Melanotan II research: what the published studies show

Identity, and Three Molecules It Is Not

Melanotan II is a cyclic lactam analogue of alpha-melanotropin, with the ring closed between the side chains of an aspartate at position 5 and a lysine at position 10.^[1] Its sequence is Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH2 and it corresponds to the alpha-MSH(4-10) fragment rather than the whole hormone.^[1]

Three neighboring molecules are named here so they can be kept out. Afamelanotide is a different alpha-MSH analogue. Bremelanotide, sold separately on this site, is derived from this one. Alpha-MSH is the endogenous parent, and no result from any of the three appears below.

The Design Paper, and What It Measured

A 1989 paper designed cyclic lactam fragment analogues of alpha-melanotropin.^[1] Melanotan II is the alpha-MSH(4-10) member of that series, arrived at through structure-activity work and molecular dynamics.^[1]

Potency was measured in amphibian and reptile skin bioassays, not on mammalian receptors.^[1] The lizard skin scale sets alpha-MSH at 1.^[1] This member scored about 90, the corresponding 4-13 analogue about 100, and the glutamate-bridged versions only 6 and 9.^[1] Similar results appeared in the frog skin assay but the analogues were much less potent there.^[1]

Ring size mattered too.^[1] Cyclic melanotropins with 23-membered rings showed about 100-fold higher melanotropic potency than alpha-MSH, with selectivity for lizard over frog melanocyte receptors, and changing the ring size from 23 reduced potency.^[1]

The Human Receptor Subtypes, and the One That Was Not Tested

Melanotan II and SHU9119, with five cyclic disulphide alpha-MSH analogues, were tested on cells transiently expressing the human MC1, MC3, MC4 and MC5 receptors.^[2] The cyclic lactams showed higher overall affinity than any of the cyclic disulphide analogues tested.^[2]Substituting D-Phe7 with D-Nal(2')7 in the cyclic lactam shifted selectivity toward MC4. Those substituted compounds are different molecules from this one.^[2]

A 1999 study calls it a potent nonselective agonist and uses it as the comparator for modified analogues at the human MC3, MC4 and MC5 receptors.^[3] Replacing Nle4 with proline gave affinity and agonist potency at hMC4 similar to Melanotan II, with about 400-fold lower potency at hMC5 and about 20-fold lower at hMC3.^[3]

MC2R was not tested in either study.^[2][3] A 1995 paper states in its introduction that the MC2 receptor primarily recognizes only ACTH peptides.^[4] That is background about the receptor, not a measurement of this compound at it, and the live page's claim of "no activity at MC2R" is an inference from it rather than a result. It is withdrawn.

The Antagonist Series Built on the Same Scaffold

Substituting a bulky aromatic residue at position 7 of the Melanotan II scaffold produces potent and selective melanocortin antagonists.^[4] The D-p-iodophenylalanine and D-2'-naphthylalanine analogues each gave pA2 values of 10.3 in the frog skin assay.^[4] The D-2'-naphthylalanine compound was a potent MC4 antagonist at pA2 9.3 with minimal agonist activity.^[4]

The D-p-chloro and D-p-fluoro analogues showed no antagonist activity at any melanotropin receptor and were full agonists in the frog skin assay.^[4] These are analogues, not this compound, and the section is here because the scaffold is shared and the results are frequently attributed to the parent.

The Clinical Literature Arising From Unregulated Use

This section reports case reports. Each is a single patient, none is controlled, and none establishes causation. They are here because they are a large share of what is indexed on this compound, and reporting the receptor work without them would misdescribe the literature.

On melanocytic lesions, a 2012 report describes melanoma in situ associated with melanotan use, and notes that reports of dysplastic naevi and melanoma associated with melanotropic peptides already existed.^[5] A separate 2012 report followed a man's naevi by sequential video dermoscopy before and during use of an internet-purchased alpha-MSH-like preparation.^[6] The dermoscopic changes observed made it difficult to differentiate a naevus from a melanoma.^[6] That is a diagnostic problem as well as a lesion one.^[6]

