Product description
What is Melanotan II?
Melanotan II (MT-II, Ac-Nle-c[Asp-His-D-Phe-Arg-Trp-Lys]-NH₂) is a synthetic cyclic heptapeptide that is an analog of the natural hormone α-melanotropin (α-MSH – α-Melanocyte-Stimulating Hormone). The peptide was developed in the early 1990s at the University of Arizona by a research team seeking safe tanning agents without exposure to UV radiation.
Unlike the linear analog Melanotan I (afamelanotide, now FDA-registered as Scenesse® for the treatment of erythropoietic protoporphyria), Melanotan II is a cyclic peptide with lower receptor selectivity. Cyclization of the peptide chain through an amide bond between the ε-amino group of lysine and the γ-carboxyl group of aspartic acid gives the peptide increased metabolic stability and biological activity.
MT-II shows affinity for the melanocortin receptors MC1R, MC3R, MC4R and MC5R, with particularly strong activity toward MC1R (pigmentation) and MC4R (sexual functions and appetite regulation).
Mechanism of action
Melanotan II acts as a non-selective agonist of melanocortin receptors, producing diverse biological effects depending on the receptor activated:
MC1R receptor activation – melanogenesis – The MC1R receptor is expressed mainly on skin melanocytes. Its activation by MT-II stimulates the conversion of tyrosine to eumelanin – the dark brown-black pigment that efficiently absorbs UV radiation and protects epidermal cells from oxidative stress. At the same time, production of pheomelanin is inhibited – the light pigment with lower chemical stability, which in the presence of UV can generate free radicals and increase the risk of mutations.
MC4R receptor activation – sexual functions – The MC4R receptor is located mainly in the central nervous system (hypothalamus, limbic system, spinal cord). Its activation by MT-II triggers a central pathway of sexual arousal independent of peripheral stimulation. This effect includes both erectile function in men and sexual arousal in women. MC4R also modulates dopaminergic pathways associated with motivation and desire.
Effect on the MC3R receptor – energy regulation – The MC3R receptor participates in appetite regulation and energy homeostasis. Activation of this receptor by MT-II may lead to appetite suppression.
Action on the MC5R receptor – MC5R is expressed in sebaceous glands, the pancreas and other tissues. Its role in the context of MT-II is less understood, but it may affect secretory functions.
No activity toward MC2R – MT-II does not show significant affinity for the MC2R receptor (ACTH receptor in the adrenal cortex), which differentiates it from native ACTH and limits its effect on the hypothalamic-pituitary-adrenal axis.
Research directions
Melanotan II has been the subject of phase I and II clinical trials in several indications, although none of them led to registration of the drug.
Research on skin pigmentation
Early phase I clinical studies showed that subcutaneous administration of MT-II at doses of 0.01-0.03 mg/kg induces visible skin darkening (face, upper body, buttocks) after only 5 doses given every other day, measured by quantitative reflectometry. The pigmentation effect persisted for at least a week after administration ended, without UV exposure.
Research on sexual function in men
In a double-blind, placebo-controlled crossover study in 20 men with erectile dysfunction (Wessells et al.), subcutaneous administration of MT-II induced erections in 17 of the 20 subjects. The peptide increased penile rigidity (measured by RigiScan), the level of sexual desire and caused spontaneous erections 1-5 hours after administration, depending on dose. The characteristic complex of prodromal symptoms included yawning and stretching.
Research on sexual function in women
Studies showed that MT-II increases sexual desire and genital arousal also in women, which was a breakthrough discovery of a central mechanism of sexual arousal acting independently of sex. On the basis of these observations, Palatin Technologies developed bremelanotide (PT-141) – a modified metabolite of MT-II, which received FDA approval in 2019 as Vyleesi® for the treatment of hypoactive sexual desire disorder in premenopausal women.
Research on appetite regulation
Because of its agonist activity at MC3R and MC4R, MT-II was studied for appetite suppression and potential use in obesity. In animal models, the peptide reduced food intake.
Behavioral research
A 2019 study showed that MT-II improved social deficits in mice with autistic traits, suggesting a potential effect on social behavior through modulation of melanocortin pathways in the central nervous system.
