Melanotan I (Afamelanotide): Research Profile

The peptide known as Melanotan I stands apart from its more controversial cousin, Melanotan II, in one crucial respect: it's actually FDA-approved. While internet forums and underground labs have flooded the market with unregulated synthetic tanning peptides, afamelanotide—the pharmaceutical name for Melanotan I—has taken a different path entirely. It's not a cosmetic tanning agent. It's a prescription medication manufactured by Clinuvel Pharmaceuticals and approved by the FDA, EMA, and Australian TGA for treating a rare genetic condition that makes sunlight unbearable.

This distinction matters. When people search for "Melanotan I," they're often looking for information about the original alpha-MSH analog that sparked decades of melanocortin research. What they find is a story that spans three decades, from early tanning research in Arizona to a 2019 FDA approval for erythropoietic protoporphyria (EPP), a disease so rare that only about 10,000 people worldwide have it. This article examines what Melanotan I is, how it works, what the clinical evidence shows, and how it compares to the cyclic peptide that borrowed its name.

The science here is straightforward: afamelanotide is a linear 13-amino-acid peptide that selectively activates the melanocortin-1 receptor (MC1R), driving melanin production and providing photoprotection. Unlike Melanotan II, which hits multiple melanocortin receptors and produces a cascade of effects from appetite suppression to sexual arousal, Melanotan I focuses almost exclusively on pigmentation. That receptor selectivity is why it earned regulatory approval while its structural relative remains banned in most countries.

Quick Facts
What Is Melanotan I (Afamelanotide)?
Chemical Structure and Properties
Mechanism of Action
Clinical Research and Evidence
Melanotan I vs. Melanotan II
Safety Profile and Side Effects
Legal Status and Availability
Frequently Asked Questions
Bottom Line

Quick Facts

Property	Details
Full Name	Afamelanotide
Brand Name	SCENESSE®
Peptide Type	Linear tridecapeptide, synthetic α-MSH analog
Receptor Target	Melanocortin-1 receptor (MC1R) - highly selective
Sequence	Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH₂
Molecular Formula	C₇₈H₁₁₁N₂₁O₁₉
Half-Life	~30 minutes (plasma); ~15 hours (implant release)
Manufacturer	Clinuvel Pharmaceuticals
FDA Approval	October 2019
EMA Approval	December 2014 (commercial launch June 2016)
Approved Indication	Prevention of phototoxicity in adult patients with erythropoietic protoporphyria (EPP)
Administration	16 mg subcutaneous implant every 2 months
Prescription Status	Prescription-only medication in all approved markets

What Is Melanotan I (Afamelanotide)?

Melanotan I, now known by its international nonproprietary name afamelanotide, is a synthetic analog of alpha-melanocyte stimulating hormone (α-MSH), a naturally occurring peptide hormone that regulates pigmentation in humans. The "Melanotan" name comes from its early development in the 1980s at the University of Arizona, where researchers were investigating peptides that could induce tanning with minimal sun exposure.

α-MSH is a 13-amino-acid peptide derived from the precursor protein proopiomelanocortin (POMC). It plays multiple roles in human physiology: stimulating melanin production, regulating appetite, modulating inflammation, and influencing sexual behavior. The endogenous hormone binds to several melanocortin receptors (MC1R, MC3R, MC4R, MC5R), each triggering different physiological responses.

Afamelanotide differs from natural α-MSH by only two amino acids, but those substitutions are strategic. The replacement of methionine with norleucine at position 4 and the substitution of L-phenylalanine with D-phenylalanine at position 7 improve biological efficacy in two key ways: greater affinity for the MC1R receptor and a longer biological half-life. These modifications make afamelanotide more potent and longer-lasting than the endogenous hormone it mimics.

The peptide works by binding to MC1R on melanocytes—the pigment-producing cells in skin—triggering a cascade that increases eumelanin synthesis. Eumelanin is the dark, photoprotective form of melanin that absorbs UV radiation and scavenges free radicals, providing natural defense against sun damage. This mechanism makes afamelanotide fundamentally different from tanning beds or sun exposure, which damage DNA to trigger a defensive tanning response. Afamelanotide induces melanogenesis directly, without requiring UV-induced DNA damage.

Chemical Structure and Properties

Afamelanotide is a linear tridecapeptide—meaning it consists of 13 amino acids arranged in a straight chain, as opposed to the cyclic structure of Melanotan II. Its sequence is:

Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH₂

Breaking this down:

Ac- (N-terminal acetylation) protects the peptide from enzymatic degradation
Nle (norleucine) at position 4 replaces methionine, preventing oxidation and improving stability
D-Phe (D-phenylalanine) at position 7 creates an additional hydrogen bond with the MC1R receptor's transmembrane domain 2, boosting affinity and resistance to enzymatic breakdown
-NH₂ (C-terminal amidation) further protects against degradation

The molecular formula is C₇₈H₁₁₁N₂₁O₁₉, with a molecular weight of approximately 1,646 Da. The peptide is highly selective for MC1R over other melanocortin receptors. While α-MSH is a non-selective full agonist at MC1R, MC3R, MC4R, and MC5R, afamelanotide's structural modifications shift its binding profile heavily toward MC1R. This receptor selectivity is why afamelanotide produces primarily pigmentation effects without the appetite suppression (MC4R), sexual effects (MC3R/MC4R), or sebaceous gland modulation (MC5R) seen with less selective melanocortin agonists.

The D-Phe7 substitution is particularly important. Research shows that this single amino acid change creates an extra hydrogen bond with the transmembrane 2 domain of MC1R, improving both binding affinity and cAMP production—the intracellular signaling molecule that drives melanogenesis. In functional assays, afamelanotide demonstrates superior potency compared to α-MSH in stimulating cAMP production in melanocytes expressing MC1R.

