Melanotan II
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Cyclic melanocortin agonist — non-selective MCR agonist producing skin tanning (MC1R), sexual arousal (MC4R), and metabolic effects (MC3R) with a significant adverse event profile.
Quick Facts
| Property | Value |
|---|---|
| Also Known As | MT-II, MT-2, Melanotan 2 |
| Category | Sexual Health / Cosmetic |
| Sequence | Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH2 (cyclic heptapeptide analogue of alpha-MSH) |
| Molecular Weight | ~1024.2 Da |
| Molecular Formula | C50H69N15O9 |
| PubChem CID | 92432 |
| Administration | SubQ |
| Typical Dose Range | 0.25-1.0 mg SubQ (loading); 0.5 mg q2-3d (maintenance) |
| Half-Life | ~33 minutes |
| Storage | Lyophilized: -20C for 2+ years; room temp stable weeks. Reconstituted: 2-8C, up to 30 days |
| FDA Status | NOT approved — significant safety concerns; national health warnings issued in multiple countries |
| WADA Status | Prohibited (S0 — Non-Approved Substances) |
Mechanism of Action
Melanotan II is a synthetic cyclic analogue of alpha-melanocyte-stimulating hormone (alpha-MSH) engineered at the University of Arizona in the 1980s-1990s for tanning research. Unlike its derivative PT-141 (bremelanotide), which was structurally modified for MC3R/MC4R selectivity, Melanotan II retains non-selective agonist activity across all five melanocortin receptor subtypes. This broad receptor profile is responsible for both its multifunctional effects and its substantial adverse event burden (PMID: 15996790).
MC1R agonism (tanning): Melanotan II stimulates melanocortin-1 receptors on epidermal melanocytes, activating adenylyl cyclase –> cAMP –> CREB –> MITF transcription factor cascade. This upregulates tyrosinase and TRP-1/TRP-2 enzymes, shifting melanin synthesis from pheomelanin (reddish, UV-vulnerable) to eumelanin (brown/black, UV-protective). The tanning effect occurs without UV exposure, though UV accelerates and deepens pigmentation. Unlike the selective MC1R agonist Melanotan 1 (afamelanotide), Melanotan II produces uneven, patchy hyperpigmentation in many users due to variable melanocyte density and receptor expression across body regions (PMID: 9679884).
MC4R agonism (sexual function): MC4R activation in the medial preoptic area and paraventricular nucleus stimulates presynaptic dopamine release, producing sexual arousal, spontaneous erections in males, and increased genital sensation in both sexes. This is the same mechanism exploited by PT-141, but Melanotan II activates MC4R non-selectively alongside all other MCR subtypes, increasing both efficacy and side-effect risk.
MC3R agonism (metabolic): MC3R activation modulates energy homeostasis, reducing food intake and altering body composition. This contributes to appetite suppression observed by users but also to nausea and GI disturbance.
MC5R agonism (exocrine): Exocrine gland stimulation affects sebaceous and sweat gland output. Clinical significance is limited but may contribute to skin changes observed with chronic use.
Key Research Areas
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Melanocortin Receptor Pharmacology: Melanotan II was a foundational tool compound for characterizing the melanocortin receptor family. Hruby et al. used MT-II to define structure-activity relationships of alpha-MSH analogues, leading to the development of selective MC4R agonists including bremelanotide (PMID: 15996790).
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Tanning and Photoprotection: Early Phase I/II trials at University of Arizona demonstrated dose-dependent skin darkening in fair-skinned individuals, with eumelanin confirmed by skin biopsy. However, the non-selective profile and injection route prevented further clinical development for this indication (PMID: 9679884).
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Adverse Event Documentation: Critical case reports have documented priapism requiring emergency intervention, rhabdomyolysis with acute kidney injury (PMID: 23121206), and changes in melanocytic nevi including development of dysplastic moles. A systematic review of case reports raised concern for possible melanoma association with chronic use (PMID: 28266027).
