Melanotan 1 (Afamelanotide / Scenesse)

Where it comes from

The starting point lies in the 1980s at the University of Arizona: tanning the skin before sun exposure and thus creating built-in light protection. For this purpose, more stable copies were built of the body’s own tanning hormone alpha-MSH, which is broken down in the blood within seconds.

The first usable copy was described in 1980: the same 13 amino acids, exchanged at 2 positions, hence the technical name NDP-alpha-MSH. It was resistant to breakdown in serum and 26 times more potent than alpha-MSH in the cell assay. Later an Australian company licensed the active substance as afamelanotide.

How it works

Melanotan 1 is linear and acts mainly on the melanocortin-1 receptor of pigment cells; it is not strictly selective, and in the laboratory it also activates the MC3, MC4 and MC5 receptors. Melanotan 2 is smaller, ring-shaped and also acts on the receptors for appetite and erection. This explains why the notorious side effects of its smaller sibling hardly occur here.

The core effect: the receptor is activated and the pigment cells form eumelanin. This pigment sits above the cell nucleus and filters light, including the visible portion that conventional sunscreen lets through.

The same receptor explains the genetics of skin types: in loss-of-function variants, typical of red hair and very fair skin, it works weakly, and pigment formation shifts toward reddish pheomelanin. This protects less well and is considered an oxidative burden, which partly explains the increased melanoma risk of these skin types independently of UV.

The disease it is approved for

Erythropoietic protoporphyria is a rare genetic defect in the metabolism of the blood pigment. Those affected accumulate protoporphyrin in the skin, which forms aggressive oxygen radicals under light. The result is burning pain attacks after a few minutes, often already with visible light. In Europe, at least 1 in 140,000 people is affected.

Sunscreen hardly helps, because the trigger is mainly visible light. A dense eumelanin canopy filters exactly that, and afamelanotide builds up this protection without those affected having to go into the sun for it.

It is administered as an implant containing 16 mg of active substance, which a specialist center places under the skin every 2 months; 3 implants a year are recommended, at most 4. It is prescription-only specialist medicine.

What the approval studies showed

The basis is two randomized, double-blind, placebo-controlled trials from 2015: 74 patients in the EU, 94 in the US. The primary endpoint was the number of hours in direct sunlight without pain.

In the US trial, the value after 6 months was 69.4 versus 40.8 hours; in the EU trial after 9 months, 6.0 versus 0.8 hours, plus 77 instead of 146 phototoxic reactions. Quality of life rose in both trials, and side effects were mostly mild.

The European agency cites a study with 93 patients in which the pain-free time over 6 months was 116 versus 61 hours. It notes that the gain was small and granted approval under exceptional circumstances because, owing to the rarity of the disease, complete data could not be obtained. The US agency relied on 3 studies with 244 patients at 22 centers.

What came afterwards

Because the approval was tied to conditions, observation continued. At 2 porphyria centers in Rome and Zurich, 115 patients were followed over up to 8 years and 1,023 implants: quality of life rose from 31 percent of the maximum value to 74 percent and stayed there, and adverse effects were minor. The German post-authorization safety study covered 200 patients, with a safety profile as in the trials.

An Austrian analysis of 20 patients from 2023 shows the everyday difference: the tolerated time until a phototoxic reaction rose from a median of 15 to 250 minutes, and the proportion of patients with phototoxic reactions fell from 88 to 33 percent.

Research is going beyond the approval, furthest in vitiligo: there, afamelanotide in addition to narrowband UVB therapy was superior to light therapy alone, most clearly in darker skin types.

Tanning and the gray market

That afamelanotide tans the skin has been shown in humans, but the data are old and small: in 1991, 28 healthy men received 10 injections over 12 days; the skin darkened measurably, but not on placebo, with the peak 1 to 3 weeks after the last dose. A proof of principle, not a basis for cosmetic use.

On the gray market, Melanotan 1 is sold as a research peptide for injection. Reports describe an even tan, good tolerability, nausea at the beginning, flushing and new freckles. These are reports, not evidence; the approval applies to the implant given by a specialist.