Mechanism of Action

Afamelanotide's mechanism centers on the melanocortin-1 receptor (MC1R), a G protein-coupled receptor expressed primarily on melanocytes in the skin and hair follicles. When afamelanotide binds to MC1R, it triggers a well-characterized signaling cascade:

Step 1: Receptor Binding and Activation Afamelanotide binds to the MC1R receptor on the melanocyte cell surface. MC1R is coupled to the stimulatory G protein Gαs, which activates adenylyl cyclase when the receptor is occupied.

Step 2: cAMP Production Adenylyl cyclase converts ATP to cyclic AMP (cAMP), a second messenger molecule that accumulates in the cell. Studies show afamelanotide produces higher cAMP levels than natural α-MSH due to its enhanced receptor affinity.

Step 3: PKA Activation and CREB Phosphorylation Rising cAMP levels activate protein kinase A (PKA), which phosphorylates the transcription factor CREB (cAMP response element-binding protein). Phosphorylated CREB enters the nucleus and binds to gene promoters.

Step 4: MITF Upregulation CREB activation increases expression of microphthalmia-associated transcription factor (MITF), the master regulator of melanocyte function. MITF controls genes involved in melanin synthesis, melanocyte proliferation, and survival.

Step 5: Melanogenic Enzyme Expression MITF upregulates key melanogenic enzymes:

Tyrosinase (rate-limiting enzyme in melanin synthesis)
TRP-1 (tyrosinase-related protein 1)
TRP-2 (dopachrome tautomerase)

Step 6: Eumelanin Synthesis These enzymes convert the amino acid tyrosine through a series of oxidation steps into eumelanin, the brown-black photoprotective pigment. Eumelanin is packaged into melanosomes and transferred to surrounding keratinocytes, where it forms a protective cap over cell nuclei.

Photoprotection Beyond Pigmentation While pigmentation is the visible result, afamelanotide provides photoprotection through multiple mechanisms:

UV Absorption: Eumelanin absorbs and dissipates UV radiation as harmless heat
Free Radical Scavenging: Melanin neutralizes reactive oxygen species (ROS) generated by UV exposure
DNA Protection: The melanosome cap shields nuclear DNA from direct UV damage
Anti-inflammatory Effects: MC1R activation modulates immune responses and reduces UV-induced inflammation

Research on the MC1R pathway reveals additional benefits. MC1R signaling activates DNA repair mechanisms and reduces oxidative stress even beyond the direct protective effects of melanin. Melanocytes with functional MC1R show improved responses to UV-induced DNA damage compared to those with loss-of-function MC1R variants.

Receptor Selectivity Afamelanotide's selectivity for MC1R distinguishes it from other melanocortin agonists. While Melanotan II binds MC1R, MC3R, and MC4R with roughly similar affinity, afamelanotide shows markedly higher selectivity for MC1R. This explains why afamelanotide produces primarily pigmentation effects without significant appetite suppression (MC4R-mediated) or sexual effects (MC3R/MC4R-mediated).

The pharmacokinetic profile supports sustained MC1R activation. Although the peptide has a plasma half-life of only 30 minutes, the subcutaneous implant formulation releases afamelanotide over several days. Following implant administration, most of the 16 mg dose releases within the first 48 hours, with over 90% released by day 5. The median time to peak plasma concentration (Tmax) is 36 hours, with a mean Cmax of 3.7 ng/mL. Plasma levels remain detectable for about 7 days—far less than the 60-day dosing interval—suggesting that the initial melanogenic stimulus triggers persistent melanin production that continues after the peptide clears.

Clinical Research and Evidence

Afamelanotide's clinical development focused primarily on erythropoietic protoporphyria (EPP), the rare genetic disorder that earned it FDA approval. However, research has explored its potential in several other conditions characterized by photosensitivity or pigmentation disorders.

Erythropoietic Protoporphyria (EPP)

EPP is caused by deficiency of the enzyme ferrochelatase, the final step in heme biosynthesis. This deficiency causes protoporphyrin IX to accumulate in red blood cells, plasma, and tissues. When protoporphyrin-laden blood circulates through sun-exposed skin, the protoporphyrin absorbs visible light (especially blue light around 400-410 nm), triggering a photochemical reaction that generates reactive oxygen species. The result is acute, severe pain within minutes of sun exposure, followed by burning, tingling, erythema, and edema.

EPP typically presents in early childhood. Affected children cry and experience severe pain within minutes of sun exposure, often before any visible skin changes appear. The pain can last hours to days. Repeated phototoxic reactions lead to chronic skin changes: thickening, waxy scarring, and lichenification, particularly on the face and hands. About 5-20% of EPP patients develop progressive liver disease from protoporphyrin accumulation, occasionally progressing to liver failure requiring transplantation.

Before afamelanotide, EPP management was purely avoidance-based: staying indoors, wearing protective clothing, and using physical sunscreens (zinc oxide/titanium dioxide—chemical sunscreens don't block the visible light wavelengths that trigger EPP reactions). Beta-carotene showed modest benefits in some patients but lacked robust evidence. No systemic therapies were approved.

Pivotal Clinical Trials

The FDA approval of SCENESSE® was based on three multicenter, randomized, double-blind, placebo-controlled trials involving 244 adult EPP patients:

Study CUV029 (European Union, n=74) Patients received either 16 mg afamelanotide implants or placebo every 60 days over 9 months. Primary endpoint: total hours of sun exposure without pain between 10 AM and 6 PM.

Results:

Median pain-free sun exposure: 6.0 hours (afamelanotide) vs. 0.8 hours (placebo), P=0.005
Number of phototoxic reactions: 77 (afamelanotide) vs. 146 (placebo), P=0.04
Quality of life improvements were statistically significant across multiple measures

Study CUV030 (United States, n=94) Similar design over 6 months (4 implant cycles).

