Melanotan II
Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH2 (Melanotan-II, MT-II); also written Ac-Nle4-Asp5-His6-D-Phe7-Arg8-Trp9-Lys10 alpha-MSH4-10-NH2
Melanotan II is a synthetic cyclic heptapeptide analog of alpha-melanocyte-stimulating hormone that activates melanocortin receptors MC1R, MC3R, MC4R, and MC5R, producing skin darkening, sexual arousal, and appetite suppression in humans. It remains investigational with no regulatory approval for any indication (PMID 8637402; NCT07437560).
Last updated: 2026-03-11
Safety Summary
The most commonly reported side effect is nausea, which is dose-dependent and may diminish with repeated use. The Phase I study described it as 'mild nausea, not requiring antiemetic treatment' at most dose levels (PMID 8637402), while the Wessells et al. study reported 'a low percentage experiencing severe nausea' (PMID 11035391; EXA-11ab76cea01f). Facial flushing and spontaneous penile erections were observed in the Phase I study, with erections lasting 1-5 hours depending on dose (PMID 8637402). Appetite suppression is a direct MC4R-mediated effect (PMID 10951699). Dermatological concerns include darkening of existing moles and appearance of new nevi, documented in multiple case reports. Oral mucosa pigmentation was documented in a 2026 case report, with buccal pigmentation resolving after 1 month but gingival pigmentation persisting with reduced intensity at 3 months (PMID 41752902). The FDA Category 2 listing cites published case reports of melanoma, posterior reversible encephalopathy syndrome, sympathomimetic toxidrome, and priapism. A case of melanotan-induced priapism required cavernosal aspiration and irrigation with intracavernosal phenylephrine injection; the patient did not recover erectile function at 4-week follow-up (PMID 30796078; EXA-11ab76cea01f). Rhabdomyolysis has been reported in case reports. The melanoma risk question remains unresolved: a 2013 review found no conclusive evidence MT-II causes melanoma. and a 2021 review concluded that increased melanoma risk in MT users can probably be explained by more UV exposure.
Known Side Effects
common
common
common
common
common
common
uncommon
uncommon
uncommon
rare
rare
rare
rare
Who Should NOT Use This
MT-II stimulates melanocyte proliferation and melanin production. The Phase 2 vitiligo trial (NCT07437560) explicitly excludes patients with history of melanoma, dysplastic nevus syndrome, or other high-risk skin cancer history. The FDA Category 2 listing cites melanoma as a reported serious adverse event.
The Phase 2 vitiligo trial (NCT07437560) excludes patients with clinically significant uncontrolled hypertension or cardiovascular disease. Transient blood pressure changes have been observed. Rated as warning rather than contraindication because the evidence comes from trial exclusion criteria only, without direct evidence of harm.
The Phase 2 vitiligo trial (NCT07437560) excludes pregnant or breastfeeding individuals. No reproductive safety data are available. Complete absence of safety data in this vulnerable population warrants the stronger designation.
The Phase 2 vitiligo trial (NCT07437560) excludes patients with prior melanocortin agonist treatment within 6 months to avoid confounding effects.
Talk to Your Doctor
Before considering Melanotan II, discuss it with your healthcare provider. Ask about potential interactions with your current medications, whether it is appropriate for your health conditions, and what monitoring may be needed.
Sources: [1-13]
Evidence Assessment
Multiple smaller human studies exist but no completed Phase 2 or Phase 3 RCTs with published results. The Phase I study by Dorr et al. 1996 (PMID 8637402) enrolled 3 subjects and demonstrated tanning efficacy. Wessells et al. 2000 (PMID 11035391, cited in EXA-11ab76cea01f) studied 20 men with ED with 17/20 achieving erection. Dorr et al. 2004 (PMID 15262693, cited in EXA-11ab76cea01f) studied MT-II combined with solar UV in human volunteers. A 2015 review identified 18 clinical trials and 21 clinical case presentations (EXA-11ab76cea01f, citing Brennan et al. 2014). A Phase 2 RCT for vitiligo (NCT07437560) began recruiting in February 2026 but has no results yet. The evidence base is real but still limited: studies are small, old, and not confirmatory. This supports Tier 3 but not higher.
1Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study.PMID 8637402
Dorr RT et al. - Life Sciences (1996) - Phase I clinical trial - N=3 (healthy male volunteers)
Single-blind, alternating-day, placebo-controlled trial. Subcutaneous MT-II or saline given daily Monday-Friday for 2 weeks, alternating between active and placebo, yielding approximately 5 active doses. Starting dose 0.01 mg/kg, escalated by 0.005 mg/kg to 0.025-0.03 mg/kg. Two of 3 subjects showed increased pigmentation (face, upper body, buttock) measurable by quantitative reflectance 1 week after dosing ended. Mild nausea at most dose levels. Stretching/yawning complex correlated with onset of spontaneous penile erections lasting 1-5 hours. 0.03 mg/kg produced Grade II somnolence/fatigue in 1 of 2 subjects. Recommended single dose for future studies: 0.025 mg/kg/day.
Limitations: Very small sample (N=3), all male, short duration, single-center.
2Melanocortin receptor agonists, penile erection, and sexual motivation: human studies with Melanotan II.PMID 11035391
Wessells H et al. - International Journal of Impotence Research (2000) - Clinical study (human) - N=20 (men with erectile dysfunction)
17 out of 20 men experienced penile erection following MT-II administration. Side effects included nausea and yawning, with a low percentage experiencing severe nausea. Demonstrated clinically relevant pro-erectile effects mediated by central melanocortin pathways.
Limitations: Primary abstract not in local paper set; findings summarized from EXA-11ab76cea01f secondary source.
3Effects of a superpotent melanotropic peptide in combination with solar UV radiation on tanning of the skin in human volunteers.PMID 15262693
Dorr RT et al. - Archives of Dermatology (2004) - Clinical study (human) - Not specified in available source
Demonstrated that MT-II combined with solar UV radiation produces tanning effects in human volunteers. Referenced through EXA-11ab76cea01f source.
Limitations: Full study details not available in source data; cited via EXA-11ab76cea01f.
4Role of the melanocortin-4 receptor in metabolic rate and food intake in mice.PMID 10951699
Chen AS et al. - Transgenic Research (2000) - Animal study - Wildtype and MC4R knockout mice
Intraperitoneal MT-II increased metabolic rate in wildtype mice, while MC4R knockout mice were insensitive to MT-II effects on both metabolic rate and food intake. Confirmed MC4R as the mediator of MT-II acute effects on basal metabolic rate and food intake.
Limitations: Animal model only; doses and metabolic effects may not translate directly to humans.
5Topical MTII Therapy Suppresses Melanoma Through PTEN Upregulation and Cyclooxygenase II Inhibition.PMID 31968661
Wu JC et al. - International Journal of Molecular Sciences (2020) - In vitro and animal study - B16-F10 melanoma cell line; C57BL/6 tumor-bearing mice
Topical MTII inhibited migration, invasion, and colony-forming capability of melanoma cells despite not affecting proliferation. In vivo, topical MTII significantly attenuated tumor progression. MTII dose-dependently increased PTEN protein levels, reduced PTEN phosphorylation, inhibited AKT/NFkB signaling, and suppressed COX-2 expression and PGE2 production. MC1R identified as critical receptor via antibody neutralization studies.
Limitations: Mouse melanoma model (B16-F10); topical application route differs from subcutaneous injection used by humans. Cannot be directly extrapolated to human melanoma risk assessment.
6Melanotan-II reverses autistic features in a maternal immune activation mouse model of autism.PMID 30629642
Minakova E et al. - PLoS One (2019) - Animal study - Male MIA mice
Continuous MT-II administration for 7 days reversed social behavioral deficits in maternal immune activation mouse model of autism, producing rescue of social behavioral metrics. Suggests melanocortin system involvement in social behavior regulation.
Limitations: Single animal model, male mice only, short treatment duration. No human studies for this indication.