On systemic toxicity and rhabdomyolysis, a 2012 clinical toxicology report describes a man presenting two hours after use with diffuse body aches, sweating, anxiety and tremors.^[7] Blood pressure was 151/85 and heart rate 130, peaking at 146.^[7]Creatine phosphokinase was 1,760 IU/L on presentation and rose to 17,773 IU/L twelve hours later, with creatinine 2.25 mg/dL and troponin 0.23 ng/mL.^[7] Urinalysis showed blood with red cell casts and almost no red cells.^[7] He was managed in intensive care for three days, and creatine phosphokinase fell to 2,622 IU/L with creatinine improving to 1.23 mg/dL.^[7]

That case carries something most do not.^[7] The substance was analyzed by mass spectrometry and confirmed as Melanotan II against an industry-purchased standard. The usual objection to case reports on unregulated products, that the material may not have been what it was sold as, does not apply to this one. That paper drew a letter to the editor and an author response, at PMIDs 23537392 and 23551090; neither was read for this page and neither is cited.

On priapism, a 2021 report describes an acute ischemic episode following use.^[8] Cavernosal aspiration and irrigation with intracavernous phenylephrine did not achieve detumescence, and operative penoscrotal decompression was required.^[8]The same paper notes that Melanotan II has been investigated as a candidate agent in erectile dysfunction, which is the reason a derived analogue exists.^[8]

Two further relevant records are excluded for having no indexed abstract, named so nobody adds them later: PMID 24334249, eruptive naevi and darkening of pre-existing naevi, Eur J Dermatol 2014; and PMID 28905366, on unregulated use as a public health interest to Australian dermatologists, Australas J Dermatol 2017. Both were checked and both lack an abstract.

What Is Actually in Material Sold Online

Vials sold as injectable skin-tanning products were purchased from three online shops and analyzed by liquid chromatography with ultraviolet detection and tandem mass spectrometry, with identity verified by retention time and five qualifying fragment-ion ratios.^[9]Each shop claimed 10 mg of Melanotan II per vial. The measured content ranged from 4.32 to 8.84 mg.^[9] Samples from two shops carried unknown impurities of 4.1 to 5.9 per cent; impurities in the third shop's samples were below the quantification limit.^[9] The authors conclude that users of such products may be exposed to a range of potential harms given that the products are manufactured, distributed and supplied from an illicit market.^[9]

A separate 2021 study characterized Melanotan II and bremelanotide in eight samples confiscated by police alongside anabolic steroids, hormone modulators and stimulants.^[10] It is cited for what it shows about the market these compounds circulate in, not for any biological result.^[10]

Regulatory Status

Melanotan II is the active ingredient of no prescription medicine and has no approved human use.

A different alpha-MSH analogue does hold approval, which is why the two are confused. That approval covers a separate molecule and says nothing about this one. No result for that molecule appears anywhere on this page.

On the WADA Prohibited List, this page asserts nothing. The live list could not be read here. A section number must be checked against the live list before any doping statement is published.

State of the Evidence

Roughly 278 records are indexed for melanotan and 242 for melanotan II. Ten are cited here.

The pharmacology and the clinical literature answer different questions.^{[1][2][3][5][6][7][8]} The receptor work establishes what the molecule binds and how potent it is in cell and skin assays. The case literature records what happened to people who used unregulated product. Neither speaks to the other, and this page keeps them in separate sections for that reason.

Every human report cited here is a case report.^[5][6][7][8] Case reports establish that something happened and can suggest a cause. They establish neither incidence nor causation. No controlled human trial of this compound was located.

Two of the four case reports concern the pigment system and two do not.^[5][6][7][8] Melanoma in situ and dermoscopic confounding sit close to what the molecule is designed to do. Rhabdomyolysis and priapism do not.

The product-content work matters for reading everything above.^[9] Vials claiming 10 mg contained between 4.32 and 8.84 mg, with unidentified impurities up to 5.9 per cent, so any case report on internet-purchased material carries an open question about what was administered. Reference 7 is the exception, because the substance in that case was analyzed and confirmed.^[7]

Authorship concentrates in the pharmacology, with Victor Hruby an author of references 1, 2 and 4.^[1][2][4] The clinical reports come from unrelated groups in different countries.

Nothing here is extrapolated from a neighbor. Bremelanotide is sold separately here and no result from it appears above, and no alpha-MSH result appears at all.