Melanotan II

Melanotan II (MT-II) is a synthetic cyclic heptapeptide analogue of alpha-melanocyte-stimulating hormone (α-MSH). It activates melanocortin receptors — primarily MC1R in skin melanocytes and MC4R in the hypothalamus — producing UV-independent skin darkening, appetite suppression, and (at clinical doses) spontaneous penile erection. It was developed at the University of Arizona by the Hadley/Hruby group in the 1980s–1990s and reached Phase I clinical testing for cosmetic tanning. It is not approved anywhere. Clinuvel Pharmaceuticals abandoned cosmetic MT-II development in the 2000s, pivoting to the structurally related linear analogue Melanotan I (afamelanotide / Scenesse), which is FDA-approved for erythropoietic protoporphyria. MT-II remains unregulated and is widely sold illicitly for cosmetic tanning. It has no direct aging-hallmark evidence and no DrugAge entry as of 2026-05-09.

Identity

• PubChem CID: 92432
• ChEMBL ID: CHEMBL430239 (resolved via PubChem CID 92432 cross-reference)
• DrugBank ID: not assigned (unapproved; illicit cosmetic use)
• WHO-INN: not assigned
• InChIKey: JDKLPDJLXHXHNV-MFVUMRCOSA-N (from PubChem)
• Molecular formula: C50H69N15O9
• Molecular weight: 1024.2 Da
• Chemical class: cyclic heptapeptide (synthetic α-MSH analogue)
• Core sequence: Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH2 — cyclized via lactam bond between Asp³ and Lys¹⁰

The cyclic constraint was introduced to improve receptor affinity and resistance to proteolytic degradation relative to linear α-MSH. The D-Phe residue at position 4 (vs. L-Phe in native α-MSH) further stabilises the pharmacophore conformation required for high-affinity melanocortin receptor binding.

MT-I vs MT-II disambiguation

This page covers Melanotan II (MT-II), the cyclic heptapeptide. Melanotan I (MT-I / afamelanotide / Scenesse) is a distinct linear peptide with a separate regulatory history.

Feature	Melanotan I (MT-I / afamelanotide)	Melanotan II (MT-II)
Structure	Linear 13-mer; [Nle4, D-Phe7]-α-MSH	Cyclic 7-mer lactam; Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH2
Regulatory status	FDA-approved 2019 (Scenesse); EMA-approved 2014	Not approved anywhere; illicit cosmetic use
Approved indication	Erythropoietic protoporphyria (EPP) — photoprotection	None
Developer	Clinuvel Pharmaceuticals	University of Arizona → Clinuvel (abandoned)
Selectivity	Relatively MC1R-selective	Non-selective: MC1R, MC3R, MC4R, MC5R
Erection side effect	Not reported at therapeutic doses	Prominent at Phase I doses (0.025 mg/kg SC)
Route (approved)	Subcutaneous implant (bioresorbable, 16 mg)	SC injection (illicit, unstandardised)

Conflation warning: Published literature on “melanotan” and “melanotans” (plural) frequently fails to distinguish MT-I from MT-II. Case reports of adverse events attributed to “melanotan” may involve MT-II purchased illicitly (variable purity; see Breindahl 2015) ¹. When reading primary literature, always confirm which peptide form was studied.

Mechanism of action

MT-II is a non-selective melanocortin receptor agonist. It activates class-A GPCRs (Gs-coupled) across multiple subtypes:

MC1R (primary cosmetic target — skin melanocytes): MC1R activation → Gs → adenylyl cyclase → cAMP → PKA → CREB / MITF phosphorylation → transcriptional upregulation of melanogenic enzymes (tyrosinase, TYRP1, TYRP2) → eumelanin synthesis. Eumelanin is the UV-protective form of melanin (photoprotective brown-black pigment), as opposed to phaeomelanin (UV-sensitising red-yellow pigment). MC1R activation thus recapitulates the UV-tanning response’s pigment-darkening component without the UV-induced DNA damage (CPDs, 6-4PPs) that normally triggers it ².

MC4R (hypothalamus — appetite/energy): MC4R is the primary anorexigenic receptor in the hypothalamic melanocortin circuit. MC4R agonism reduces food intake and increases energy expenditure. At Phase I doses, MT-II produces mild appetite suppression ³. PT-141 (bremelanotide), a structurally related MT-II derivative, was later developed as an MC4R-preferring agonist for female hypoactive sexual desire disorder (FDA-approved 2019 as Vyleesi) — a reminder that MT-II’s scaffold was pharmacologically productive, but required selectivity engineering.

