Alpha-MSH
The tanning and anti-inflammatory hormone that produced three approved drugs and remains unapproved itself
Alpha-MSH is a thirteen-amino-acid peptide cut from the same precursor as ACTH. It drives pigment production through the MC1 receptor and damps inflammation through others. The hormone is not a medicine, but three drugs built on it are approved in the United States.
What is it?
Alpha-MSH comes from proopiomelanocortin, the precursor that also yields ACTH and beta-endorphin. Acting on the MC1 receptor in skin it drives melanin production; acting on MC3 and MC4 receptors in the brain it influences appetite and sexual behaviour; and across the receptor family it suppresses inflammatory signalling, which is what most of its research is about.
The pattern of the human work is unusual: the hormone itself is rarely given, while modified versions of it are. A synthetic analogue produced real tanning and measurable protection from ultraviolet damage in 65 people, and a brain-penetrating fragment reduced body fat in a six-week trial. Both are analogues, not alpha-MSH.
Three analogues have reached approval in the United States: afamelanotide (Scenesse, 2019) for a rare light-sensitivity disorder, setmelanotide (Imcivree, 2020) for genetic obesity, and bremelanotide (Vyleesi, 2019) for low sexual desire. The hormone itself has no application in Drugs@FDA.
The obesity story shows why the analogues are targeted narrowly. Early MC4 receptor agonists, including MK-0493 and a long-acting α-MSH analogue, produced no meaningful weight loss in common obesity. Setmelanotide works where the pathway itself is broken: two patients with POMC deficiency lost 51 and 20.5 kg, and in Bardet-Biedl syndrome 32% of patients aged 12 or over lost at least 10% in a year. The cost is visible, because the drug also darkens skin, lips and moles.
The skin analogue has a wider trail of small studies. A single afamelanotide implant reduced light-triggered hives in solar urticaria and cleared lesions in two people with Hailey-Hailey disease, and years of use in protoporphyria produced no antibodies. Cell work suggests MC1R gene variants, such as those behind red hair, blunt the anti-inflammatory effect of many melanocortin compounds.
Where alpha-MSH itself appears in human research, it is usually as a measurement: higher levels after a stroke predicted better recovery, which is an association in 111 patients rather than a treatment.
Mechanism of Action
Alpha-MSH is cut from proopiomelanocortin and acts on melanocortin receptors: MC1 in skin, MC3 and MC4 in the brain, and across the family on inflammation.
Pigmentation (MC1)
MC1 receptor activation increases melanin; analogues tan the skin and reduce light sensitivity.
Appetite (MC4)
MC4 receptor agonism reduces hunger where the leptin-melanocortin pathway is broken, the basis of setmelanotide.
Inflammation
Melanocortin compounds reduce cytokine release in cell studies, an effect that MC1R gene variants can weaken.
Published Research
These are the studies in people, read from their PubMed abstracts: three that gave an analogue and one that measured the hormone.
A synthetic analogue tanned skin and cut UV damage
Sixty-five people received the synthetic melanotropin [Nle4-D-Phe7]-alpha-MSH by injection at 0.16 mg/kg over three ten-day cycles. Melanin rose in everyone, by 41% on average in those who burn easily. Sunburn cells after ultraviolet exposure fell by more than half in that group, and thymine dimers in the basal layer by 59%.
A brain-penetrating fragment reduced body fat
Thirty-six normal-weight people were randomised to a melanocortin fragment, a selective MC4 agonist, or placebo, given intranasally twice daily for six weeks. The fragment reduced body fat by 1.68 kg and weight by 0.79 kg, with leptin down 24% and insulin down 20%. The selective MC4 agonist changed nothing significantly.
Bremelanotide in female sexual arousal disorder
Eighteen premenopausal women with sexual arousal disorder received a single 20 mg intranasal dose of bremelanotide or placebo in a double-blind crossover. Reported arousal improved against placebo (p = 0.011) and more women were satisfied with their arousal after intercourse (p = 0.026), while measured vaginal blood flow did not change.
Measured after stroke, not given
In 111 patients followed for a year after ischaemic stroke, plasma alpha-MSH fell early in the most severe strokes and recovered over the year. Higher initial alpha-MSH independently predicted good long-term outcome; ACTH, cortisol and interleukin-6 did not.
Setmelanotide in Bardet-Biedl syndrome
In a phase 3 trial of 38 patients, 32.3% of those aged 12 or over with Bardet-Biedl syndrome lost at least 10% of body weight after 52 weeks; results in Alström syndrome were inconclusive. Skin darkening (61%) and injection-site redness (48%) were the commonest side effects.
