Alpha-Melanocyte-Stimulating Hormone (alpha-MSH)
Evidence: CNeuroendocrine / Appetite-Energy Balance Signaling
Evidence Snapshot
What this grade covers
A for identity within the POMC pathway and human MC4R receptor-axis genetics (Krude 1998, Farooqi 2003 -- both precursor-context/receptor-context relative to direct alpha-MSH measurement, not direct-subject evidence themselves). C for direct human plasma alpha-MSH observational measurement (Katsuki 2001, Vehapoglu 2016). Explicit firewall: NONE of Afamelanotide's, Melanotan II's, Bremelanotide's, or Setmelanotide's clinical outcomes may raise this grade. Beta-MSH evidence (Lee 2006) is EXCLUDED from this grade entirely -- it is a different peptide. No human alpha-MSH administration study exists. Overall page grade: C.
Regulatory Context
Native alpha-MSH is an endogenous human hormone and is not itself an FDA-approved drug product. Afamelanotide (Scenesse) and Bremelanotide (Vyleesi) are each FDA-approved for their own specific indication; Setmelanotide (Imcivree) is FDA-approved for its own specific indication(s); Melanotan II is NOT FDA-approved for any indication. None of these four synthetic analogue drugs' approval, efficacy, or safety data extend to native alpha-MSH.
In Plain English
A quick, research-focused overview. It does not replace, and cannot outrank, the detailed evidence below.
What is it?
A POMC-pathway melanocortin hormone, MC4R's natural activator.
Why are researchers interested in it?
Studied for its role in appetite/energy-balance signaling and as the natural counterpart to several synthetic analogue drugs.
What does the evidence look like?
Direct human evidence is observational plasma measurement only (adult and pediatric cohorts); no administration study of native alpha-MSH exists.
Biggest things to know
Correlates with AgRP and metabolic markers in direct human plasma studies; human POMC-deficiency and MC4R-mutation genetics establish the pathway's importance in humans.
What don't we know yet?
Whether any of the four synthetic analogue drugs' trial outcomes demonstrate anything about native alpha-MSH itself -- they do not, and their evidence must not be transferred here.
Research Takeaway
Native alpha-MSH(1-13) is a POMC/ACTH-pathway melanocortin peptide; human POMC loss-of-function mutations cause severe early-onset obesity, adrenal insufficiency, and red hair pigmentation.
Evidence boundary: Must be framed as precursor/pathway evidence, not direct alpha-MSH measurement.
See all 5 evidence claims →Quick Summary
Native alpha-MSH is a melanocortin hormone in the POMC pathway that activates MC4R, the same receptor targeted by several distinct synthetic analogue drugs (Afamelanotide, Bremelanotide, and Setmelanotide, each separately FDA-approved for its own indication; Melanotan II, not FDA-approved). Direct human evidence for native alpha-MSH itself is limited to blood measurement studies.
Mechanism & Research Overview
Native alpha-MSH is a melanocortin hormone in the POMC pathway that activates MC4R, the same receptor targeted by several distinct synthetic analogue drugs (Afamelanotide, Bremelanotide, and Setmelanotide, each separately FDA-approved for its own indication; Melanotan II, not FDA-approved). Direct human evidence for native alpha-MSH itself is limited to blood measurement studies.
Evidence Claims
Individual scientific statements drawn from the sources cited below, each shown with the specific evidence boundary that statement does not establish.
Supported
Native alpha-MSH(1-13) is a POMC/ACTH-pathway melanocortin peptide; human POMC loss-of-function mutations cause severe early-onset obesity, adrenal insufficiency, and red hair pigmentation.
Does not establish
Evidence boundary: Must be framed as precursor/pathway evidence, not direct alpha-MSH measurement.
Supported
Human MC4R mutations (the melanocortin-4 receptor, alpha-MSH's primary receptor) cause severe obesity with a genotype-severity correlation, in a 500-proband cohort.
Does not establish
Evidence boundary: Receptor-axis evidence only, not direct alpha-MSH intervention evidence.
Sources: Clinical Spectrum of Obesity and Mutations in the Melanocortin 4 Receptor Gene
Supported
Direct plasma alpha-MSH measurement shows it correlates with plasma AgRP, independent of total fat area, in a 15-obese/15-nonobese-men cohort; a separate pediatric cohort measured both hormones together in underweight, healthy, and obese children.
Does not establish
Evidence boundary: Association only; the only direct human alpha-MSH measurement in the frozen set.
Sources: Plasma levels of agouti-related protein are increased in obese men; Alpha-Melanocyte-Stimulating Hormone and Agouti-Related Protein: Do They Play a Role in Appetite Regulation in Childhood Obesity?
Supported
Beta-MSH (a different POMC-derived melanocortin peptide, not alpha-MSH) carries a rare human variant (Tyr221Cys) with impaired MC4R activation, identified in obese probands.
Does not establish
Evidence boundary: Must NEVER be cited as alpha-MSH evidence under any circumstance.
Sources: A POMC variant implicates beta-melanocyte-stimulating hormone in the control of human energy balance
Supported
Afamelanotide (Scenesse) and Bremelanotide (Vyleesi) are each FDA-approved for their own specific indication; Setmelanotide (Imcivree) is FDA-approved for its own specific indication(s); Melanotan II is NOT FDA-approved for any indication. All four are synthetic melanocortin analogue drugs/programs, chemically and regulatorily distinct from native alpha-MSH, with distinct regulatory statuses from one another.
Does not establish
Evidence boundary: These 4 sources' own clinical efficacy/safety data may NEVER raise native alpha-MSH's evidence grade, regardless of any individual analogue's own approval status.