Results:

Median duration of pain-free time: 69.4 hours (afamelanotide) vs. 40.8 hours (placebo), P=0.04
Quality of life measures showed consistent improvement
Adverse events were primarily mild; no serious adverse events were attributed to the study drug

Study CUV039 Additional confirmatory trial with consistent efficacy findings.

Long-Term Observational Data

A longitudinal study followed 115 EPP patients receiving up to 8 years of afamelanotide treatment (1,023 total implants administered). Findings included:

Sustained efficacy over years of treatment
Consistent safety profile with no new adverse events emerging over time
Short- and long-term safety profiles were comparable
No reports of skin cancer during extended follow-up
Minimal differences in safety for patients over age 70

Post-marketing surveillance in Europe (patients treated since 2016 commercial launch) confirms the favorable safety profile, with no unexpected serious adverse effects over multiple years of real-world use.

Mechanistic Rationale in EPP

Afamelanotide's benefit in EPP goes beyond cosmetic tanning. The induced eumelanin provides several protective mechanisms:

Light absorption: Eumelanin absorbs the 400-410 nm blue light wavelengths that activate protoporphyrin
Free radical scavenging: Melanin neutralizes the reactive oxygen species generated when protoporphyrin absorbs light
Physical barrier: The melanin cap in keratinocytes provides additional shielding
Anti-inflammatory effects: MC1R activation reduces inflammatory responses to phototoxic injury

A 2024 study found that afamelanotide provides dose-dependent protection against EPP-associated liver damage, suggesting benefits beyond photoprotection. Patients receiving consistent year-round treatment showed improved liver function parameters compared to those with intermittent use.

Vitiligo

Vitiligo is an autoimmune condition causing loss of melanocytes, resulting in depigmented patches on the skin. Current FDA-approved treatments (as of 2025) are limited to topical ruxolitinib (a JAK inhibitor) for patients with less than 10% body surface area involvement who haven't responded to topical steroids. No systemic therapies are approved.

Clinuvel launched a global Phase III trial (CUV105) in October 2023 to evaluate afamelanotide 16 mg combined with narrowband UVB (NB-UVB) phototherapy versus NB-UVB monotherapy in adolescent and adult patients with non-segmental vitiligo, particularly those with Fitzpatrick skin types III-VI. The study enrolled over 200 patients across three continents, completing enrollment in May 2025.

Study Design:

Treatment Arm 1: Afamelanotide implant every 3 weeks + NB-UVB phototherapy twice weekly
Treatment Arm 2: NB-UVB phototherapy twice weekly alone
Primary Endpoint: Degree of repigmentation
Results Expected: Second half of 2026

Early interim observations suggest faster repigmentation onset in the combination arm, though full data analysis is ongoing. The rationale is that afamelanotide stimulates surviving melanocytes to produce more melanin, while NB-UVB modulates the autoimmune attack and stimulates melanocyte migration from hair follicles to repopulate depigmented areas.

If successful, this would represent the first approved systemic therapy for vitiligo—a significant unmet need in dermatology.

Polymorphous Light Eruption and Other Photodermatoses

Polymorphous light eruption (PLE) is a common sun-induced skin condition affecting up to 20% of people in temperate climates. It presents as itchy papules, vesicles, or plaques hours to days after sun exposure, typically in spring when skin first encounters intense UV after winter. The exact mechanism remains unclear but involves immune responses to UV-modified skin antigens.

Clinuvel conducted trials between 2007 and 2011 exploring afamelanotide in PLE, solar urticaria, and acne vulgaris, though results were not published in peer-reviewed journals. Anecdotal reports and conference presentations suggested benefit in severe, treatment-refractory PLE cases, but regulatory pursuit focused on EPP where the unmet need was more acute.

A 2021 review noted that afamelanotide's "dual photoprotective and anti-inflammatory effects make it a promising therapy for other photosensitive dermatologic diseases resistant to conventional treatment." Small case series have reported benefit in severe PLE unresponsive to standard measures (sun avoidance, sunscreens, photohardening, immunosuppressants).

Other Research Areas

Hailey-Hailey Disease: Case reports describe improvement in this rare blistering disorder.

Stroke: A 2023 Phase IIa proof-of-concept study evaluated afamelanotide in acute ischemic stroke patients, exploring MC1R's neuroprotective and anti-inflammatory effects. While feasibility and safety were demonstrated, efficacy signals were not strong enough to justify Phase III development in stroke.

Photoaging and Skin Cancer Prevention: While not actively studied in clinical trials, the photoprotective mechanism suggests potential applications in high-risk populations (organ transplant recipients, those with high melanoma risk). However, no trials have pursued this indication.

Melanotan I vs. Melanotan II

The names sound similar, but Melanotan I (afamelanotide) and Melanotan II are distinct peptides with different structures, mechanisms, effects, and legal statuses.

