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Melanotan II

Skin & Tanning

a.k.a. MT-II

Non-selective melanocortin agonist

Melanotan II (MT-II) is a synthetic cyclic peptide analog of alpha-melanocyte stimulating hormone (α-MSH).

§Dosing at a glance

2 protocols · from the research
What it's forDoseHow oftenHowFor how long
Erectile Dysfunction (Human Studies)0.025 mg/kg—SubcutaneousInjected just under the skin, into the fat layer.—
Important Note0.025 mg/kg———

Approximate values pulled from the research — double-check before dosing.

§01Summary

Melanotan II (MT-II) is a synthetic cyclic peptide analog of alpha-melanocyte stimulating hormone (α-MSH) that activates melanocortin receptors throughout the body and brain. Originally developed to study pigmentation and sexual function, it has been investigated across several areas including erectile dysfunction, appetite regulation, and skin repigmentation. In early human studies, MT-II has been reported to initiate penile erections in men with both psychogenic and organic erectile dysfunction, with roughly 80–85% of participants responding in small crossover trials2,4. It also appears to increase sexual desire through central nervous system activity3,4. In animal research, MT-II reduces food intake and increases metabolic rate through activation of melanocortin-4 receptors (MC4R) in the hypothalamus5,8, and may influence fat metabolism by increasing sympathetic nervous system drive to adipose tissue7,13. A Phase 2 clinical trial is currently investigating MT-II as an adjunct to narrowband UV-B phototherapy for vitiligo repigmentation1. Commonly reported side effects in human studies include nausea, yawning, stretching, and decreased appetite2,3,4. MT-II's broad receptor activity across multiple melanocortin receptor subtypes underlies both its range of potential applications and its side effect profile.

This is the layperson summary. Mechanism, dosing, the evidence base, and the published literature are in the sections below — every claim links to its source.

§02In depth

Melanotan II (MT-II) is a synthetic cyclic heptapeptide analog of α-melanocyte stimulating hormone (α-MSH), the endogenous ligand derived from post-translational processing of pro-opiomelanocortin (POMC). It acts as a non-selective agonist across multiple melanocortin receptor subtypes, including MC1R, MC3R, MC4R, and MC5R, with particularly well-characterized activity at MC3R and MC4R5,8. These G protein-coupled receptors signal primarily through Gαs-coupled pathways, activating adenylyl cyclase and elevating intracellular cAMP, which drives downstream phosphorylation cascades including the ERK/CREB pathway identified as a molecular integrator of satiety signaling in nucleus tractus solitarius (NTS) neurons12.

In the hypothalamus, MC4R activation in the paraventricular nucleus (PVN) and ventromedial hypothalamus (VMH) mediates MT-II's anorectic and metabolic effects. Direct PVN injection of MT-II potently suppresses food intake, confirming this nucleus as a primary locus of MC4R-mediated feeding regulation8. MC4R agonism in the VMH increases peripheral glucose uptake in skeletal muscle, brown adipose tissue (BAT), and the heart, with effects on BAT glucose uptake also mediated through the PVH14. At a circuit level, leptin's glucose-regulatory effects in the VMH appear to be entirely downstream of melanocortin receptor activation, as they are abolished by the MC3/4R antagonist SHU911914. MC4R is extensively co-expressed in sympathetic outflow neurons projecting to both interscapular BAT (~80% co-expression in PVH neurons) and inguinal white adipose tissue (>60% co-expression across multiple brain regions)11,13, providing a neuroanatomical substrate for MT-II's capacity to stimulate thermogenesis and depot-selective lipolysis via the sympathetic nervous system7.

MT-II's pro-erectile effects are mediated centrally through MC4R, with downstream activation of oxytocinergic neurons in the hypothalamus constituting an important effector pathway, as demonstrated by the attenuation of MC4R agonist-induced erections by oxytocin receptor antagonism in rats16. MC4R is also expressed presynaptically on vagal afferent fibers projecting to the NTS, where MT-II modulates glutamatergic synaptic transmission and enhances visceral satiety signaling from the gastrointestinal tract15. In the brainstem, fourth ventricular MTII administration selectively reduces meal size rather than meal frequency, indicating action on satiety magnitude rather than hunger initiation, and this effect requires ERK pathway integrity10,12.

Beyond canonical melanocortin receptors, IP administration of MT-II in mice triggers profound, transient hypothermia and hypometabolism through off-target mast cell activation and histamine H1 receptor stimulation — a mechanism entirely independent of MC1R, MC3R, MC4R, and MC5R17. MT-II also modulates presynaptic MC3/4R on adrenal chromaffin cells, influencing sympathetic input strength during fasting states18. The connectivity between the melanocortin system and oxytocin neuron activity in the PVN, demonstrated by the blunted PVN response to MT-II in Sim1-haploinsufficient mice, further illustrates the circuit-level complexity of melanocortin signaling in energy homeostasis6.