Sexual arousal (MC4R, central): At Phase I doses (0.025 mg/kg SC), MT-II produced spontaneous penile erections in 2 of 3 subjects (persisting 1–5 hours) ³. This was an incidental finding that later generated the bremelanotide/PT-141 development program for erectile dysfunction and HSDD, distinct from the cosmetic-tanning indication.

MC3R, MC5R: MT-II binds MC3R (hypothalamic energy balance, less well characterised than MC4R) and MC5R (exocrine glands). Clinical consequences at cosmetic doses are not well characterised. no-mechanism

Pharmacokinetics

Route: Subcutaneous injection (Phase I; illicit use). No approved oral form exists — melanocortin peptides are rapidly degraded in the GI tract.

Stability advantage of cyclic structure: The lactam bridge between Asp³ and Lys¹⁰ reduces proteolytic susceptibility and constrains the peptide backbone into the bioactive conformation. Half-life is substantially longer than for linear α-MSH (which has a plasma half-life of minutes). Formal PK data from the Dorr 1996 Phase I are not reported in the abstract; dose-response-unclear for MT-II human PK parameters.

Product quality in illicit supply: LC-MS/MS analysis of three illicit internet-sold MT-II vials found actual content of 4.3–8.8 mg per vial versus the 10 mg labelled dose, with unknown impurities at 4–6% ¹. This adulteration renders dose estimation impossible from illicit products.

Clinical evidence

Phase I tanning study (Dorr 1996) ³

The first and pivotal Phase I human study: 3 healthy adult male volunteers received MT-II subcutaneously at escalating doses (0.01–0.03 mg/kg) on alternating days over two weeks (5 total injections). Two subjects demonstrated visible increased skin pigmentation (face, upper body, buttocks). Spontaneous penile erections lasting 1–5 hours post-injection occurred in 2 of 3 subjects. Adverse effects included mild nausea and somnolence at higher doses. Authors concluded: “MT-II has tanning activity in humans given only 5 low doses” and recommended 0.025 mg/kg as the basis for further trials.

Critical limitations: n=3; all male; no placebo control; pilot study only. The tanning effect was subjectively assessed; the erection side-effect dominated subsequent development attention and diverted the program toward sexual dysfunction rather than cosmetic tanning.

Evidence quality:

Dimension	Status
Pathway conserved in humans?	yes (MC1R melanocortin signalling is conserved)
Phenotype conserved?	yes (tanning confirmed)
Replicated in humans?	no independent replication in published form

Off-label and illicit use landscape

MT-II is sold globally as an unlicensed injectable peptide for cosmetic tanning, primarily via internet pharmacies. A qualitative study of online forums (n=205 user accounts; 623 discussion entries) documented that motivation for use included pre-holiday tanning and fitness-competition preparation, and that users routinely combined MT-II with sunbed sessions to amplify tanning ⁴. This co-use pattern is critical to interpreting the melanoma risk signal below.

Active clinical trial

One recruiting trial (ClinicalTrials.gov, searched 2026-05-09): NCT07437560, Phase 2 — MT-II as adjunct to narrowband UVB phototherapy for repigmentation in stable nonsegmental vitiligo (not an aging or cosmetic-tanning indication). clinical-trials-active: 1.

Safety and melanoma risk

Adverse effects at Phase I doses

Reported in Dorr 1996 ³: mild nausea, somnolence, spontaneous penile erections. These are on-target pharmacological effects (MC4R: erections; MC4R/MC3R: CNS effects). Nausea is a class effect of systemic melanocortin agonism.

Additional case reports from illicit use: acute ischemic priapism (a urological emergency requiring surgical intervention) has been reported in three cases in the literature — Dreyer et al. 2019 (BMJ Case Reports), Nelson et al. 2012 (Clin Toxicol; concurrent with a pain pill, complicated by rhabdomyolysis), and the Mallory 2021 index case (55-year-old male, 2 mg SC, 30-hour priapism requiring operative penoscrotal decompression after phenylephrine failure; new erectile dysfunction at 15-week follow-up) ⁵. Cardiovascular effects (hypertension, tachycardia) at supraphysiological doses have been reported anecdotally in online communities; no systematic characterisation exists. long-term-unknown

Melanoma and melanocytic naevi

Eruptive melanocytic naevi (mole proliferation): A systematic review of eruptive melanocytic nevi (Burian and Jemec 2019, n=multiple case series pooled) identified melanotan as a suspected trigger in 41% of cases ⁶. Five associated melanoma cases were documented in that review, though the authors noted: “the nature of the data precluded assessment of risk of malignant transformation.”