Feature	Melanotan I (Afamelanotide)	Melanotan II
Structure	Linear 13-amino-acid peptide	Cyclic 7-amino-acid peptide with lactam bridge
Receptor Targets	MC1R-selective	MC1R, MC3R, MC4R (non-selective)
Primary Effects	Skin pigmentation, photoprotection	Pigmentation, appetite suppression, sexual arousal, erectile function
Tanning Profile	Gradual, even tan over weeks	Faster, deeper tan (often uneven)
Sexual Effects	None reported	Increased libido and erectile function (MC4R-mediated)
Appetite Effects	None	Appetite suppression (MC4R-mediated)
Metabolic Effects	Minimal	Fat loss, glucose/lipid regulation
Nausea	19% in clinical trials (mild)	Very common (can be severe)
Other Side Effects	Injection site reactions (21%), headache, mild flushing	Nausea, flushing, appetite loss, spontaneous erections, changes in libido, hypertension
Clinical Development	Extensive Phase III data in EPP; ongoing Phase III in vitiligo	No completed Phase III trials; abandoned by pharmaceutical developers
FDA Status	Approved (2019)	Not approved; classified as unapproved drug
Legal Status	Prescription medication	Illegal to sell/distribute in most jurisdictions; not legal for human use
Manufacturer	Clinuvel Pharmaceuticals (pharmaceutical-grade)	None (available only from research chemical suppliers and underground labs)
Quality Control	GMP manufacturing, consistent dosing and purity	Highly variable; often contaminated or misdosed
Safety Data	Thousands of patient-years in clinical trials and post-marketing surveillance	Primarily case reports and adverse event reports; no systematic safety studies
Medical Supervision	Required (prescription, administered by trained healthcare providers)	None (typically self-administered from unregulated sources)

Why Are They So Different?

The structural difference is fundamental. Melanotan I retains the linear structure similar to natural α-MSH, with just two amino acid substitutions that boost stability and MC1R affinity. Melanotan II underwent cyclization—forming a lactam bridge between amino acids to create a ring structure—and lost six amino acids in the process. This dramatically altered its receptor binding profile.

Cyclization makes Melanotan II more potent (requiring lower doses) but far less selective. It hits MC1R with similar potency to Melanotan I, but also strongly activates MC3R and MC4R. MC4R activation in the hypothalamus suppresses appetite and increases energy expenditure, explaining reports of weight loss and reduced hunger. MC3R and MC4R activation in brain regions controlling sexual behavior explain the erectile and libido effects. These effects led some to explore Melanotan II for sexual dysfunction, culminating in the development of PT-141 (bremelanotide), a Melanotan II derivative approved for hypoactive sexual desire disorder in women.

Safety Considerations

Melanotan I's safety profile comes from rigorous clinical trials: three pivotal randomized controlled trials, long-term observational studies, and years of post-marketing surveillance in Europe, the US, and Australia. Adverse events are well-characterized, mostly mild, and serious adverse events are rare and generally unrelated to the drug.

Melanotan II's safety profile comes from case reports, poison control data, and adverse event surveillance of unregulated products. Reports include:

Severe nausea and vomiting
Dangerous hypertension
Priapism (prolonged, painful erections requiring emergency treatment)
Rhabdomyolysis (muscle breakdown)
Acute kidney injury
Severe hyperpigmentation (darkening of moles, new nevi)
Potential links to melanoma (unproven but concerning given effects on melanocytes)

The unregulated nature of Melanotan II compounds the problem. Products sold online or in gyms lack quality control. Testing by regulatory agencies has found:

Mislabeling (wrong dose, wrong peptide)
Contamination with bacteria or endotoxin
Presence of other substances not listed on labels
Highly variable purity and potency

Legal and Regulatory Status

Melanotan I (afamelanotide/SCENESSE®) is a prescription medication approved by:

FDA (US, October 2019)
EMA (European Union, December 2014)
TGA (Australia, October 2020)

It can only be obtained with a valid prescription for the approved indication (EPP). Off-label use is possible through normal prescribing channels but is not the intended use.

Melanotan II has never been approved by any major regulatory authority. It is classified as an unapproved drug and is illegal to sell or distribute for human use in most countries, including the US, UK, EU nations, Canada, and Australia. Some sellers market it "for research purposes only" to skirt regulations, but purchasing it for personal use exists in a legal gray area and using it constitutes use of an unapproved drug with unknown purity and safety.

Bottom Line: Similar Names, Entirely Different Profiles

Despite sharing a name and heritage, Melanotan I and Melanotan II should not be conflated. One is a pharmaceutical medication with proven efficacy and safety in a specific patient population, manufactured under strict quality standards, and available by prescription. The other is an unapproved research chemical with broader effects, significant safety concerns, no quality control, and an illegal status in most jurisdictions.

Safety Profile and Side Effects

Afamelanotide's safety profile has been extensively characterized through clinical trials involving hundreds of patients and years of post-marketing surveillance in three major markets. The safety data come from three pivotal randomized controlled trials (244 subjects), long-term observational studies (up to 8 years of treatment), and ongoing pharmacovigilance in Europe, the US, and Australia since commercial launch.

Common Side Effects

From Pivotal Clinical Trials (vs. Placebo):

Side Effect	Afamelanotide	Placebo
Implant site reaction	21%	10%
Nausea	19%	14%
Headache	Common	Common
Nasopharyngitis	Common	Common
Throat pain	7%	4%
Fatigue	6%	3%
Dizziness	4%	3%
Back pain	Common	Common

Implant Site Reactions: The most common adverse effect, occurring in about one in five patients. Reactions include mild pain, redness, swelling, or bruising at the subcutaneous implant site, typically resolving within days. Proper implantation technique by trained providers minimizes these reactions.

Nausea: Reported by 19% of patients in clinical trials compared to 14% receiving placebo, suggesting some cases are related to the underlying condition rather than the drug. Nausea is usually mild and transient, occurring within hours after implant insertion and resolving within 24-48 hours. It rarely requires treatment.

Hyperpigmentation: Diffuse skin darkening is expected and desired in EPP patients (it's the mechanism of benefit). However, about one-third of patients experience mild hyperpigmentation at the implant site, and a few patients reported darkening of pre-existing moles and freckles. No cases of malignant transformation were reported, but patients with atypical nevi or melanoma history require careful dermatologic monitoring.

