Melanotan I vs. Melanotan II: Safety & Efficacy

Both Melanotan I and Melanotan II started in the same lab, shared the same goal, and trace their lineage to the same natural hormone. Yet they diverge in nearly every way that matters — how they bind receptors, what they do inside the body, how regulators treat them, and what risks they carry. One became an FDA-approved drug. The other remains an unregulated compound sold through gray-market websites, flagged by health authorities on three continents.

This comparison breaks down the pharmacology, clinical evidence, safety data, and regulatory status of each peptide so you can understand what the science actually shows.

Origin Story: From Arizona to Two Divergent Paths

In the 1980s, researchers at the University of Arizona set out to create a synthetic version of alpha-melanocyte-stimulating hormone (α-MSH), the body's natural pigmentation trigger. The goal was pragmatic: develop a compound that could darken skin without UV exposure, potentially reducing skin cancer rates in sun-drenched populations.

They synthesized Melanotan I first — a 13-amino-acid linear peptide that swaps methionine for norleucine at position 4 and L-phenylalanine for D-phenylalanine at position 7. These two substitutions make it far more resistant to enzymatic breakdown than native α-MSH, giving it a longer half-life and greater potency at its target receptor.

Then came Melanotan II, a shorter, cyclic heptapeptide (seven amino acids) locked into a ring structure by a lactam bridge between aspartic acid and lysine. That ring makes it more compact, more metabolically stable, and more promiscuous — it binds strongly to multiple melanocortin receptors instead of just one.

During early human trials, Melanotan II produced an unexpected side effect: spontaneous penile erections. Researchers abandoned it as a tanning compound and pivoted the sexual arousal findings into a new line of investigation, eventually spawning PT-141 (bremelanotide), a metabolite of Melanotan II that the FDA approved in 2019 for hypoactive sexual desire disorder in premenopausal women.

Melanotan I, meanwhile, was licensed to an Australian company called Epitan (later renamed Clinuvel Pharmaceuticals), which steered it through clinical trials toward a medical indication: erythropoietic protoporphyria (EPP), a rare genetic disorder that makes sunlight excruciatingly painful.

Two peptides from the same lab. Two radically different trajectories.

The Receptor Question: Selective vs. Broad-Spectrum

Understanding why these peptides behave so differently requires a brief look at the melanocortin receptor system. The body has five melanocortin receptors (MC1R through MC5R), each governing distinct functions:

• MC1R — Found primarily on melanocytes (pigment cells) in the skin. Controls melanin production and plays a role in DNA repair after UV damage.
• MC2R — Located in the adrenal cortex. Regulates cortisol synthesis. Neither Melanotan I nor II binds here significantly.
• MC3R — Expressed in the brain and peripheral tissues. Involved in energy homeostasis and inflammatory regulation.
• MC4R — Located in the hypothalamus and other brain regions. Regulates appetite, energy expenditure, and sexual function. Mutations here are the most common monogenic cause of human obesity.
• MC5R — Found widely in peripheral tissues. Governs exocrine gland function (particularly sebaceous glands) and may modulate immune responses.

Melanotan I is a selective MC1R agonist. It binds strongly to the pigmentation receptor and has minimal meaningful activity at MC3R, MC4R, or MC5R. This selectivity keeps its effects largely confined to the skin.

Melanotan II is a nonselective agonist. It hits MC1R hard enough to produce significant tanning, but it also binds aggressively to MC3R, MC4R, and MC5R. That broad receptor profile is why it produces effects well beyond skin darkening — sexual arousal (MC4R), appetite changes (MC3R and MC4R), and alterations in exocrine function (MC5R).

The practical takeaway: Melanotan I does one thing well. Melanotan II does several things at once, and not all of them are desirable.

Efficacy: What Each Peptide Actually Does

Pigmentation

Both peptides increase melanin production, but they do so at different speeds and through slightly different receptor engagement.

Melanotan II produces noticeable skin darkening at lower cumulative doses and over a shorter timeline. This potency is part of its appeal in the unregulated tanning market — users report visible color change within days.

Melanotan I works more gradually. In clinical trials for EPP, pigmentation developed steadily over weeks, not days. The change is subtler and more uniform, reflecting its targeted action on MC1R without the overlapping central nervous system effects.

