. PT-141: a melanocortin agonist for the treatment of sexual dysfunction. Ann N Y Acad Sci. 2003;994:96–102.
- Langan EA, Nie Z, Rhodes LE. Melanotropic peptides: more than just ‘Barbie drugs’ and ‘sun-tan jabs’? Br J Dermatol. 2010;163(3):451–455.
- Langendonk JG, et al. Afamelanotide for erythropoietic protoporphyria. N Engl J Med. 2015;373(1):48–59.
- Habbema L, et al. Risks of unregulated use of alpha-melanocyte-stimulating hormone analogues: a review. Int J Dermatol. 2017;56(10):975–980.
- US FDA. Scenesse (afamelanotide) prescribing information, NDA 210797. 2019.
- European Medicines Agency. Scenesse: European public assessment report. 2014.
View the Melanotan I product listing → | View Melanotan II →
Look up your lot Certificate of Analysis →
For laboratory and research use only. Not for human consumption. Afamelanotide is approved in the EU and US only as the prescription product Scenesse for erythropoietic protoporphyria; material sold for research use is not an approved medicine. Melanotan II is not approved by any regulatory authority. This article summarizes published research for informational purposes and is not medical advice, nor a recommendation or protocol for use.
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