Serious Adverse Events

Five patients receiving afamelanotide in pivotal trials experienced six serious adverse events (SAEs). All SAEs resolved completely without lasting effects, and investigators deemed all were "not related" or "unlikely to be related" to afamelanotide. The SAEs included infections, hospitalizations for EPP exacerbations, and events related to underlying medical conditions.

Long-term observational data through 8 years of treatment showed no new safety signals emerging over time. The safety profile remained consistent whether patients used afamelanotide short-term or for multiple years.

Rare but Noteworthy

Infections: Listed as a rare but potentially serious adverse event in prescribing information, though the rate was not higher than placebo in trials.

Melanocytic Nevi: Increased nevi (moles) or darkening of existing nevi has been reported. While no cases of melanoma were attributed to afamelanotide in clinical trials or post-marketing surveillance (which includes up to 10 years of use via compassionate access programs), the theoretical concern exists. Patients are advised to have baseline skin examinations and periodic monitoring by dermatology.

Cardiovascular: No cardiovascular safety signals emerged in trials. Unlike Melanotan II (which has been associated with hypertension), afamelanotide's MC1R selectivity avoids cardiovascular effects seen with less selective melanocortin agonists.

Contraindications and Precautions

Pregnancy and Lactation: Afamelanotide is Pregnancy Category C. Animal studies showed no fetal harm, but no adequate human studies exist. It should only be used in pregnancy if potential benefit justifies potential risk. It's unknown whether afamelanotide is excreted in breast milk.

Liver Disease: While EPP itself can cause liver disease, and some data suggest afamelanotide may protect against EPP-related liver damage, patients with significant hepatic impairment were excluded from pivotal trials. Monitoring liver function is recommended in EPP patients regardless of treatment.

Renal Impairment: Patients with significant renal dysfunction were excluded from trials. No dose adjustments are recommended for mild impairment, but use caution in moderate to severe renal disease.

Skin Cancer History: Patients with melanoma or history of melanoma were excluded from trials. Given the theoretical concern that increasing melanin production could affect pre-existing melanocytes (including potentially malignant ones), afamelanotide should be used cautiously, if at all, in patients with personal history of melanoma or high melanoma risk (multiple dysplastic nevi, family history, etc.). Regular dermatologic surveillance is essential.

Photosensitizing Medications: While not a contraindication, patients on photosensitizing drugs (certain antibiotics, diuretics, NSAIDs) should be counseled that afamelanotide doesn't eliminate all photosensitivity—it specifically addresses the protoporphyrin-mediated phototoxicity of EPP.

Drug Interactions

No significant drug-drug interactions have been identified. The peptide undergoes proteolytic degradation rather than hepatic metabolism via cytochrome P450 enzymes, making pharmacokinetic interactions unlikely. Afamelanotide doesn't affect the metabolism of other drugs.

Post-Marketing Surveillance

European post-marketing data (since 2016 commercial launch) and US data (since 2019) have not revealed unexpected safety issues. Pharmacovigilance continues to monitor for rare adverse events, long-term effects, and use in special populations. As of 2025, the safety profile remains consistent with that established in clinical trials.

Comparison to Unregulated "Melanotan"

A critical safety distinction: pharmaceutical-grade afamelanotide (SCENESSE®) manufactured by Clinuvel under Good Manufacturing Practices (GMP) is entirely different from unregulated "melanotan" products sold online, in gyms, or through unlicensed clinics. These products:

Lack quality control (variable potency, purity, and sterility)
Often contain bacterial contamination or endotoxin
May be mislabeled (wrong dose, wrong peptide, or even entirely different substances)
Provide no medical supervision or safety monitoring

Multiple case reports document serious adverse events from unregulated melanocortin peptides, including severe infections, rhabdomyolysis, acute kidney injury, priapism, and dangerous hypertension. These products should not be confused with pharmaceutical-grade afamelanotide.

Overall Safety Assessment

Afamelanotide demonstrates an acceptable safety profile in its approved population (adult EPP patients). The most common adverse effects are mild and transient. Serious adverse events are rare and have not been causally linked to the drug in clinical trials. Long-term data through 8 years of continuous use show no cumulative toxicity or new safety signals.

The risk-benefit calculation is favorable for EPP patients, whose quality of life is severely impaired by the inability to tolerate sunlight. For a disease with no alternative systemic therapies and profound lifestyle limitations, the side effect profile of afamelanotide is well-tolerated. Future trials in other indications (such as vitiligo) will need to establish whether the risk-benefit ratio remains favorable in populations without the same severe sun sensitivity.

Legal Status and Availability

Afamelanotide's legal status is clear and unambiguous: it is a prescription-only medication approved by major regulatory authorities for a specific medical indication.

Regulatory Approvals

United States The FDA approved SCENESSE® (afamelanotide implant) on October 8, 2019 as the first FDA-approved treatment to increase pain-free light exposure in adult patients with erythropoietic protoporphyria (EPP). The approval was granted under the following regulatory pathways:

Priority Review: For drugs treating serious conditions with significant unmet medical needs
Orphan Drug Designation: For diseases affecting fewer than 200,000 people in the US (EPP affects approximately 4,000 Americans)

European Union The European Medicines Agency (EMA) granted marketing authorization in December 2014. This was issued under "exceptional circumstances," requiring post-authorization safety studies (PASS) to monitor both safety and effectiveness in all EPP patients receiving treatment. Commercial marketing began in June 2016. The drug is authorized in all EU member states.

Pricing was established through German AMNOG arbitration in April 2017, setting annual treatment costs between €56,404 and €84,606 per patient per year (approximately 6-8 implants annually). Clinuvel adopted a uniform global pricing policy based on this framework.

Australia The Therapeutic Goods Administration (TGA) approved afamelanotide in October 2020, making it available to Australian EPP patients through authorized prescribers.