§04Evidence & efficacy

Evidence base
290Studies
112Human
118Animal

Erectile Dysfunction:
MT-II has been reported to initiate penile erections in men with psychogenic erectile dysfunction, with 8 of 10 subjects (80%) developing clinically apparent erections versus minimal placebo response in a double-blind crossover study (mean tip rigidity >80%: 38.0 vs 3.0 minutes, p=0.0045)2. In a separate crossover study including men with organic erectile dysfunction risk factors, MT-II produced subjective erections in 63% of active injections versus 5% of placebo injections, with mean tip rigidity duration of 45.3 vs 1.9 minutes (p=0.047)3. Erections have been reported to occur without sexual stimulation, consistent with a centrally mediated pro-erectile mechanism4. MT-II also appears to increase sexual desire in treated men, with 68% of subjects reporting increased desire following active dosing versus 19% following placebo (p<0.01)4.

Appetite and Metabolic Regulation:
In animal models, MT-II reduces food intake and increases metabolic rate through MC4R activation5,8,10, reduces meal size via brainstem melanocortin signaling10,12, and increases peripheral glucose uptake in skeletal muscle, brown adipose tissue, and heart when administered centrally14. MT-II also increases sympathetic outflow to subcutaneous white adipose tissue depots and brown adipose tissue, suggesting fat-mobilizing and thermogenic activity beyond appetite suppression alone7,11,13. These mechanisms are being explored in ongoing mammalian research.

Vitiligo:
A Phase 2 RCT investigating MT-II as an adjunct to narrowband UV-B phototherapy for nonsegmental vitiligo repigmentation is currently underway, with results not yet available1.

§05Safety

In human studies conducted at a dose of 0.025 mg/kg subcutaneous injection, the most frequently reported adverse effects of MT-II are nausea, yawning, stretching, and decreased appetite2,3,4. Nausea was reported more often with MT-II than placebo across multiple trials2,3,4, and severe nausea occurred in approximately 21% of active injections in one crossover study3 and in approximately 12.9% of subjects in another4. These gastrointestinal effects were transient and did not require treatment in the studies reporting them2. Increased sexual desire was also observed as a pharmacodynamic effect rather than a conventional adverse event3,4.

In animal models, IP administration of MT-II has been shown to cause profound, transient hypothermia and hypometabolism in mice through an off-target mechanism involving mast cell activation and histamine H1 receptor stimulation, independent of any of the five canonical melanocortin receptors17. This pathway is not yet characterized in humans. MT-II also increases heart rate and body temperature in rodents following brainstem administration, reflecting sympathetic activation10, and centrally administered MT-II increases sympathetic outflow to select adipose and brown adipose tissue depots7,11. These autonomic effects are being characterized in ongoing research.

Cardiovascular effects, melanocytic stimulation including potential effects on nevi, and melanoma risk are noted as monitoring priorities in the registered vitiligo trial protocol1, reflecting known theoretical concerns from prior uncontrolled human use rather than documented trial findings.

§06History

Melanotan II was developed in the late 1980s and early 1990s at the University of Arizona by researchers including Mac Hadley, Victor Hruby, and colleagues, as part of a program to create stable, potent synthetic analogs of α-melanocyte stimulating hormone (α-MSH). The original research goal was to develop a tanning agent that could protect against UV-induced skin damage by stimulating melanogenesis without UV exposure. Early pharmacological characterization established MT-II as a cyclic, proteolytically stable analog with high potency at multiple melanocortin receptors.

Initial human investigation in the 1990s unexpectedly revealed potent pro-erectile activity, leading to a pivotal double-blind crossover study published in 1998 demonstrating statistically significant induction of penile erections in men with psychogenic erectile dysfunction2. Follow-up human studies extended these findings to men with organic ED risk factors and documented increased sexual desire as a distinct central effect3,4. These results, published around 2000, generated substantial scientific interest in melanocortin receptor agonism as a therapeutic target for sexual dysfunction, ultimately contributing to the development of bremelanotide (PT-141), an MC4R-preferring derivative that received FDA approval for hypoactive sexual desire disorder in women in 2019.

Parallel animal research through the 2000s established MT-II as a foundational pharmacological tool for dissecting melanocortin receptor function in energy homeostasis, thermogenesis, and glucose metabolism5,7,8,10,11,12,13,14, generating a large mechanistic literature. More recently, MT-II has entered formal clinical development for vitiligo, with a registered Phase 2 RCT underway as of 20261, representing its first structured regulatory-pathway investigation in a dermatological indication.

§07References