Research on melanoma
The relationship between MT-II and skin cancer (melanoma) remains a matter of debate. A 2013 systematic review found no clear evidence of the peptide's carcinogenicity, and a 2020 in vivo study showed that MT-II inhibited melanoma progression in mice. A 2021 review concluded that the increased melanoma risk in MT-II users can probably be explained by greater UV exposure associated with tanning-seeking behavior.
Scientific context
The history of Melanotan II illustrates the complex trajectory of peptide drug development. Initially developed as a tanning agent protecting against skin cancer, the peptide turned out to have significant effects on sexual function discovered by chance during pigmentation studies, when one researcher self-administered a double dose and experienced prolonged erection.
This accidental discovery led to the separation of development paths:
- Melanotan I (afamelanotide) – a linear peptide with greater MC1R selectivity, developed by Clinuvel Pharmaceuticals for the treatment of protoporphyria
- Bremelanotide (PT-141) – an MT-II metabolite with MC4R selectivity, developed by Palatin as a drug for desire disorders
The comparison of Melanotan I vs II shows the importance of receptor selectivity in peptide drug design. MT-II, with its broader activity profile, has stronger sexual effects, while MT-I retains stronger pigmentation effects with fewer side effects.
Safety profile in studies
In published clinical studies, MT-II caused a range of adverse effects, the frequency and severity of which were dose-dependent:
Common short-term events:
- Nausea (the most common side effect)
- Sudden facial flushing (flushing)
- Fatigue and drowsiness
- Spontaneous erections (in men)
- Yawning and stretching
Potential long-term concerns:
- Darkening of nevi and moles (reversible)
- Appearance of new melanocytic nevi
- Melanonychia (nail discoloration)
- Rhabdomyolysis (a case described after overdose)
In the described overdose case (6 mg – 6 times the recommended starting dose), the patient experienced sympathomimetic symptoms, rhabdomyolysis and renal dysfunction, requiring hospitalization in the ICU.
MT-II remains an unapproved substance, available mainly on the online black market, which is associated with the risk of contamination and lack of standardization.
Bibliography – latest scientific studies
- Hadley ME, Dorr RT. Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization. Peptides. 2006;27(4):921-930. PubMed
- Dorr RT, Lines R, Levine N, et al. Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study. Life Sci. 1996;58(20):1777-1784. PubMed
- Wessells H, Fuciarelli K, Hansen J, et al. Synthetic melanotropic peptide initiates erections in men with psychogenic erectile dysfunction: double-blind, placebo controlled crossover study. J Urol. 1998;160(2):389-393. PubMed
- Diamond LE, Earle DC, Heiman JR, et al. An effect on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide (PT-141), a melanocortin receptor agonist. J Sex Med. 2006;3(4):628-638. PubMed
- Uckert S, Bannowsky A, Albrecht K, Kuczyk MA. Melanocortin receptor agonists in the treatment of male and female sexual dysfunctions: results from basic research and clinical studies. Expert Opin Investig Drugs. 2014;23(11):1477-1483. PubMed
- Nelson ME, Bryant SM, Aks SE. Melanotan II injection resulting in systemic toxicity and rhabdomyolysis. Clin Toxicol (Phila). 2012;50(10):1169-1173. PubMed
- Evans-Brown M, Dawson RT, Chandler M, McVeigh J. Use of melanotan I and II in the general population. BMJ. 2009;338:b566. PubMed
- Giuliano F, Clément P, Droupy S, et al. Melanotan-II: Investigation of the inducer and facilitator effects on penile erection in anaesthetized rat. Neuroscience. 2006;138(1):293-301. PubMed
- Brennan R, Wells JSG, Van Hout MC. The injecting use of image and performance-enhancing drugs (IPED) in the general population: a systematic review. Health Soc Care Community. 2017;25(5):1459-1531. PubMed
- Diamond LE, Earle DC, Rosen RC, et al. Discovery that a melanocortin regulates sexual functions in male and female humans. Ann N Y Acad Sci. 2005;1046:210-224. PubMed