Other Markets As of 2025, these three markets (US, EU, Australia) represent the only jurisdictions where afamelanotide is commercially approved. The manufacturer has not pursued regulatory approval in other countries, partly due to the small global patient population (approximately 10,000 EPP patients worldwide).

Prescription Requirements

SCENESSE® is available only by prescription from licensed physicians. In the US, it is not classified as a controlled substance (it has no abuse potential), but it is a prescription-only medication due to its specialized administration requirements and the need for proper diagnosis and monitoring.

The drug is not available through retail pharmacies. Instead, it is distributed through a specialty pharmacy network and administered at certified treatment centers. The implant must be inserted by healthcare providers trained in the subcutaneous implantation procedure, typically dermatologists or specialists in porphyria management.

The prescribing information specifies that patients must have a confirmed diagnosis of EPP (typically via genetic testing showing ferrochelatase or ALAS2 mutations and elevated erythrocyte protoporphyrin levels). The treatment is not indicated for, and should not be prescribed for, cosmetic tanning or other uses outside the FDA-approved indication.

Insurance Coverage

United States Most insurance plans cover SCENESSE® for the approved EPP indication, though prior authorization is typically required. The annual cost without insurance would exceed $100,000 based on US pricing (approximately $13,000-$17,000 per implant, with 6 implants typically needed annually). Clinuvel has patient assistance programs for eligible uninsured or underinsured patients.

European Union Coverage varies by country and health system. In countries where pricing negotiations were completed, national health services or statutory insurance typically cover the treatment for diagnosed EPP patients. In the UK, NICE (National Institute for Health and Care Excellence) initially did not recommend NHS coverage based on cost-effectiveness calculations, though specialized porphyria centers may access it through other mechanisms.

Black Market and Unregulated Products

While pharmaceutical-grade afamelanotide is prescription-only, unregulated products marketed as "Melanotan" or "Melanotan I" are sold online, in some gyms, tanning salons, and through unlicensed "anti-aging" or "wellness" clinics. These products are illegal.

Legal Status of Unregulated Melanotan Products:

United States: Selling unapproved drugs for human use violates federal law. The FDA has issued warning letters to companies selling melanotan products. Possession for personal use occupies a legal gray area (generally not prosecuted), but use constitutes taking an unapproved drug of unknown safety and purity.
United Kingdom: Classified as an unlicensed medicine. Selling it is illegal; possession for personal use is not explicitly illegal but is strongly discouraged by health authorities.
European Union: Member states classify it as an unauthorized medicinal product. Sale and distribution are prohibited.
Australia: Classified as a prescription-only medicine, making possession without a prescription illegal.

Some sellers attempt to skirt regulations by labeling products "for research purposes only" or "not for human consumption," but this doesn't change their legal status when sold to consumers for self-administration.

Why This Matters: Unregulated products carry serious risks beyond legal concerns:

No quality control: Testing by regulatory agencies has found bacterial contamination, incorrect dosing (some vials contained 2-3 times the labeled amount), and mislabeling.
Unknown purity: May contain degradation products, manufacturing impurities, or even entirely different substances.
No medical supervision: Lack of proper diagnosis, dosing guidance, or monitoring for adverse effects.
Counterfeit risk: Some products claiming to be Melanotan I actually contain Melanotan II or other peptides.

Case reports of serious adverse events (severe infections, organ damage, rhabdomyolysis) have been linked to unregulated melanotan products, though causality is difficult to establish given the unknown composition of these products.

Off-Label Use

Off-label prescribing of approved medications is legal and common in medical practice. In theory, a physician could prescribe SCENESSE® for conditions other than EPP (for example, severe polymorphous light eruption unresponsive to other treatments). However, several factors limit this:

The specialized distribution system and administration requirements make access difficult outside EPP centers
Insurance would not cover off-label use
The high cost (~€56,000-€84,000 annually) makes patient self-pay unrealistic
The implant administration requires trained providers

In practice, off-label use appears to be rare. Clinuvel's vitiligo development program (if successful) would expand the approved indications, potentially making the drug accessible to a larger patient population.

Future Indications

If the Phase III vitiligo trial (CUV105) demonstrates efficacy, Clinuvel will likely seek regulatory approval for this indication in the US and EU. Results are expected in the second half of 2026, with potential regulatory submissions in 2027. Vitiligo affects approximately 0.5-2% of the global population (millions of people), which would dramatically expand the patient population eligible for treatment compared to EPP's ~10,000 patients worldwide.

Other potential indications (polymorphous light eruption, solar urticaria, other photodermatoses) could follow if clinical development resumes in these areas.

Frequently Asked Questions

Is Melanotan I the same as Melanotan II?

No. Despite similar names, they are structurally and functionally different peptides. Melanotan I (afamelanotide) is a linear 13-amino-acid peptide that selectively targets MC1R, producing primarily pigmentation and photoprotection. Melanotan II is a cyclic 7-amino-acid peptide that non-selectively activates MC1R, MC3R, and MC4R, producing pigmentation plus appetite suppression, sexual effects, and metabolic changes. Melanotan I is FDA-approved; Melanotan II is not approved anywhere and is illegal to sell in most countries.

Can I buy Melanotan I for tanning?

No. Pharmaceutical-grade afamelanotide (SCENESSE®) is only available by prescription for erythropoietic protoporphyria. It cannot legally be prescribed for cosmetic tanning. Products sold online or in gyms as "Melanotan I" are unregulated, illegal, and potentially dangerous due to lack of quality control and unknown purity. These should be avoided.

How long does Melanotan I take to work?

In EPP clinical trials, patients typically saw increases in pain-free sun exposure starting 2-4 weeks after the first implant, with peak effects around 6-8 weeks. Pigmentation changes (visible tanning) follow a similar timeline—gradual darkening over several weeks. This is slower than Melanotan II, which often produces visible tanning within 1-2 weeks. The slower onset reflects afamelanotide's more targeted MC1R activation and the natural timeline of melanogenesis.

