Section 01
What it's used for
Approved Skin-Sensitivity Drug
Afamelanotide, sold as Melanotan I or Scenesse, is an approved medicine for erythropoietic protoporphyria (EPP), a rare inherited disease causing skin to become painfully and dangerously sensitive to sunlight and other light sources.
▸Clinical wording
Afamelanotide (Melanotan I, Scenesse) is approved for erythropoietic protoporphyria.
Reducing Inflammation in Animals
In animal studies, alpha-MSH and related peptide analogs reduced inflammation in models of inflammatory bowel disease (IBD), joint inflammation (arthritis), and inflammation in the brain and nervous system (neuroinflammation).
▸Clinical wording
α-MSH and analogs reduce inflammation in models of IBD, arthritis, and neuroinflammation.
Approved for Genetic Obesity
Setmelanotide, which acts on the brain's MC4R receptor that helps control hunger, is an approved medicine for a form of obesity caused by rare genetic changes in the POMC, LEPR, or PCSK1 genes, which normally help regulate body weight.
▸Clinical wording
Setmelanotide (MC4R agonist) is approved for genetic obesity from POMC/LEPR/PCSK1 deficiency.
Approved for Low Sexual Desire
Bremelanotide, known as PT-141, is an approved medicine for hypoactive sexual desire disorder (HSDD), a persistent, unwanted lack of interest in sex that causes personal distress and is not explained by another medical cause.
▸Clinical wording
Bremelanotide (PT-141) approved for HSDD.
Section 02
Mechanism of Action
Switching pigment cells to darker pigment
- In cultured human pigment cells, the peptide docks onto a surface receptor (MC1R).
- Docking raises an internal messenger (cAMP) that switches on the master pigment gene (MITF).
- Three pigment-making enzymes increase, shifting output toward the darker pigment (eumelanin).
- When that receptor signals poorly, the cells make the lighter red-yellow pigment instead.
▸Clinical wording
MC1R-cAMP-PKA-CREB-MITF axis in eumelanin synthesis
In cultured human melanocytes and melanoma lines, α-MSH binds MC1R, a seven-transmembrane receptor whose Gαs subunit dissociates on agonist binding and stimulates adenylyl cyclase. Rising cAMP activates PKA, which phosphorylates CREB; the MITF promoter carries a consensus CRE, so MITF transcription increases and with it the melanogenic enzymes tyrosinase, TYRP1 and DCT. The reported net effect in these systems is a shift from pheomelanin toward eumelanin. When MC1R signalling is impaired and cAMP stays low, cysteine incorporation favours pheomelanin instead. The same Gs-cAMP logic is shared across the MC1R-MC5R family.
Turning down the inflammation switch
- In human cell lines, the peptide stopped a master inflammation switch (NF-κB) reaching the nucleus.
- Blocking the internal messenger cAMP removed the effect, and adding cAMP directly reproduced it.
- A related switch (AP-1) was left untouched, so the block is selective.
- Reviews report lower inflammatory signals and higher anti-inflammatory ones in cell and rodent models.
▸Clinical wording
cAMP-dependent block of NF-kB nuclear translocation
Electrophoretic mobility shift assays showed that α-MSH abolished TNF-driven NF-κB activation in human cell lines and also suppressed activation by LPS, okadaic acid and ceramide, while leaving AP-1 untouched. Western blotting showed that IκBα degradation and p65 nuclear translocation were both blocked. Inhibitors of adenylate cyclase and of PKA reversed the effect and dibutyryl-cAMP reproduced it, placing the block downstream of cAMP. Reviews map MC1R and MC3R onto monocytes, macrophages, lymphocytes and neutrophils, where melanocortins lower TNF-α, IL-1 and IL-6, raise IL-10 and suppress iNOS-derived nitric oxide in cell and rodent inflammation models.
Pigment cells after ultraviolet damage
- In lab-grown human pigment cells, the peptide prevented cell death caused by ultraviolet light.
- It acted neither as a filter nor by adding pigment, while DNA damage marks fell.
- Protection vanished in cells unable to repair DNA, pointing to repair rather than survival signalling.