Photoprotection

This is where Melanotan I separates itself from a simple tanning agent. When afamelanotide (the pharmaceutical form of Melanotan I) binds MC1R, it does not just trigger melanin synthesis. It activates a cascade of protective processes:

• Eumelanin production independent of UV exposure. Unlike the body's natural tanning response, which requires UV-induced skin damage to initiate α-MSH release, afamelanotide stimulates eumelanin synthesis on its own. Eumelanin — the brown-black pigment, as opposed to the reddish pheomelanin — absorbs UV radiation and scavenges reactive oxygen species.
• Enhanced DNA repair. MC1R activation upregulates nucleotide excision repair (NER), the body's primary mechanism for fixing UV-induced DNA lesions like thymine dimers. Research has demonstrated roughly a 50% reduction in sunburn cells following Melanotan I administration.
• Anti-inflammatory signaling. Afamelanotide suppresses pro-inflammatory cytokines and stimulates interleukin-10 secretion, reducing the inflammatory component of UV damage.

This multi-layered photoprotection is why Clinuvel pursued afamelanotide for EPP rather than as a cosmetic tanning product. It functions less like a tanning bed and more like an internal sunscreen with built-in repair mechanisms.

Melanotan II also increases melanin production and therefore confers some UV protection. But its photoprotective profile has not been studied with anywhere near the same rigor, and its nonselective receptor binding introduces complications that led researchers to abandon it as a photoprotection candidate decades ago.

Sexual Function

Melanotan I has minimal effect on sexual arousal. Its selectivity for MC1R means it largely bypasses the hypothalamic circuits that govern libido.

Melanotan II, through its strong MC4R activity, produces pronounced effects on sexual function. In men, this includes spontaneous erections, increased libido, and in clinical studies, measurable improvements in erectile response. In women, increased arousal has been reported, though the data is thinner.

These sexual effects were significant enough to spawn a separate drug development program. PT-141 (bremelanotide) — a metabolite of Melanotan II that differs by a single chemical modification (a hydroxyl group where Melanotan II has an amide) — was engineered to maximize MC4R-mediated sexual effects while minimizing pigmentation. The FDA approved bremelanotide (brand name Vyleesi) in June 2019 for hypoactive sexual desire disorder in premenopausal women.

Appetite and Metabolism

Melanotan II's MC3R and MC4R activity produces appetite-suppressing effects in some users. This is pharmacologically consistent — MC4R activation is a well-established anorexigenic (appetite-reducing) pathway, and MC4R loss-of-function mutations are the most common monogenic cause of severe obesity.

Melanotan I does not produce meaningful appetite changes because it does not significantly engage MC3R or MC4R.

FDA Status: One Approved, One Not

Melanotan I (Afamelanotide / Scenesse)

The FDA approved afamelanotide on October 8, 2019, under the brand name Scenesse, for increasing pain-free light exposure in adult patients with erythropoietic protoporphyria. It received priority review and orphan drug designation. The European Medicines Agency had approved it earlier, in 2014. Australia followed.

The approved formulation is a 16 mg subcutaneous implant administered every 60 days by a healthcare professional. It is classified as a first-in-class medication — no other drug targeting this mechanism existed before it.

Two Phase III trials supported the approval. In the U.S. trial (94 patients), the median number of hours spent in direct sunlight on pain-free days over 180 days was 64 hours for afamelanotide versus 41 hours for placebo. In the European trial (74 patients), the median was 6 hours versus 0.75 hours. Long-term observational data covering 115 patients treated with over 1,000 implants across up to eight years showed sustained efficacy and an acceptable safety profile.

An important caveat: afamelanotide is approved only for EPP. Its safety and effectiveness as a cosmetic tanning agent in healthy individuals have not been established, and it is not indicated for that use.

Melanotan II

Melanotan II has never been approved by the FDA, EMA, TGA (Australia's Therapeutic Goods Administration), or any other national regulatory agency for any indication. No manufacturer has completed the clinical trial program required for approval.

It is illegal to sell Melanotan II for human consumption in the United States, United Kingdom, Australia, and Canada. The FDA has issued warning letters to companies marketing tanning injections. Australia's TGA has explicitly urged consumers to avoid products containing melanotan. Despite this, the peptide remains widely available through online vendors marketing it as a "research chemical."