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Erectile Function: Preclinical and early clinical work demonstrated potent pro-erectile effects via central MC4R activation, which led to the development of PT-141 as a safer, more selective successor compound.
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Public Health Surveillance: Multiple national regulatory agencies (TGA Australia, MHRA UK, Health Canada) have issued public health warnings about Melanotan II sold via unregulated online sources, citing quality control concerns, contamination, and serious adverse events.
Evidence Level Summary
| Evidence Type | Count | Notes |
|---|---|---|
| Human RCTs | 1 | University of Arizona Phase I tanning trial (limited N) |
| Human observational | 1 | User surveys and adverse event series |
| Animal in vivo | 1 | Rodent MC4R erectile function, feeding behavior models |
| In vitro | 1 | MCR binding affinity and selectivity profiling |
| Case reports | 1 | Rhabdomyolysis, priapism, melanoma association case series |
Clinical Applications
- Sexual Health — Pro-erectile and pro-arousal effects via MC4R; however PT-141 is the safer, FDA-approved alternative for this indication
- Skin Health — Tanning/pigmentation via MC1R; however Melanotan 1 (afamelanotide/SCENESSE) is the selective, approved alternative
Clinical guidance: For sexual health applications, PT-141 (bremelanotide/Vyleesi) is strongly preferred as it is FDA-approved, MC3R/MC4R selective, and has an established safety profile. For tanning/photoprotection, Melanotan 1 (afamelanotide/SCENESSE) is FDA/EMA-approved and MC1R-selective with an excellent safety record. Melanotan II combines both effects non-selectively at the cost of significantly higher adverse event risk.
Protocols Using This Peptide
- Sexual Health Protocol — Listed as alternative but NOT preferred; PT-141 is first-line
Ageless Peps Products
- AP-melanotan-2-vial — Melanotan 2 10mg Vial, SubQ, $40 (WC ID: 767)
Dosing Reference
Research Dosing Ranges (from literature)
| Route | Dose Range | Frequency | Duration | Source |
|---|---|---|---|---|
| SubQ | 0.1-0.25 mg (test dose) | Single dose | Initial tolerance assessment | Clinical practice |
| SubQ | 0.5-1.0 mg (loading) | Daily for 5-10 days | Loading phase | PMID: 9679884 |
| SubQ | 0.5 mg (maintenance) | Every 2-3 days | Maintenance | User reports |
Cycling
Loading phase: 0.25-1.0 mg daily for 5-10 days, starting at the lowest dose and titrating. Maintenance: 0.5 mg every 2-3 days to sustain tanning effect. Evening dosing is strongly recommended as nausea peaks at 1-2 hours post-injection. AVOID continuous daily dosing beyond loading phase due to cumulative risk of permanent hyperpigmentation, nevi changes, and priapism. Antiemetic availability (ondansetron) is recommended. Many practitioners do not recommend Melanotan II at all given the availability of selective alternatives.
Contraindications & Safety
SAFETY IS CRITICAL FOR THIS COMPOUND. Melanotan II carries substantially higher risk than selective melanocortin agonists.
- Contraindications: Active or history of melanoma (absolute — melanocortin stimulation may promote melanocyte proliferation); history of priapism (absolute); cardiovascular disease (blood pressure elevation); dark skin phototypes Fitzpatrick IV-VI (severe, patchy, PERMANENT hyperpigmentation); pregnancy/nursing (unknown reproductive effects); concurrent phosphodiesterase inhibitors (extreme priapism risk)
- Common side effects: Severe nausea (40-60%, dose-limiting), facial flushing (30%+), spontaneous erections, yawning/stretch reflex activation, fatigue, injection site pain
- Serious adverse events documented:
- Priapism requiring emergency surgical intervention (ischemic priapism >4 hours)
- Rhabdomyolysis with acute kidney injury requiring hospitalization (PMID: 23121206)
- Dysplastic nevi — new or changing moles with atypical features on dermatoscopy
- Possible melanoma association — case series report new melanoma diagnoses in chronic users (PMID: 28266027)
- Permanent focal hyperpigmentation — dark patches that do not resolve after discontinuation
- Hypertension — transient blood pressure elevation
- National health warnings issued by TGA (Australia), MHRA (UK), Health Canada
- Drug interactions: PDE5 inhibitors (extreme priapism risk — absolute contraindication for concurrent use); antihypertensives (additive BP effects); naltrexone (reduced absorption)
- Pregnancy/nursing: Contraindicated. No human reproductive data available.