- A second study reported faster damage clearance and less ultraviolet-driven hydrogen peroxide through the same receptor.
▸Clinical wording
Melanocyte survival and photoproduct clearance after UVB
In normal human melanocytes in vitro, α-MSH blocked UVB-induced apoptosis without acting as a filter and without inducing melanin; Bcl-2, Bcl-x, Bax, p53, CD95 and CD95L were unchanged, while cyclobutane pyrimidine dimers fell. The protection disappeared in nucleotide-excision-repair-deficient fibroblasts, pointing to repair rather than survival signalling alone. A separate study found that α-melanocortin acting through MC1R rescued human melanocytes from UV-induced apoptosis, engaged an Akt-dependent pathway, raised MITF phosphorylation and expression, accelerated dimer removal and lowered UV-induced hydrogen peroxide.
Hunger neurons controlled by a channel
- In mouse feeding neurons, this receptor (MC4R) controlled firing through a potassium channel, not cAMP.
- Alpha-MSH closes that channel (Kir7.1), which makes the neuron fire faster.
- The hunger peptide AgRP opens the same channel instead and quietens the cell.
- The authors proposed this explains feeding that continues after the receptor is no longer occupied.
▸Clinical wording
MC4R coupling to Kir7.1 in hypothalamic feeding neurons
Recordings from mouse paraventricular nucleus neurons showed that MC4R controls firing through the inwardly rectifying potassium channel Kir7.1 rather than through Gαs and cAMP. α-MSH closes Kir7.1, depolarising the neuron and increasing its firing rate; AgRP behaves as a biased agonist that opens the channel and hyperpolarises the cell, an action separable from its competitive antagonism at the orthosteric site. The authors proposed that this ion-channel arm accounts for the sustained feeding response that follows AgRP release and outlasts simple receptor occupancy.
Nerve pathways behind erection in mice
- A drug targeting this receptor increased erectile responses in normal mice but not in receptor-lacking mice.
- Mating behaviour rose with the drug and was reduced in the receptor-lacking animals.
- The receptor sat in nerve fibres of penis, spinal cord and brain, not in erectile smooth muscle.
- Restoring the receptor only on oxytocin neurons normalised ejaculation timing in the knockout mice.
▸Clinical wording
MC4R circuits in erectile and copulatory behaviour
A selective non-peptide MC4R agonist increased erectile activity evoked by cavernous nerve stimulation in wild-type mice but not in Mc4r-null mice, and copulatory behaviour was enhanced by the agonist and diminished in knockouts. RT-PCR and in situ hybridisation placed MC4R in rat and human penis, rat spinal cord, hypothalamus, brainstem and pelvic ganglion, in nerve fibres and glans mechanoreceptors, but not in corpus cavernosum smooth muscle cells. Re-expressing MC4R only on oxytocin neurons of null mice restored normal ejaculation latency, implicating oxytocinergic relays.
Section 03
Biological Pathways
- MC1R-cAMP-PKA-CREB-MITF axisIn cultured human melanocytes, alpha-MSH binding MC1R raises cAMP and activates PKA and CREB, inducing MITF and tyrosinase, TYRP1 and DCT, shifting synthesis from pheomelanin toward eumelanin.
- cAMP block of NF-kB signalingIn human cell lines, alpha-MSH raised cAMP to block NF-kB activation driven by TNF, LPS and okadaic acid, blocking IkBa degradation and p65 nuclear entry while sparing AP-1 and lowering TNF-a, IL-1 and IL-6.
- MC4R-Kir7.1 feeding circuitIn mouse paraventricular neurons, alpha-MSH closes the potassium channel Kir7.1 downstream of MC4R, depolarizing the cell; AgRP acts as a biased agonist that opens Kir7.1, blunting firing to sustain feeding.
- MC4R-oxytocin sexual circuitsIn mice, a selective MC4R agonist increased cavernous nerve evoked erection and copulatory behavior, an effect lost in Mc4r-null animals; restoring MC4R on oxytocin neurons rescued ejaculation latency.
