Melanotan I

1. Overview  

Melanotan I, also known as Afamelanotide, is a synthetic analogue of the naturally occurring alpha-melanocyte-stimulating hormone (α-MSH). It acts as a potent agonist of the melanocortin 1 receptor (MC1R), which stimulates melanin production in skin cells. Initially developed to promote skin pigmentation and reduce UV damage risk, Melanotan I has also shown promise in protecting against phototoxic reactions in patients with erythropoietic protoporphyria (EPP)—a rare genetic disorder that causes extreme sensitivity to sunlight. 

Afamelanotide has been approved in the European Union and the United States (under the brand name Scenesse) for the management of EPP, where it increases tolerance to sunlight and improves patients’ quality of life. Beyond its approved use, research continues into its potential effects on DNA repair, oxidative stress, and immune modulation.

2. Key Human Clinical Findings

In a Phase III, double-blind, placebo-controlled trial involving 91 patients with erythropoietic protoporphyria, subcutaneous implantation of Melanotan I (16 mg every 60 days) significantly improved sunlight tolerance. Participants receiving Afamelanotide were able to spend a median of 6 hours more in direct sunlight per day without pain compared to those given placebo. These results demonstrated both a photoprotective effect and a measurable improvement in daily functioning and mood.

A separate Phase II study found that Melanotan I accelerated skin pigmentation in light-skinned individuals, reducing UV-induced DNA damage markers such as cyclobutane pyrimidine dimers. This suggests a potential role in skin-cancer prevention, though this application remains investigational.

Additional preclinical research has highlighted its anti-inflammatory and cytoprotective properties through melanocortin receptor signaling. Studies in animal models have reported improved wound healing and reduced oxidative stress in tissues exposed to UV or ischemic injury.

3. Safety and Tolerability

Clinical data show that Melanotan I is generally well tolerated when administered through the approved subcutaneous implant formulation. The most frequently observed side effects include nausea, flushing, increased pigmentation, and mild fatigue, typically transient in nature. No major systemic toxicities have been reported in long-term EPP studies.

Because of its potent biological activity, unregulated or compounded versions of Melanotan I available online have raised safety concerns, as their purity, dose consistency, and safety data are not verified. In controlled medical use, however, Afamelanotide’s safety record remains strong, with no significant long-term adverse effects documented in regulatory trials.

4. Summary

Melanotan I (Afamelanotide) is a synthetic peptide that enhances natural skin pigmentation and offers protection from UV-induced damage. Its most significant clinical use is in erythropoietic protoporphyria, where it enables sunlight tolerance and improves quality of life. Beyond its approved use, studies suggest potential applications in photoprotection, oxidative-stress modulation, and inflammatory control. Overall, Melanotan I represents a valuable research tool and a proven clinical therapy for light-sensitivity disorders, with a favorable safety and efficacy profile demonstrated across multiple human trials.

References

1. Langendonk JG et al. Afamelanotide for Erythropoietic Protoporphyria. N Engl J Med. 2015;373:48–59.

2. Bissonnette R et al. Melanotan-I Induces Photoprotection and Reduces DNA Damage in Human Skin. J Invest Dermatol. 2002;119(5):1242–1249.

3. Scenesse® – FDA Approval Summary, 2019