Does Melanotan I cause cancer?

There is no evidence from clinical trials or post-marketing surveillance (including up to 10 years of use via compassionate access programs) that afamelanotide causes skin cancer. However, theoretical concerns exist because it stimulates melanocytes. Patients with personal history of melanoma were excluded from trials. Anyone using afamelanotide should have baseline and periodic skin examinations by a dermatologist to monitor for new or changing moles. The drug provides photoprotection, which could theoretically reduce skin cancer risk, but long-term epidemiological data are not yet available.

What's the difference between Melanotan I and PT-141?

PT-141 (bremelanotide) is a derivative of Melanotan II, not Melanotan I. PT-141 is a cyclic melanocortin agonist FDA-approved for hypoactive sexual desire disorder in premenopausal women. It works via MC4R activation in brain regions controlling sexual desire and has minimal tanning effects. Melanotan I is a linear melanocortin agonist selective for MC1R, used for photoprotection in EPP, with no sexual effects. The two peptides have entirely different structures, mechanisms, and clinical applications.

How much does SCENESSE® cost?

In the European Union, annual treatment costs range from €56,404 to €84,606 (approximately $60,000-$90,000 USD), based on 6-8 implants per year at €9,400-€10,600 per implant. In the UK, each implant costs approximately £13,209 ($17,000 USD) plus VAT. US pricing is similar. Insurance typically covers the cost for diagnosed EPP patients (with prior authorization), but out-of-pocket costs would be prohibitive. Patient assistance programs exist for eligible uninsured or underinsured patients.

Can I use Melanotan I if I have vitiligo?

Currently, no. Afamelanotide is not approved for vitiligo treatment. However, a Phase III clinical trial (CUV105) is ongoing, evaluating afamelanotide combined with narrowband UVB phototherapy versus phototherapy alone. If the trial succeeds, regulatory approval for vitiligo could follow (likely 2027-2028). Until then, the drug is only approved for EPP and cannot legally be prescribed for vitiligo outside of clinical trials.

Does Melanotan I suppress appetite or affect libido?

No. Unlike Melanotan II, which activates MC4R (appetite suppression) and MC3R/MC4R (sexual effects), afamelanotide is highly selective for MC1R. Clinical trials did not report changes in appetite, weight, or sexual function. This receptor selectivity is a key distinction between the two peptides.

How is SCENESSE® administered?

It is a 1.7 cm subcutaneous implant containing 16 mg of afamelanotide, inserted under the skin (usually around the hip or abdomen) by a trained healthcare provider. The procedure takes about 15 minutes and is performed under local anesthesia. The implant is bioabsorbable—it doesn't need to be removed. Most of the drug releases over the first 5 days, though effects last longer due to persistent melanogenesis. Implants are repeated every 2 months.

Is Melanotan I safe long-term?

Long-term safety data through 8 years of continuous use show no cumulative toxicity or new safety signals. The safety profile in long-term observational studies matched that seen in short-term clinical trials. Post-marketing surveillance in Europe (since 2016) and the US (since 2019) has not identified unexpected adverse events. However, data are limited to EPP patients; long-term safety in other populations (if approved for vitiligo or other indications) would need to be established through ongoing monitoring.

What are the side effects of Melanotan I?

The most common side effects are injection site reactions (21% of patients—redness, swelling, pain at implant site), nausea (19%), headache, and fatigue. These are generally mild and transient. Darkening of pre-existing moles occurs in some patients, requiring dermatologic monitoring. Serious adverse events are rare and have not been causally linked to the drug in clinical trials. The safety profile is substantially better than Melanotan II, which causes frequent severe nausea, blood pressure changes, and sexual side effects.

Bottom Line

Melanotan I—now known as afamelanotide and marketed as SCENESSE®—stands as the pharmaceutical success story in a peptide class marred by regulatory failures and underground markets. While its cyclic cousin Melanotan II became infamous for gym-floor distribution and "Barbie drug" panic headlines, afamelanotide took the legitimate path: rigorous clinical development, FDA approval, and integration into medical practice for a real therapeutic need.

The science is solid. Afamelanotide is a rationally designed α-MSH analog with two strategic amino acid substitutions that boost MC1R affinity and metabolic stability. Its receptor selectivity means it does what melanocortin agonists were originally designed to do—stimulate melanin production for photoprotection—without the appetite suppression, sexual effects, and safety concerns that torpedoed pharmaceutical development of broader-spectrum melanocortin agonists.

The clinical evidence is robust. Three pivotal Phase III trials involving 244 EPP patients demonstrated statistically significant increases in pain-free sun exposure, reductions in phototoxic reactions, and quality-of-life improvements. Long-term data through 8 years of treatment and European post-marketing surveillance since 2016 confirm sustained efficacy and an acceptable safety profile. For EPP patients whose lives are defined by avoiding daylight, afamelanotide represents the first systemic treatment option approved by major regulatory authorities.

But the bigger picture extends beyond EPP. The ongoing Phase III vitiligo trial (results expected 2026) could open afamelanotide to a patient population orders of magnitude larger than the ~10,000 EPP patients worldwide. If successful, it would address an unmet need in autoimmune depigmentation where only limited topical options exist. Potential future applications in polymorphous light eruption and other photodermatoses could further expand its utility, positioning afamelanotide as a cornerstone therapy in photoprotection and pigmentation disorders.