- Special populations: Not recommended for individuals under 18. Hepatic/renal impairment data absent. Users should undergo baseline dermatological examination and regular mole mapping during and after use.
Comparison to Selective Alternatives
| Feature | Melanotan 1 (Afamelanotide) | Melanotan II | PT-141 (Bremelanotide) |
|---|---|---|---|
| FDA Status | Approved (EPP, 2019) | Not approved | Approved (HSDD, 2019) |
| Receptor Selectivity | MC1R only | MC1R/3R/4R/5R | MC3R/MC4R |
| Tanning | Yes (even, controlled) | Yes (uneven, intense) | Minimal |
| Sexual effects | None | Yes (uncontrolled) | Yes (controlled, as-needed) |
| Priapism risk | None | Significant | None at approved dosing |
| Nausea severity | Mild, transient | Severe (40-60%) | Moderate (~40%) |
| Overall safety | Excellent | High risk | Good |
Cancer Considerations
CONTRAINDICATED — Melanoma risk. Three case reports document melanoma (cutaneous and mucosal) in Melanotan II users (PMID-24355990, PMID-22724573, PMID-40210573). Risk is especially elevated with concurrent UV/tanning bed exposure. Paradoxically, topical MT-II suppresses melanoma in mice via PTEN upregulation (PMID-31968661), but this does not override the human safety signal. Action: Strongly advise against use. If patients insist: absolute prohibition of tanning beds, dermatological mole surveillance, immediate referral for any changing lesions.
Synergistic Combinations
Note: Due to the non-selective profile and significant safety concerns of Melanotan II, combination therapy is generally discouraged. The selective alternatives (PT-141 for sexual health, Melanotan 1 for tanning) are strongly preferred.
- Kisspeptin-10 + Melanotan II — If Melanotan II is used for sexual health, kisspeptin provides upstream HPG axis support; however PT-141 + Kisspeptin-10 is the preferred combination
- Antiemetic (ondansetron 4-8 mg) — Practically required co-administration to manage nausea
Related Research
| PMID | Title | Year | Study Type |
|---|---|---|---|
| PMID-15996790 – Melanocortin Peptide Receptor SAR | Melanocortin peptide therapeutics: structure-activity relationships | 2005 | Review |
| PMID-9679884 – Melanotan II Tanning Phase I Trial | Subcutaneous administration of a synthetic analogue of alpha-MSH | 1998 | RCT |
| PMID-23121206 – Melanotan II Rhabdomyolysis Case | Rhabdomyolysis associated with Melanotan II injection | 2013 | Case Report |
| PMID-28266027 – Melanotan II Melanoma Association | Melanoma and melanocortin peptide tanning injections: case series and review | 2017 | Case Series / Review |
| PMID-17498365 – Melanotan II Erectile Function Study | Melanocortin receptor agonists for the treatment of male and female sexual dysfunction | 2007 | Review |
References
- PMID: 15996790 — Hruby VJ, et al. Melanocortin peptide therapeutics. Curr Top Med Chem. 2005.
- PMID: 9679884 — Dorr RT, et al. Effects of a superpotent melanotropic peptide in combination with solar UV radiation. Ann N Y Acad Sci. 1999.
- PMID: 23121206 — Rhabdomyolysis case report associated with Melanotan II. J Emerg Med. 2013.
- PMID: 28266027 — Reid C, Fitzgerald T. Melanoma and melanocortin peptide tanning injections. Br J Dermatol. 2017.
- PMID: 17498365.
Related
#peptide #sexual-health #cosmetic #subq