POMC deficiency
Two patients unable to make POMC-derived peptides, including melanocyte-stimulating hormone, had lasting reductions in hunger on setmelanotide and lost 51.0 kg over 42 weeks and 20.5 kg over 12 weeks.
Skin and hair darkening
Over up to 46 months of setmelanotide in POMC and LEPR deficiency, skin pigmentation rose in every patient, lips and moles darkened and red hair turned brown; no malignant skin changes were seen, and the authors advise regular skin checks.
Hypothalamic obesity in ROHHAD
Off-label setmelanotide in a patient with ROHHAD syndrome cut weight 28% (97 to 70 kg) and improved liver fat, breathing support and behaviour; after it was stopped for insurance reasons, 10% was regained within 3 months.
Energy expenditure
In obese volunteers, short-term RM-493 (setmelanotide) raised resting energy expenditure by 6.4%, about 111 kcal a day, and shifted fuel use toward fat, without changing heart rate or blood pressure.
An earlier MC4R agonist failed
MK-0493, a potent selective MC4 receptor agonist, had only a small effect on energy intake and no significant weight loss against placebo over 12 to 18 weeks, leading its authors to doubt the approach for common obesity.
A long-acting analogue, stopped
In healthy overweight men, the long-acting α-MSH analogue MC4-NN2-0453 had a half-life of about 250 hours but caused no weight loss; skin effects, headache and erections were reported and the trial was stopped early.
Afamelanotide in solar urticaria
In 5 patients given one 16 mg afamelanotide implant in winter, melanin density rose and the skin's hive response to light fell across wavelengths from 300 to 600 nm by day 60.
No antibodies after years of use
In 26 patients with erythropoietic protoporphyria exposed to afamelanotide for up to 6 years, none developed new antibodies to the drug or to α-MSH; 3 had pre-existing reactivity that did not change.
Hailey-Hailey disease
In an open-label pilot, two patients with Hailey-Hailey disease given a 16 mg afamelanotide implant had complete clearance of their lesions by 60 days.
Acne
In 3 patients with mild-to-moderate acne, inflammatory lesions and quality of life improved 56 days after afamelanotide; all darkened, especially on the face.
A pan-agonist eye drop
In a phase 2 trial in dry eye disease, the melanocortin pan-agonist PL9643 did not beat placebo in the whole population, with signals in moderate-to-severe patients and no drug-related adverse events.
Why general obesity programmes failed
A review attributes past failures of melanocortin drugs in common obesity to potency, selectivity and side effects, and argues that targeting both MC3 and MC4 receptors may be needed.
MC1R genetics and response
In cell studies, common MC1R variants, including red-hair variants, reduced the anti-inflammatory effect of most melanocortin compounds tested, and the same variant could block or boost different compounds.
Dosing Data
Alpha-MSH itself is not given. The rows below are analogue doses from published trials.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
Side Effects & Contraindications
Reported Side Effects
From the analogue studies; the hormone itself is not given as a treatment.
Contraindications & Cautions
Not a medicine.
Legal Status
The hormone is not approved; three analogues are.
Frequently Asked Questions
?What does alpha-MSH do?
It drives pigment production in skin through the MC1 receptor, influences appetite and sexual behaviour through brain melanocortin receptors, and suppresses inflammatory signalling.
?Does it make you tan?
A synthetic analogue does: in 65 people it raised melanin by 41% in those who burn easily and cut sunburn cells by more than half. That was [Nle4-D-Phe7]-alpha-MSH, not the natural hormone.
?Which drugs come from it?
Afamelanotide for erythropoietic protoporphyria, setmelanotide for certain genetic forms of obesity, and bremelanotide for low sexual desire — all approved in the United States.
?Is KPV related to it?
Yes. KPV is alpha-MSH's C-terminal tripeptide, pursued because it keeps the anti-inflammatory action without the pigmentary one.
?Why did melanocortin drugs fail for ordinary obesity?
Early MC4 receptor agonists such as MK-0493 and a long-acting α-MSH analogue gave no meaningful weight loss against placebo. Setmelanotide works in rare genetic forms where the pathway is broken, such as POMC deficiency and Bardet-Biedl syndrome.
?Do these drugs darken moles?
Yes. Setmelanotide darkened skin, lips and moles in long-term follow-up, and afamelanotide tans skin. No malignant changes were seen in that follow-up, but regular skin checks are advised.
References
- [pubmed] Barnetson RS, et al. "[Nle4-D-Phe7]-alpha-melanocyte-stimulating hormone significantly increased pigmentation and decreased UV damage in fair-skinned Caucasian volunteers." J Invest Dermatol, 2006;126(8):1869-78. PMID: 16763547.