The regulatory status is unambiguous. This is a prescription medication, FDA and EMA approved, manufactured to pharmaceutical standards, and distributed through controlled channels. It is not a cosmetic tanning agent. It cannot be legally obtained without a prescription for the approved indication. Unregulated products sold as "Melanotan I" are illegal, uncontrolled in quality, and carry serious safety risks. The distinction between pharmaceutical-grade afamelanotide and black-market peptides is not semantic—it's the difference between medicine and Russian roulette with vials of unknown purity.

For researchers, clinicians, and patients navigating the peptide landscape, afamelanotide illustrates what happens when science meets regulatory rigor. It took decades—from 1980s tanning research in Arizona to 2019 FDA approval—but the result is a medication with proven efficacy, characterized safety, and legitimate medical applications. That's the story of Melanotan I: not a shortcut to a tan, but a treatment for people who desperately need protection from the sun.

Medical Disclaimer: This article is for educational purposes only and does not constitute medical advice. Afamelanotide (SCENESSE®) is a prescription medication approved only for erythropoietic protoporphyria. It should only be used under medical supervision with a valid prescription for an approved indication. Do not purchase unregulated peptides sold online or through unlicensed sources—these products are illegal, lack quality control, and pose serious health risks. Consult a healthcare provider for diagnosis, treatment options, and medical guidance regarding photosensitivity disorders or pigmentation concerns.

References

Harms, J. H., et al. (2009). α-Melanocyte-stimulating hormone: production and degradation. Peptides, 30(11), 1885-1890. https://pmc.ncbi.nlm.nih.gov/articles/PMC3936413/
Lim, H. W., et al. (2015). Afamelanotide for Erythropoietic Protoporphyria. New England Journal of Medicine, 373(1), 48-59. https://www.nejm.org/doi/full/10.1056/NEJMoa1411481
Biolcati, G., et al. (2015). Long-term observational study of afamelanotide in 115 patients with erythropoietic protoporphyria. British Journal of Dermatology, 172(6), 1601-1612. https://pubmed.ncbi.nlm.nih.gov/25494545/
U.S. Food and Drug Administration. (2019). SCENESSE® (afamelanotide) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210797s000lbl.pdf
Harms, J. H., et al. (2016). Melanocortin 1 Receptor: Structure, Function, and Regulation. Frontiers in Genetics, 7, 95. https://pmc.ncbi.nlm.nih.gov/articles/PMC4885833/
Aguilera, P., et al. (2023). Melanocortin 1 Receptor (MC1R): Pharmacological and Therapeutic Aspects. International Journal of Molecular Sciences, 24(15), 12152. https://pmc.ncbi.nlm.nih.gov/articles/PMC10418475/
Clinuvel Pharmaceuticals. (2023). CLINUVEL starts global Phase III vitiligo study. https://www.clinuvel.com/wp-content/uploads/2023/10/20231018-cuv-starts-global-phase-iii-vitiligo-study.pdf
Kadurina, M., & Kerl, H. (2021). Immunopathogenesis and management of polymorphic light eruption. Dermatologic Therapy, 34(6), e15167. https://pubmed.ncbi.nlm.nih.gov/34676645/
U.S. Food and Drug Administration. (2019). NDA 210797 Multi-Discipline Review. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/210797Orig1s000MultidisciplineR.pdf
Drugs.com. (2019). Scenesse (afamelanotide) FDA Approval History. https://www.drugs.com/history/scenesse.html
Balwani, M., & Desnick, R. J. (2012). The porphyrias: advances in diagnosis and treatment. Blood, 120(23), 4496-4504. https://www.ncbi.nlm.nih.gov/books/NBK563141/
Kühne, B., et al. (2024). German Cohort Observational Study to Investigate the Short- and Long-Term Safety and Clinical Effectiveness of Afamelanotide 16 mg (SCENESSE) in Patients With Erythropoietic Protoporphyria (EPP). Dermatology, 240(2), 191-199. https://pmc.ncbi.nlm.nih.gov/articles/PMC11906902/
LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. (2024). Afamelanotide. NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK602608/
Slominski, A., et al. (2004). The role of alpha-melanocyte-stimulating hormone in cutaneous biology. Journal of Investigative Dermatology Symposium Proceedings, 9(1), 11-17. https://pubmed.ncbi.nlm.nih.gov/9487022/
Böhm, M., et al. (2025). An overview of benefits and risks of chronic melanocortin-1 receptor activation. Journal of the European Academy of Dermatology and Venereology, 39(1), 20269. https://pmc.ncbi.nlm.nih.gov/articles/PMC11664455/
Clinuvel Pharmaceuticals. (2025). CLINUVEL recruits 200 patients in Phase III vitiligo trial CUV105. https://www.clinuvel.com/2025/05/clinuvel-recruits-200-patients-in-phase-iii-vitiligo-trial-cuv105-20250507/
Clinuvel Pharmaceuticals. (2017). CLINUVEL reaches agreement on German SCENESSE® pricing through AMNOG Arbitration Board. https://www.globenewswire.com/news-release/2017/04/12/959306/0/en/CLINUVEL-reaches-agreement-on-German-SCENESSE-pricing-through-AMNOG-Arbitration-Board.html
National Organization for Rare Disorders. (2024). Erythropoietic Protoporphyria. https://rarediseases.org/rare-diseases/erythropoietic-protoporphyria/
Giuliano, A. R., & Nolan, B. V. (2020). Pharmacokinetics and Pharmacodynamics of Afamelanotide and its Clinical Use in Treating Dermatologic Disorders. Clinical Pharmacokinetics, 56(3), 293-303. https://link.springer.com/article/10.1007/s40262-016-0501-5
Brugués, A. P., et al. (2014). Alpha-Melanocyte Stimulating Hormone: An Emerging Anti-Inflammatory Antimicrobial Peptide. BioMed Research International, 2014, 874610. https://pmc.ncbi.nlm.nih.gov/articles/PMC4130143/

Table of Contents