Safety Profiles: A Stark Contrast

Melanotan I (Afamelanotide)

The clinical safety data for afamelanotide is substantial. Long-term follow-up in EPP patients — 314 patient-years of exposure across 115 individuals — found:

• Common side effects: Headache, nausea, fatigue, and injection site reactions. These were generally mild and transient.
• Pigmentation changes: About 30% of patients reported pigmentation-related changes, but all biopsied naevi were benign. No melanocyte malignancies were identified.
• No evidence of increased melanoma risk. Because eumelanin absorbs UV radiation and scavenges free radicals, some researchers have hypothesized that MC1R activation may actually be protective against melanoma, though this remains under investigation.
• High adherence rates: Patients continued treatment over years, suggesting the benefit-to-risk ratio was favorable enough to sustain long-term use.

Afamelanotide is also being evaluated as a photoprotective therapy in xeroderma pigmentosum, another condition involving extreme UV sensitivity, which reflects ongoing confidence in its safety profile.

Melanotan II

The safety data for Melanotan II comes primarily from short-term studies, case reports, and adverse event databases — not the kind of controlled long-term follow-up that afamelanotide has undergone.

Common side effects documented in clinical research and case reports include:

• Nausea — Reported in roughly 41% of subjects in a study of 80 male participants. This is one of the most consistent findings across all Melanotan II research.
• Facial flushing — Frequent, likely mediated by peripheral melanocortin receptor activation.
• Stretching and yawning — An unusual but frequently reported effect, occurring in 56% of subjects in the same study. This appears to be a central nervous system effect mediated by MC3R and MC4R.
• Fatigue and drowsiness — Common, particularly in the hours following injection.
• Appetite suppression — Expected given MC4R activation.

Serious adverse events documented in the medical literature include:

• Priapism. Multiple case reports describe prolonged, painful erections lasting 30+ hours after Melanotan II injection. One published case involved a 55-year-old man who required surgical decompression after cavernosal aspiration and phenylephrine injection failed to resolve the erection. Another case involved a 60-year-old man who developed priapism within 30 minutes of injecting 10 mg — ten times the commonly discussed dose — along with tachycardia, agitation, and profuse sweating.
• Rhabdomyolysis. A 39-year-old man who injected 6 mg (approximately six times the commonly discussed starting dose) developed diffuse muscle pain, tremors, tachycardia to 146 bpm, and a creatine phosphokinase level of 17,773 IU/L, requiring ICU admission for three days.
• Mole changes and potential melanoma link. Long-term use has been associated with darkening of existing moles, formation of new moles, and atypical melanocytic naevi. Published case reports describe melanoma developing in patients using Melanotan II — including a 42-year-old woman who developed melanoma on an abdominal nevus three months after a one-week course, and a 66-year-old man who developed melanoma in situ after four weeks of use. The causal relationship is not definitively established, but the biological plausibility is real: stimulating melanocyte proliferation through nonselective receptor activation, particularly when combined with UV exposure from tanning beds, could accelerate malignant transformation.
• Renal infarction. Documented in case reports, though the mechanism is not fully characterized.

Contamination and dosing risks compound the problem. Because Melanotan II is sold as a powder requiring reconstitution and self-dosing, errors are common. There is no quality control, no standardized concentration, and no guarantee that the product contains what the label claims. The Dutch Poisons Information Center reported a surge in Melanotan II adverse event consultations beginning in 2012, a pattern mirrored by poison control centers in other countries.

The Mole and Melanoma Question

This deserves special attention because it is the concern that most directly affects long-term health.

Melanotan II stimulates melanocyte proliferation through multiple receptor pathways. When you combine that pharmacological action with UV exposure — which most recreational users are also getting, since the whole point is to tan — you create conditions that may favor melanocytic transformation. The published case reports of melanoma in Melanotan II users, while not proof of causation, are consistent with what the pharmacology would predict.

Melanotan I, by contrast, stimulates eumelanin production through selective MC1R activation without the broad melanocyte stimulation driven by MC3R, MC4R, and MC5R engagement. Moreover, MC1R activation triggers DNA repair mechanisms (nucleotide excision repair) that actually help correct UV-induced mutations — the very mutations that drive melanoma development. The long-term safety data from EPP patients, including biopsied moles that all proved benign, supports a fundamentally different risk profile.

This distinction matters. Both peptides make skin darker. But the pathway to that darkness, and its downstream consequences, appear to be meaningfully different.