Case reports of melanoma: Habbema et al. 2017 (literature review, n=case reports) documented four reports of melanomas emerging from existing moles during or shortly after melanotan use ⁷. The review notes: “conclusive evidence linking these phenomena is lacking” and emphasises that melanotan use is embedded in UV-seeking behaviour (sunbed co-use), making causal attribution to the peptide itself vs. sunbed UV exposure impossible in retrospective case data.

Attribution question: The user-provided framing states “a 2021 review noted increased melanoma incidence among users, though authors attributed this to UV-seeking behavior rather than the peptide itself.” The specific 2021 review with this exact framing was not identified in the literature search (searches for 2020–2023 reviews on melanotan + melanoma + UV-seeking returned no matching 2021 review paper). The Gilhooley 2021 qualitative user-experience study ⁴ documented UV-seeking co-use patterns (sunbeds) but did not measure melanoma incidence. The closest matching source for the UV-attribution argument is Habbema 2017 ⁷, which acknowledged the co-variate but stopped short of attribution. This attribution claim requires source confirmation by wiki-verifier. needs-replication

Plausible biological mechanism for direct risk: MC1R agonism theoretically could stimulate melanocyte proliferation independently of UV. MC1R signalling through MITF upregulates not only melanogenic enzymes but also survival factors. However, whether supraphysiological MC1R agonism is pro-tumorigenic in human melanocytes has not been tested in adequately powered studies. The existing evidence base is retrospective case-series and qualitative observation. no-mechanism

Current evidence summary: The melanoma signal is real in case reports and plausible mechanistically, but population-level incidence data with adequate UV-exposure adjustment do not exist. The translation-gap classification translation-blocked-safety reflects this uncertainty — the safety profile cannot be characterised without prospective data.

Regulatory history

Event	Year	Notes
MT-II synthesis / first characterisation	~1985–1991	Hadley and Hruby group, University of Arizona; Levine N, Dorr RT et al.
Phase I tanning pilot (Dorr et al.)	1996	n=3; established proof-of-concept; erection side effect flagged
Clinuvel begins clinical development of MT-I (afamelanotide)	early 2000s	Pivoted from MT-II to linear MT-I (better safety profile, no erection SE, EPP indication)
Clinuvel abandons MT-II	~2000s	MT-II’s non-selective receptor profile and side-effect burden drove pivot; MT-I suited EPP indication
EMA approval: afamelanotide (Scenesse) for EPP	2014	MT-I, not MT-II
FDA approval: afamelanotide (Scenesse) for EPP	2019	MT-I, not MT-II
MT-II illicit market grows	2000s–present	Internet-sold vials; unregulated; inconsistent purity
MT-II banned in UK (unlicensed medicine)	ongoing	Sale illegal; multiple EU jurisdictions ban sale
NCT07437560 — MT-II for vitiligo (Phase 2)	2026–present	First institutional trial; vitiligo repigmentation indication; not cosmetic tanning

Classification and aging context

• SENS strategy: Not applicable — no direct aging-damage correspondence
• Hallmarks: None directly established (hallmarks: [], R36 wave-1 convention)
• DrugAge entry: Not present as of 2026-05-09 unsourced
• Aging relevance: None demonstrated. The UV-independent tanning mechanism is theoretically relevant to skin cancer prevention by reducing UV exposure needed to achieve tanning, but no population-level photoprotection evidence exists for MT-II.
• Energy-sensing note: MC4R appetite suppression converges on the same downstream effectors (food intake reduction, energy expenditure) as CR/mTOR interventions, but MT-II has not been studied in aging-biology contexts.