7Melanotan-induced priapism: a hard-earned tan.PMID 30796078
Dreyer BA et al. - BMJ Case Reports (2019) - Case report - N=1
Low-flow priapism after abdominal subcutaneous Melanotan II injection. Managed with cavernosal aspiration, irrigation, and intracavernosal phenylephrine injection. Patient did not recover erectile function at 4-week follow-up.
Limitations: Single case report. Details in local source set come from EXA-captured secondary source.
8Changes in Oral Mucosa Associated with Melanotan II Injections: A Case Report.PMID 41752902
Bonchev A - Life (Basel, Switzerland) (2026) - Case report - N=1
Three-month follow-up of patient self-administering MT-II injections over 64 days. Brown pigmentation observed on attached gingiva and buccal mucosa. At 1-month follow-up after discontinuation, buccal pigmentation nearly disappeared. At 3-month follow-up, gingival pigmentation persisted with reduced intensity. First published data on timeline for resolution of oral pigmentation from MT-II.
Limitations: Single case report. No controls. Self-administered unregulated product with unknown purity/dose.
9A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of Melanotan II as an Adjunct to Narrowband UV-B Phototherapy in Adults With Stable Nonsegmental Vitiligo (MTII-VIT)NCT07437560
Hudson Biotech (sponsor) - ClinicalTrials.gov (2026) - Phase 2 RCT (recruiting) - N=60 (estimated enrollment)
Recruiting as of February 2026. Quadruple-masked, 1:1 randomization to MT-II or placebo plus standardized NB-UVB for 24 weeks. Primary outcome: change in VASI total score at 24 weeks. Safety monitoring includes adverse event collection, vital signs, and focused skin examinations including monitoring of nevi. Study sites include Peking University Shenzhen Hospital. Not FDA-regulated. No results available yet. Study description identifies it as an example interventional study record.
Limitations: No results yet -- still recruiting. Not FDA-regulated study.
10An unhealthy glow? A review of melanotan use and associated clinical outcomes.
Brennan R et al. - Performance Enhancement & Health (2014) - Review - Identified 18 clinical trials and 21 clinical case presentations
Comprehensive review of melanotan use and clinical outcomes. Documented multiple case reports of nevi changes, new mole formation, and other adverse effects. Established the breadth of the existing evidence base for MT-II.
Limitations: Review of heterogeneous studies and case reports, not a systematic review with meta-analysis. Referenced through EXA-11ab76cea01f.
11The MC4 receptor and control of appetite.PMID 17043670
Adan RAH et al. - British Journal of Pharmacology (2006) - Review - N/A (review article)
MC4R activity affects meal size and meal choice but not meal frequency. The efficacy of MC4R agonists to reduce food intake is affected by diet type. Notes that application of MCR agonists in humans has revealed side effects including penile erections.
Limitations: Review article, not primary research. MC4R focus rather than MT-II specifically.
12MC1R, the cAMP pathway, and the response to solar UV: extending the horizon beyond pigmentation.PMID 24807163
Garcia-Borron JC et al. - Pigment Cell & Melanoma Research (2014) - Review - N/A (review article)
MC1R activates cAMP pathway leading to eumelanin synthesis. MC1R polymorphisms are a major source of variation in human pigmentation, UV response, and skin cancer susceptibility. MC1R functions as a melanoma susceptibility gene.
Limitations: Review article focused on MC1R biology, not MT-II specifically.
13A single-centre, prospective, qualitative analysis of knowledge, attitudes and behaviour of sunbed use among patients attending a pigmented lesion clinic in a tertiary referral centre.PMID 40584950
Lai FY et al. - Skin Health and Disease (2025) - Prospective survey - N=104 consecutive patients
Survey of 104 patients attending pigmented lesion clinic in Ireland. Documented use of unregulated tan-enhancing agents including Melanotan I and II among sunbed users. Users of tan-enhancing agents also used sunbeds more frequently.
Limitations: Single-center, self-reported survey. Does not quantify MT-II-specific prevalence or outcomes.