Who Uses These Peptides and Why

Afamelanotide (Melanotan I)

The approved patient population is small: adults with EPP, estimated to affect roughly 1 in 75,000 to 1 in 200,000 people. These patients experience severe pain, burning, and swelling upon exposure to visible light. For them, afamelanotide is not a cosmetic choice — it is a treatment that allows them to participate in normal outdoor life. Clinical trial data showed that treated patients spent significantly more time outdoors without pain compared to placebo.

Clinuvel is also investigating afamelanotide for other photosensitivity conditions, including xeroderma pigmentosum and variegate porphyria.

Melanotan II

The vast majority of Melanotan II use is cosmetic. Users, often young adults influenced by social media (the compound has been called the "Barbie drug" on TikTok), inject it or use nasal sprays to darken their skin without prolonged sun exposure. Some users also seek its libido-enhancing effects.

This population is self-dosing an unregulated compound purchased from unverified online sources, with no medical supervision, no standardized dosing, and no long-term safety data. Health authorities in the U.S., U.K., and Australia have issued repeated warnings. The FDA has attempted enforcement actions against sellers, but the online market persists.

For those interested in the broader context of peptides marketed for sunless tanning, it is worth noting that no tanning peptide — including Melanotan I — is approved for cosmetic use. The gap between "darkens skin" and "safe for cosmetic tanning" is precisely the gap that clinical trials are designed to evaluate, and Melanotan II has never completed that evaluation.

Head-to-Head Comparison

Category	Melanotan I (Afamelanotide)	Melanotan II
Structure	Linear, 13 amino acids	Cyclic, 7 amino acids
Receptor binding	Selective MC1R agonist	Nonselective (MC1R, MC3R, MC4R, MC5R)
Primary effect	Pigmentation + photoprotection	Pigmentation + sexual arousal + appetite suppression
Tanning speed	Gradual (weeks)	Rapid (days)
DNA repair	Yes — upregulates nucleotide excision repair	Not demonstrated
Sexual side effects	Minimal	Pronounced (erections, increased libido)
Common adverse effects	Headache, nausea, fatigue (mild)	Nausea (41%), flushing, yawning, drowsiness
Serious adverse events	None identified in long-term data	Priapism, rhabdomyolysis, mole changes, renal infarction
Melanoma risk signal	No — may be protective	Yes — case reports of melanoma; biological plausibility
FDA status	Approved (Scenesse, 2019) for EPP	Not approved for any indication
Long-term safety data	Yes — 8 years, 115 patients, 314 patient-years	No controlled long-term data
Legal status for tanning	Not approved for cosmetic use	Illegal to sell for human consumption

The Bottom Line

Melanotan I and Melanotan II are not interchangeable. They are not even close.

Melanotan I, in its pharmaceutical form as afamelanotide, is an FDA-approved medication with a defined mechanism, controlled manufacturing, clinical trial data, long-term safety follow-up, and a specific therapeutic indication. Its MC1R selectivity confines its effects largely to the skin, where it produces both pigmentation and genuine photoprotection through eumelanin synthesis and DNA repair upregulation.

Melanotan II is an unregulated, unapproved compound with broad receptor activity that produces a grab bag of effects — some desired (tanning, sexual arousal), some dangerous (priapism, rhabdomyolysis), and some potentially devastating (melanoma risk in the context of concurrent UV exposure). It has no standardized manufacturing, no clinical trial program, and no long-term safety data. What exists in the published literature is a patchwork of short-term studies and alarming case reports.

The pharmacology tells the story clearly. Receptor selectivity is not an abstract concept — it is the reason one of these peptides went through a decade of clinical development and earned regulatory approval, while the other remains a cautionary tale about what happens when a biologically active compound enters widespread unregulated use.

Neither peptide is approved as a cosmetic tanning agent. But if you are trying to understand the science behind these two compounds, the evidence points in one direction: selectivity matters, regulation matters, and the difference between a medicine and an uncontrolled substance is not a technicality. It is the entire point.

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This article is for educational purposes only. PeptideJournal.org does not sell peptides and has no financial relationships with peptide manufacturers or distributors. Melanotan I (afamelanotide/Scenesse) is approved only for erythropoietic protoporphyria. Melanotan II is not approved for human use by any regulatory agency. Consult a healthcare professional before considering any peptide-based therapy.