What the studies show

Langendonk et al., New England Journal of Medicine 2015

Two randomized, double-blind, placebo-controlled trials with implants of 16 mg every 60 days: 74 patients in the EU over 180 days, 94 in the US over 270 days. The primary endpoint was pain-free hours in direct sun. US after 6 months: 69.4 versus 40.8 hours (median). EU after 9 months: 6.0 versus 0.8 hours, plus 77 instead of 146 phototoxic reactions. The endpoint was met in both trials.

Biolcati et al., British Journal of Dermatology 2015

Long-term observation at 2 centers: 115 patients, 1,023 implants, up to 8 years. Disease-specific quality of life rose from 31 to 74 percent of the maximum and stayed there. 3 patients felt their expectations were not met; 23 percent discontinued for other reasons. Adverse effects were minor, mostly nausea. Without a control group.

Lim et al., JAMA Dermatology 2015

Randomized trial at 3 sites on vitiligo, 55 participants with 15 to 50 percent of body surface affected. After one month of narrowband UVB, 28 additionally received afamelanotide monthly, and 27 continued the light therapy alone. Repigmentation was significantly stronger and faster in the combination group, most clearly in darker skin types.

Where the data stop

For cosmetic tanning, there is no robust body of data. The only placebo-controlled work on it is the 1991 study with 28 men over 12 days; what was tested was skin coloration, not protection from sunburn and not safety over years. Whether more eumelanin lowers the risk of skin cancer in healthy people has not been shown; the European agency also notes that complete data on the benefits are not available, which is why approval was granted under exceptional circumstances. The benefit is also limited: in EPP, the treatment improves light tolerance, but not the vitamin D status and not the reduced bone density of these patients. For gray-market products there is no body of data, neither on content nor on purity nor on the consequences of use over years.

Status, approval and legal

Afamelanotide has been approved as Scenesse in the EU since December 22, 2014 and in the US since October 8, 2019, in each case for the prevention of phototoxicity in adults with erythropoietic protoporphyria. The European approval was granted under exceptional circumstances, with a registry and a safety study as conditions; only specialists in recognized centers may prescribe it. Any other use, in particular cosmetic tanning, is off-label, and the vials traded online are unapproved products. In sport, an unapproved preparation falls under group S0 of the World Anti-Doping Agency and is banned at all times.

Safety

For the approved implant, the picture is well documented. The most common side effects are nausea, headache and reactions at the implant site; they affected about 1 in 5 patients and were mostly mild. The active substance must not be used in patients with impaired liver or kidney function, and after insertion patients are observed for 30 minutes for allergic reactions. Long-term observation over up to 8 years and a safety study with 200 patients showed no new risk signal. None of this applies to gray-market products: content, purity and sterility are untested, and injection takes place without supervision. Regardless of origin, the pigment question remains: existing moles can darken and become harder to assess. With many or conspicuous moles and with a history of skin cancer, this belongs in the hands of a dermatologist.

Sources

• Langendonk et al., New England Journal of Medicine 2015 — afamelanotide in erythropoietic protoporphyria, two phase 3 trials
• EMA — Scenesse (afamelanotide), approval of December 22, 2014 under exceptional circumstances, product information
• FDA — Drug Trials Snapshot Scenesse: 3 studies, 244 patients, 22 centers
• FDA — Scenesse approval letter of October 8, 2019 with indication text
• Biolcati et al., British Journal of Dermatology 2015 — long-term observation of 115 patients over up to 8 years
• Homey et al., Photodermatol Photoimmunol Photomed 2025 — German post-authorization safety study, 200 patients
• Seidl-Philipp et al., JDDG 2026 — Austrian cohort, light tolerance and quality of life
• Lim et al., JAMA Dermatology 2015 — afamelanotide plus narrowband UVB in vitiligo
• Sawyer et al., PNAS 1980 — NDP-alpha-MSH: resistant to breakdown and 26 times more potent than alpha-MSH in the cell assay
• Levine et al., JAMA 1991 — skin tanning by NDP-alpha-MSH, placebo-controlled in 28 men
• Haskell-Luevano et al., J Med Chem 1997 — NDP-alpha-MSH activates all melanocortin receptors except MC2R