Section 04
Dosage Information
Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2| Route / system | Context | Range studied | Limitation |
|---|---|---|---|
| Subcutaneous implant — approved copy | SCENESSE label — a rare light-pain disease | One 16 mg dissolving implant every 2 months — about 270 µg a day if release is even, or 3–4 µg/kg for a 70–90 kg adult | Afamelanotide is a stabilised copy of α-MSH in a slow-release rod: neither the molecule nor the slow drip is free α-MSH. |
| Intravenous infusion — human study | Fifteen healthy volunteers, a blood-sugar experiment | 15, 150 and 1500 ng/kg per hour during a sugar-drink test; each volunteer got one dose level and placebo on separate visits | A few hours of blood-sugar readings, still an unreviewed preprint, no repeat dosing, no clinical outcome. The drip was needed: the peptide clears in minutes. |
| Intravenous — animal fever models | Rabbits and squirrel monkeys with induced fever | 2.5 µg per rabbit blunted both phases of the fever; 100–400 µg per monkey halved the fever curve. Doses are per animal, not per kg. | Single shots in 1–3 kg animals against a fever induced on purpose. Nobody ever published a conversion to human size, so no human dose follows. |
| Subcutaneous — self-administration | Circulating practice, outside any study | 100–500 µg per day, usually quoted as 250 µg — roughly 1–7 µg/kg for a 70–90 kg adult | Free α-MSH has never been injected under the skin in any published human study; it clears in minutes, so a daily shot cannot match the infusion. |
Results
Syringe Fill Level (100u syringe)
Set positive values for: Recommended dose per kg.
Research Use Only. This information is for educational and research purposes only. Not intended for medical advice or self-medication.
Section 05
Protocols
No protocols featuring this peptide yet. Browse All Protocols
Section 06
Stability & Storage
Lyophilised powder
The methionine residue in the native sequence is prone to oxidation, so the lyophilised powder is kept sealed and protected from moisture and air. Synthetic analogues carrying D-amino acid substitutions and cyclisation resist degradation better than the native peptide and are the form typically supplied for therapeutic use. Storage life depends on the specific analogue and the manufacturer's packaging.
After reconstitution
Once reconstituted, the solution remains sensitive to enzymatic breakdown, echoing the native peptide's short in-vivo half-life of only minutes. Analogues with D-amino acid substitutions and cyclisation hold up better once in solution. Reconstituted material is kept refrigerated and used within a limited period rather than stored long-term.
Section 07
Side Effects & Precautions
Nausea, facial flushing, skin darkening (via MC1R), appetite changes. Effects depend on receptor selectivity of the specific analog used.
Section 08
Regulatory Status
FDA / United States
Three analogues approved; native α-MSH is not
Afamelanotide (Scenesse, erythropoietic protoporphyria, 8 October 2019), bremelanotide (Vyleesi, hypoactive sexual desire disorder, June 2019) and setmelanotide (Imcivree, genetic obesity, 25 November 2020) each cleared FDA review as distinct drugs; unmodified α-MSH itself has none.
Setmelanotide (Imcivree)
Approved 2020, indication widened since
FDA approved Imcivree in November 2020 for obesity due to POMC, PCSK1 or LEPR deficiency; the label expanded to Bardet-Biedl syndrome in 2022, and in 2024 FDA accepted priority review to extend it to patients as young as two years old.
EMA / European Union
Afamelanotide was approved there first
The EMA granted Scenesse conditional marketing authorisation for the same EPP indication under exceptional circumstances in 2014, five years before its FDA approval; September 2025 removed the previous four-implant annual cap.
WADA
Only the unapproved analogues are named under S2
Melanotan I and II, sold as unregulated research chemicals, are banned as peptide hormones and mimetics; the three FDA/EMA-approved prescription drugs above are regulated separately as medicines, and bremelanotide (Vyleesi) is not itself named on the list.
Native α-MSH, an approved prescription analogue and an unapproved research chemical can share a similar name while sitting in completely different regulatory categories. Regulatory status differs between jurisdictions and changes over time — check the current documents of your own regulator before relying on any of this.