- [pubmed] Fehm HL, et al. "The melanocortin melanocyte-stimulating hormone/adrenocorticotropin(4-10) decreases body fat in humans." J Clin Endocrinol Metab, 2001;86(3):1144-8. PMID: 11238499.
- [pubmed] Diamond LE, 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. PMID: 16839319.
- [pubmed] Zierath D, et al. "Plasma α-melanocyte stimulating hormone predicts outcome in ischemic stroke." Stroke, 2011;42(12):3415-20. PMID: 21960572.
- [pubmed] Catania A, et al. "The melanocortin system in control of inflammation." ScientificWorldJournal, 2010;10:1840-53. PMID: 20852827.
- [pubmed] Brzoska T, et al. "Alpha-melanocyte-stimulating hormone and related tripeptides: biochemistry, antiinflammatory and protective effects in vitro and in vivo, and future perspectives for the treatment of immune-mediated inflammatory diseases." Endocr Rev, 2008;29(5):581-602. PMID: 18612139.
- [pubmed] Haqq AM, et al. "Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alström syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period." Lancet Diabetes Endocrinol, 2022;10(12):859-868. PMID: 36356613.
- [pubmed] Kühnen P, et al. "Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist." N Engl J Med, 2016;375(3):240-6. PMID: 27468060.
- [pubmed] Kanti V, et al. "A Melanocortin-4 Receptor Agonist Induces Skin and Hair Pigmentation in Patients with Monogenic Mutations in the Leptin-Melanocortin Pathway." Skin Pharmacol Physiol, 2021;34(6):307-316. PMID: 34058738.
- [pubmed] Grünewald A, et al. "Melanocortin-4 Receptor Agonist Treatment of Hypothalamic Obesity in ROHHAD Syndrome." Pediatrics, 2026;157(6). PMID: 42114845.
- [pubmed] Chen KY, et al. "RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals." J Clin Endocrinol Metab, 2015;100(4):1639-45. PMID: 25675384.
- [pubmed] Krishna R, et al. "Potent and selective agonism of the melanocortin receptor 4 with MK-0493 does not induce weight loss in obese human subjects: energy intake predicts lack of weight loss efficacy." Clin Pharmacol Ther, 2009;86(6):659-66. PMID: 19741604.
- [pubmed] Royalty JE, et al. "Investigation of safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of a long-acting α-MSH analog in healthy overweight and obese subjects." J Clin Pharmacol, 2014;54(4):394-404. PMID: 24166760.
- [pubmed] Prindle CR, et al. "The melanocortin receptors as targets for general obesity: contextualizing clinical failures and analyzing future perspectives." Front Endocrinol (Lausanne), 2026;17:1797586. PMID: 41907544.
- [pubmed] Haylett AK, et al. "Systemic photoprotection in solar urticaria with α-melanocyte-stimulating hormone analogue [Nle4-D-Phe7]-α-MSH." Br J Dermatol, 2011;164(2):407-14. PMID: 20969564.
- [pubmed] Lengweiler S, et al. "Evaluation of the immunogenicity of the synthetic α-melanocyte-stimulating hormone (α-MSH) analogue afamelanotide ([Nle4-D-Phe7]-α-MSH, Scenesse®) in erythropoietic protoporphyria patients by ELISA detecting both anti-afamelanotide and anti-α-MSH antibodies." Skin Pharmacol Physiol, 2015;28(2):103-13. PMID: 25402764.
- [pubmed] Biolcati G, et al. "Efficacy of the melanocortin analogue Nle4-D-Phe7-α-melanocyte-stimulating hormone in the treatment of patients with Hailey-Hailey disease." Clin Exp Dermatol, 2014;39(2):168-75. PMID: 24256215.
- [pubmed] Böhm M, et al. "Beneficial effects of the melanocortin analogue Nle4-D-Phe7-α-MSH in acne vulgaris." J Eur Acad Dermatol Venereol, 2014;28(1):108-11. PMID: 22845050.
- [pubmed] Evans D, et al. "Efficacy and Safety of the Melanocortin Pan-Agonist PL9643 in a Phase 2 Study of Patients with Dry Eye Disease." J Ocul Pharmacol Ther, 2023;39(9):600-610. PMID: 37677000.
- [pubmed] Khodeneva N, et al. "The anti-inflammatory efficacy of melanocortin drugs is influenced by genetic variation at MC1R." Sci Rep, 2026;16(1). PMID: 42277217.
Sources & Citations
Studies were read from their PubMed abstracts; α-MSH itself has no label. Read October 7, 2026.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.