Limitations and knowledge gaps

• needs-human-replication — No Phase II or Phase III tanning trial has been completed. One Phase I study (n=3; all male) is the only controlled human pharmacology data ³.
• needs-replication — Melanoma risk: population-level incidence data with objective UV-exposure co-variate adjustment do not exist.
• no-mechanism — Direct pro-melanocytic tumorigenicity of supraphysiological MC1R agonism has not been tested in melanocyte culture or in vivo at MT-II-equivalent concentrations.
• dose-response-unclear — Human PK parameters (half-life, Cmax, AUC) for MT-II were not reported in the Phase I abstract; illicit dosing is unstandardised.
• long-term-unknown — No safety data beyond short-term Phase I exposure. All long-term safety information derives from uncontrolled illicit use.
• ChEMBL ID resolved as CHEMBL430239 (verified via PubChem CID 92432 cross-reference on 2026-05-09).
• Product quality: Illicit vials contain 43–88% of stated dose with ~5% unknown impurities ¹; any “real-world” report based on illicit MT-II use is confounded by dose and purity uncertainty.
• 2021 melanoma review — source not located: Exhaustive searches in PubMed (terms: “melanotan melanoma review”, “melanotan melanoma”, “melanotan melanoma incidence”; date filters 2019–2023) and Europe PMC returned no 2021 review paper specifically measuring melanoma incidence among MT-II users with UV-seeking behavior as a confound. The closest paper is Gilhooley 2021 ⁴, a qualitative user-experience study (not an incidence study). The UV-attribution argument in the body is supported by Habbema 2017 ⁷ but the framing of a dedicated 2021 incidence review cannot be sourced. unsourced — claim removed from narrative; retained here for documentation.

Footnotes

Footnotes

1. doi:10.1002/dta.1655 · Breindahl T, Evans-Brown M, Hindersson P, McVeigh J, Bellis M, Stensballe A, Kimergård A · Drug Testing and Analysis 2015;7(2):164–172 · analytical · n=3 illicit MT-II vials (different internet shops) · LC-UV-MS/MS; actual MT-II content 4.32–8.84 mg vs 10 mg labelled; unknown impurities 4.1–5.9% in 2/3 samples · 34 citations (archive confirmed; closed access, not downloaded) ↩ ↩² ↩³

2. doi:10.1016/j.peptides.2005.01.029 · Hadley ME, Dorr RT · Peptides 2006;27(4):921–930 · review · n/a · describes MT-I and MT-II development history, receptor pharmacology, and commercialisation trajectory; describes PT-141 program for sexual dysfunction · 99 citations (archive confirmed) · not downloaded ↩

3. doi:10.1016/0024-3205(96)00160-9 · Dorr RT, Lines R, Levine N, Brooks C, Xiang L, Hruby VJ, Hadley ME · Life Sciences 1996;58(20):1777–1784 · n=3 (healthy adult males) · Phase I pilot · in-vivo (human) · model: subcutaneous MT-II 0.01–0.03 mg/kg q.o.d. × 2 weeks · primary outcome: skin pigmentation (visible) in 2/3 subjects; spontaneous erections in 2/3 subjects; nausea/somnolence at upper doses · 131 citations (archive confirmed) · not downloaded ↩ ↩² ↩³ ↩⁴ ↩⁵

4. doi:10.1159/000514492 · Gilhooley E, Daly S, McKenna D · Dermatology (Basel) 2021;237(4):546–554 · qualitative study · n=205 users (623 discussion entries) · documents UV-seeking co-use (sunbeds) as common MT-II use context; motivations: pre-holiday tanning and fitness-competition preparation; no melanoma incidence measurement · 6 citations (archive confirmed; closed access, not downloaded) ↩ ↩² ↩³

5. doi:10.1016/j.esxm.2020.100298 · Mallory CW, Lopategui DM, Cordon BH · Sexual Medicine 2021;9(1):100298 · case report · n=1 (55-year-old male; 2 mg MT-II SC to abdomen; 30-hour priapism duration on presentation) · acute ischemic priapism following MT-II SC injection; cavernosal aspiration + phenylephrine (4,500 mcg total) failed; required operative penoscrotal decompression; at 15-week follow-up patient had new erectile dysfunction (rigidity 4/10, corpora fibrosis); authors report this as third MT-II priapism case in literature (citing Dreyer 2019 BMJ Case Rep + Nelson 2012 Clin Toxicol) · gold OA (PDF verified 2026-05-09) ↩

6. doi:10.1007/s40257-019-00444-8 · Burian EA, Jemec GBE · American Journal of Clinical Dermatology 2019;20(6):819–832 · systematic review · n=multiple pooled case series · melanotan identified as trigger in 41% of eruptive melanocytic nevi cases; 5 associated melanoma cases documented; authors note precluded risk-of-malignant-transformation assessment · 31 citations (archive confirmed; closed access, not downloaded) ↩

7. doi:10.1111/ijd.13585 · Habbema L, Halk AB, Neumann M, Bergman W · International Journal of Dermatology 2017;56(10):975–980 · review · n=case reports (exact n not specified in abstract) · documents four melanoma cases during/after melanotan use; notes melanotan embedded in UV-seeking behaviour; “conclusive evidence linking these phenomena is lacking” · 28 citations (archive confirmed; closed access, not downloaded) ↩ ↩² ↩³