Section 09
Research Studies
- [1]Melanocortin 1 Receptor: Structure, Function, and RegulationHorrell EM, Boulanger MC, D'Orazio JA. · Frontiers in Genetics · 2016
- [2]Signaling Pathways in MelanogenesisD'Mello SA, Finlay GJ, Baguley BC, Askarian-Amiri ME. · International Journal of Molecular Sciences · 2016
- [3]Alpha-melanocyte-stimulating hormone inhibits the nuclear transcription factor NF-kappa B activation induced by various inflammatory agentsManna SK, Aggarwal BB. · The Journal of Immunology · 1998
- [4]Melanocortin Regulation of InflammationWang W, Guo DY, Lin YJ, Tao YX. · Frontiers in Endocrinology · 2019
- [5]alpha-Melanocyte-stimulating hormone protects from ultraviolet radiation-induced apoptosis and DNA damageBöhm M, Wolff I, Scholzen TE, Robinson SJ, Healy E, Luger TA, Schwarz T, Schwarz A. · Journal of Biological Chemistry · 2005
- [6]alpha-Melanocortin and endothelin-1 activate antiapoptotic pathways and reduce DNA damage in human melanocytesKadekaro AL, Kavanagh R, Kanto H, et al. · Cancer Research · 2005
- [7]G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neuronsGhamari-Langroudi M, Digby GJ, Sebag JA, et al. · Nature · 2015
- [8]A role for the melanocortin 4 receptor in sexual functionVan der Ploeg LH, Martin WJ, Howard AD, et al. · Proceedings of the National Academy of Sciences · 2002
- [9]Oxytocin Neurons Enable Melanocortin Regulation of Male Sexual Function in MiceSemple E, Shalabi F, Hill JW. · Molecular Neurobiology · 2019
Section 10
Frequently Asked Questions
Alpha-MSH is a 13-amino-acid hormone that activates the five melanocortin receptors (MC1R-MC5R) across different tissues. Through MC1R it drives melanin production in skin cells, through MC4R it acts on hypothalamic neurons to reduce feeding, and through MC1R/MC3R on immune cells it blocks NF-kB activation and lowers TNF-alpha, IL-1 and IL-6 while raising IL-10. It is described as a master regulator of pigmentation, inflammation, energy balance and sexual function.
No. Alpha-MSH is the natural, short-lived parent hormone; Melanotan I (afamelanotide), Melanotan II, PT-141 (bremelanotide) and setmelanotide are separate, chemically stabilised analogs built from it to last longer or hit one receptor more selectively. Afamelanotide is EMA-approved for a rare light-sensitivity disease, and setmelanotide and bremelanotide are FDA-approved for a genetic obesity and for HSDD respectively, but none of those approvals cover native alpha-MSH itself.
It is cleaved from proopiomelanocortin (POMC), a large precursor protein, which makes it an endogenous hormone rather than a synthetic compound in its natural form. A C-terminal fragment of the molecule, the tripeptide KPV, keeps the anti-inflammatory activity on its own and has been studied separately from the full peptide.
Free, unmodified alpha-MSH has only been tested in one small human study: 15 healthy volunteers received it as an intravenous infusion at 15, 150 or 1,500 ng/kg per hour during a blood-sugar test, reported so far only as an unreviewed preprint with no repeat dosing or clinical outcome. The only approved product built on it, afamelanotide, is a stabilised analog delivered as a slow-release implant, not free alpha-MSH. Outside research, 100-500 micrograms a day by injection circulates as self-administration practice, but that has never been studied in a published trial.
Not necessarily. The intravenous infusion used in the human study was needed because the native peptide clears from the blood within minutes; a once-daily shot under the skin, which is how it circulates in self-administration, cannot reproduce that continuous exposure. No published study has tested subcutaneous native alpha-MSH in people at all.
Reported effects include nausea, facial flushing, skin darkening via MC1R activation, and appetite changes. How pronounced any of these is depends on the receptor selectivity of the specific analog involved, so the source material doesn't separate out one safety profile for native alpha-MSH versus its various derivatives.