Melanotan II: pharmacology, pigmentation and safety

Melanotan II is a short, cyclic, synthetic peptide modelled on α-melanocyte-stimulating hormone (α-MSH). It was designed in academic laboratories to be more potent and longer-acting than the natural hormone, and it was tested in a handful of small human studies in the 1990s. It has never been licensed as a medicine. This review covers its pharmacology, what those early studies found, the safety signals reported since, and how it differs from the melanocortin medicines that regulators have approved.

This article summarises published research for scientific understanding. It does not describe or endorse any cosmetic, sexual or other personal use.

The melanocortin system

Melanocortins are peptides cut from a larger precursor protein, pro-opiomelanocortin (POMC). They include α-MSH and adrenocorticotropic hormone (ACTH). They act on five G protein-coupled receptors, MC1R to MC5R, and the system also has its own natural antagonists, the agouti proteins. Together these components regulate a remarkably wide range of functions, including pigmentation, adrenal steroid production, energy balance, sodium excretion, erectile responses and exocrine gland secretion^[1].

The receptors differ in what they recognise. MC2R responds essentially only to ACTH, whereas MC1R, MC3R, MC4R and MC5R all recognise α-MSH^[2]. MC1R is best known for its role in skin pigment cells. MC3R and MC4R are expressed mainly in the brain, and MC5R in a number of peripheral tissues^[2]. By the late 1990s, reviewers saw feeding, body weight and inflammation as the most promising targets for drugs acting on these receptors^[3].

From α-MSH to Melanotan II

Natural α-MSH is short-lived. In the late 1980s, a group at the University of Arizona designed cyclic analogues by linking two amino-acid side chains to form a lactam bridge. In frog and lizard skin assays, the best of these were up to about 100 times more potent than α-MSH, and their effects lasted longer^[4].

Melanotan II came from this work. It is a seven-residue lactam-bridged peptide, Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH₂, with superpotent melanotropic activity in laboratory tests^[5]. Its sister compound, melanotan I, is a linear analogue. The two were developed along different lines: melanotan I for tanning of the skin, and melanotan II for studies in male erectile dysfunction. A later derivative of melanotan II, PT-141, was taken forward by Palatin Technologies^[6], the company that also sponsored the phase 3 trials of bremelanotide^[7].

Receptor selectivity: why one peptide has many effects

Melanotan II is not selective. MC1R, MC3R, MC4R and MC5R all recognise it as a potent agonist^[2]. That is why it can affect pigmentation, which is mediated mainly by MC1R, as well as central functions such as sexual responses and body-weight regulation, in which MC4R has been implicated^[7][8].

Small structural changes can transform this profile. Replacing D-phenylalanine at position 7 of the same cyclic scaffold with the bulkier D-2′-naphthylalanine produced SHU9119. This compound is a potent antagonist at MC4R and MC3R but remains a full agonist at MC1R and MC5R^[2]. SHU9119 is now used as a research tool to block MC3R and MC4R. In conscious mice, melanotan II raised blood pressure and heart rate, and pretreatment with SHU9119 abolished these effects. That points to MC3R and MC4R pathways, and further experiments implicated increased sympathetic activity^[9].

How melanocortins drive pigmentation

Skin pigment is the body's main protection against the damaging effects of ultraviolet (UV) light. Melanocytes make two forms of melanin: eumelanin and pheomelanin. The synthesis of photoprotective eumelanin is regulated mainly by α-MSH and ACTH acting at MC1R. This activates the cyclic AMP pathway that UV-induced tanning requires^[10].

Melanocortins do more than darken the skin. In human melanocytes they stimulate proliferation and melanin production and protect the cells against UV-induced death. They also reduce hydrogen peroxide production and enhance repair of UV damage to DNA, independently of pigment^[10]. MC1R is also a melanoma susceptibility gene: certain variants are associated with red hair and a higher risk of melanoma^[10]. These points matter for safety. A compound that stimulates melanocytes acts on the same cells from which melanoma arises.

Published human research

The human studies of melanotan II were small and came from the same Arizona research group.

A summary of the two crossover studies reported severe nausea in 12.9% of participants^[13]. In the pilot study, the highest dose tested produced somnolence and fatigue in one of two participants^[5].