Sources: Risks of Unregulated Alpha-MSH Analogue Use; VYLEESI (bremelanotide injection) U.S. prescribing information; IMCIVREE (setmelanotide) injection — Prescribing Information
Safety & Evidence Limitations
Considerations reported in the sources cited on this page — not a complete list of every possible risk, and not medical advice.
Safety Consideration
Four synthetic melanocortin analogue drugs/programs exist with distinct regulatory statuses from one another -- Afamelanotide (Scenesse), Bremelanotide (Vyleesi), and Setmelanotide (Imcivree) are each FDA-approved for their own specific indication; Melanotan II is NOT FDA-approved for any indication. All four are easily confused with native alpha-MSH in casual sourcing; none of their clinical outcomes may contribute to this page's evidence grade, regardless of individual approval status.Safety Consideration
POMC, ACTH, beta-MSH, and KPV (alpha-MSH(11-13)) are each distinct from full native alpha-MSH(1-13) and must not be conflated with it or with each other.Safety Consideration
No study has administered native alpha-MSH itself to humans; direct human evidence is limited to plasma measurement.
Research Areas Being Studied
Research areas discussed on this page reflect the Neuroendocrine / Appetite-Energy Balance Signaling category and the sources cited below.
Findings Reported in Studies
Educational summary only — reported in cited studies, not a claim of proven benefit.
- Alpha-Melanocyte-Stimulating Hormone and Agouti-Related Protein: Do They Play a Role in Appetite Regulation in Childhood Obesity? (2016):
- A POMC variant implicates beta-melanocyte-stimulating hormone in the control of human energy balance (2006):
- Clinical Spectrum of Obesity and Mutations in the Melanocortin 4 Receptor Gene (2003):
- Plasma levels of agouti-related protein are increased in obese men (2001):
- Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans (1998):
Study Tables by Evidence Type
Human Studies & Clinical Data
| Title | Year | Population / Model | Dose / Duration / Finding | Safety Notes | Source |
|---|---|---|---|---|---|
| Alpha-Melanocyte-Stimulating Hormone and Agouti-Related Protein: Do They Play a Role in Appetite Regulation in Childhood Obesity? | 2016 | Underweight, healthy, and obese children | Direct plasma measurement of both alpha-MSH and AgRP in a pediatric cohort spanning underweight, healthy-weight, and obese children, assessing associations with anthropometric/nutritional markers. | ||
| A POMC variant implicates beta-melanocyte-stimulating hormone in the control of human energy balance | 2006 | 538 patients with severe, early-onset obesity | 5 unrelated probands heterozygous for a beta-MSH Tyr221Cys variant with impaired MC4R binding/activation compared to wild-type beta-MSH. This is BETA-MSH evidence, a different peptide from alpha-MSH. | ||
| Clinical Spectrum of Obesity and Mutations in the Melanocortin 4 Receptor Gene | 2003 | 500 probands with severe childhood obesity | 29 probands (5.8%) had MC4R mutations (23 heterozygous, 6 homozygous); mutation carriers had severe obesity, increased lean mass, increased linear growth, hyperphagia, severe hyperinsulinemia, with genotype-phenotype severity correlation. | ||
| Plasma levels of agouti-related protein are increased in obese men | 2001 | 15 obese men, 15 nonobese men | Plasma AGRP significantly higher in obese men than nonobese men (p<0.01); correlated with visceral fat area, total fat area, fasting insulin, glucose infusion rate, serum leptin, and plasma alpha-MSH, independent of total fat area. | ||
| Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans | 1998 | Human patients with homozygous/compound-heterozygous POMC loss-of-function mutations | Complete POMC loss-of-function causes red hair pigmentation, early-onset obesity, and congenital hypocortisolism -- establishing the human POMC-deficiency phenotype. This is precursor-context evidence, not direct alpha-MSH measurement. |
Animal / Cell / Preclinical Data
No Animal / Cell / Preclinical Data Listed Yet
This section will be updated as sources are added.
Regulatory Documents & Official Trial Registries
No Regulatory Documents & Official Trial Registries Listed Yet
This section will be updated as sources are added.
Anecdotal Reported Patterns — Not Medical Advice
Anecdotal Reported Patterns — Not Medical Advice
Reported dosing patterns are included for educational context only. They are self-reported, unverified, not medical advice, and not instructions for human use. Community-submitted patterns are not yet available in this Phase 1 prototype; this section is a placeholder reserved for moderated, aggregated community data.
Lab Markers to Discuss With a Clinician
Educational topics only — not self-monitoring instructions.
FAQ
Disclaimer
Native alpha-MSH is distinct from four synthetic melanocortin analogue drugs with different regulatory statuses (Afamelanotide, Bremelanotide, and Setmelanotide are each FDA-approved for their own indication; Melanotan II is not FDA-approved) -- none of their outcomes apply here.
Educational use only. This content is provided for informational and research-summary purposes only. It is not medical advice, not a treatment recommendation, not a dosing guide, and not a substitute for care from a licensed medical professional. Nothing here is intended to diagnose, treat, cure, prevent, or mitigate disease. Reported dosing patterns, when shown elsewhere on the site, must be labeled either as Study / Trial Dosing or Anecdotal Reported Patterns — Not Medical Advice. Community reports are self-reported, unverified, and not scientific proof.
Community-reported experiences, once enabled, must be displayed only as moderated, anonymized, or aggregated data. They are anecdotal, self-reported, unverified, and should never be presented as proof of safety, efficacy, or expected results.
Content status: Published. Last updated 2026-08-28.
Follow research updates for Alpha-Melanocyte-Stimulating Hormone (alpha-MSH)
Get notified in your MitoCore account when this profile is updated, a new study is added, or its evidence grade changes.
Get updates when new studies or safety notes are added for this peptide.
Get educational updates on new studies, evidence-grade changes, and safety notes. Educational content only — not medical advice.