Melanotan I was studied separately. In three men, it produced tanning of the forehead, arms and neck that was still present three weeks after the last dose. It was not detected in plasma when taken by mouth^[14]. Later open-label and small randomised studies combined melanotan I with UV-B or sunlight. The reported side effects were minor, mainly nausea and transient facial flushing^[15].

For melanotan II itself, the human evidence ends there. Development moved to the derivative PT-141^[6]. No large, long or independent trials of melanotan II have been identified in the sources reviewed.

Safety signals since the 1990s

After the clinical studies ended, products sold as melanotan appeared outside any regulated setting. Most of what is known about their safety since then comes from case reports.

Moles and melanoma

• Changing and new moles. A 40-year-old man with previous melanoma and multiple atypical moles used a synthetic α-MSH product. He developed crops of new moles, many with atypical features, and his existing moles darkened and grew. After he stopped, the moles progressively lightened^[16]. Another report describes new moles and darkening of existing ones within 24 hours of a single injection of melanotan II^[17]. A third concerns a 16-year-old with an inherited melanoma-prone syndrome who used melanotan injections and a tanning studio^[18].
• Melanoma. A 20-year-old woman was diagnosed with melanoma three months after a course of melanotan II combined with sunbed use^[19]. Melanoma in situ has also been reported after use of melanotan^[20].
• Reviews. A 2017 review identified four case reports of melanoma arising in existing moles during or shortly after melanotan use. It concluded that conclusive evidence of a causal link was lacking^[21]. A systematic review of eruptive moles gathered 179 published cases. It grouped melanotan with immunosuppressive drugs and chemotherapy as suspected causes, together accounting for 41% of cases^[22].

Systemic toxicity and priapism

• Sympathomimetic toxicity. A 39-year-old man injected a product bought online, using a much larger amount than the starting amount he had understood to apply. He developed agitation, a rapid heart rate, sweating, dilated pupils and rhabdomyolysis, and needed intensive care^[23].
• Priapism. Case reports describe ischaemic priapism, a urological emergency, after melanotan injection. In one, erectile function had not recovered four weeks later^[24]. In another, surgery was needed after standard treatment failed^[25].

Unregulated products

UK dermatologists noted in 2010 that the Medicines and Healthcare products Regulatory Agency had warned of two further risks: blood-borne virus transmission through shared needles, and possible impurity of the products^[26]. When the contents of a product are unknown, adverse events cannot be attributed with confidence to melanotan II itself.

Not an approved melanocortin medicine

Three melanocortin peptide agonists show what approval involves. Each is a distinct molecule, with its own receptor profile, formulation and trial programme.

Afamelanotide is given as a controlled-release implant^[28]. In its trials, patients with erythropoietic protoporphyria were able to spend longer in direct sunlight without pain than those given placebo^[29]. Bremelanotide descends from the same line of research as melanotan II^[6][7], but its approval rests on its own large trials.

None of these approvals is evidence about melanotan II. Differences in receptor selectivity, formulation, manufacturing control and clinical testing are what separate a licensed medicine from an unlicensed compound, even within the same family of peptides.

Limitations of the evidence

• Very few participants. Fewer than 25 people took part in the three melanotan II studies, all conducted by one group^[5][11][12].
• Short duration. No long-term exposure data exist, so late effects on moles, melanoma or the cardiovascular system are unknown.
• Non-selective action. Effects at MC1R, MC3R, MC4R and MC5R cannot be separated with this compound^[2].
• Uncontrolled safety data. Post-trial evidence is limited to case reports, with confounding by UV exposure and uncertain product identity^[21].

Summary

Melanotan II is a potent, non-selective melanocortin agonist that came out of rational peptide design. It darkened the skin in a small pilot study and produced erections in two small crossover studies. Nausea, yawning and stretching were common in those studies, and severe nausea was not rare. Since the trials ended, case reports have linked unregulated use to changing moles, melanoma, systemic toxicity and priapism, although causation has not been established. Approved melanocortin medicines, such as afamelanotide, bremelanotide and setmelanotide, are distinct molecules with their own evidence, and their approval says nothing about the safety of melanotan II.