Melanotan I

Afamelanotide is native alpha-MSH with two substitutions - norleucine at position 4 and D-phenylalanine at position 7 - which make it resistant to proteolysis and roughly a thousand times more potent than the parent hormone. MC1R activation raises cyclic AMP in melanocytes and shifts melanogenesis toward eumelanin, which absorbs and dissipates UV and visible light. In erythropoietic protoporphyria the benefit comes from that increased pigment shielding the skin from the visible-light wavelengths that activate accumulated protoporphyrin IX. Unlike Melanotan II it is linear rather than cyclic and much more MC1R-selective, so it does very little at MC3R and MC4R and correspondingly little to libido, appetite or nausea.

Targets: MC1R, Melanocyte adenylate cyclase, Eumelanin synthesis

• · A 16 mg bioresorbable rod about 1.7 cm long. This is the only legitimate approved use, and it is for erythropoietic protoporphyria, not cosmetics.
• · Grey-market users typically load daily for 10 to 14 days then maintain. MT-I costs several times more per visible shade than MT-II because it is a bigger, harder peptide to make - which is the main reason MT-II dominates despite being the dirtier drug.
• · Because the peptide clears fast and is not depot-formulated, injected MT-I needs more frequent dosing than the implant to hold the same colour.

Work out your exact syringe units →

• very commonSkin darkening— This is the intended effect, but it is generalised and includes areas you did not want darkened.
• very commonImplant-site reaction— Pain, bruising or a palpable nodule at the supra-iliac site.
• commonNausea— Far less than with Melanotan II, but present in about a fifth of implant recipients.
• commonHeadache— Usually early after implant placement.
• commonFatigue— Reported in the EPP trials.
• commonDarkening of existing moles— Same surveillance problem as Melanotan II - the label mandates twice-yearly skin checks.
• rareMelanocytic lesion changes— The prescribing information requires full-body skin examination twice a year for this reason.

• Personal history of melanoma or current suspicious pigmented lesions.
• Severe hepatic or renal impairment - not studied.
• Pregnancy - no adequate data.
• Cosmetic use in someone with heavily freckled or atypical-mole skin, where pigment change wrecks melanoma surveillance.

• redundantmelanotan-2 — Same pigmentation pathway; MT-I is the cleaner and much more expensive way to do it.
• cautionAnticoagulants — Relevant to implant insertion, which is a minor procedure with bleeding and bruising risk.
• synergyUV exposure — Pigmentation develops with less UV than normal, but the tan is not full sun protection.

• · Full-body skin examination every 6 months, which is what the approved label actually requires.
• · Photograph existing moles before starting.

Approved as Scenesse for erythropoietic protoporphyria in the US, EU and Australia, dispensed only through specialist centres. Injectable Melanotan I sold online is an unapproved research chemical.

• SCENESSE (afamelanotide) FDA prescribing information (label)
• Langendonk et al. 2015, afamelanotide for erythropoietic protoporphyria, New England Journal of Medicine (trial)
• EMA Scenesse summary of product characteristics (label)

Afamelanotide is native alpha-MSH with two point changes, which is why it is so much more selective than the cyclic analogues: it is essentially the endogenous ligand made unkillable. At the melanocyte it does exactly what alpha-MSH does - MC1R, Gs, adenylyl cyclase, cyclic AMP, protein kinase A, CREB phosphorylation, MITF transcription, then tyrosinase and TYRP1 upregulation and a swing from phaeomelanin to eumelanin. There is a second arm that matters in the approved indication and is usually ignored in the cosmetic conversation: MC1R signalling also upregulates nucleotide excision repair and has direct antioxidant and anti-inflammatory effects in keratinocytes, independent of pigment. In erythropoietic protoporphyria the benefit is not purely a sunshade effect. Accumulated protoporphyrin IX absorbs visible light around 400 to 410 nanometres and generates singlet oxygen, and eumelanin both absorbs those wavelengths and quenches the resulting reactive species. The reason afamelanotide does almost nothing to libido or appetite is geometry: the linear backbone binds MC1R well but is a much poorer fit at MC3R and MC4R than the lactam-bridged cyclic ring of Melanotan II, and it does not usefully reach central melanocortin receptors anyway. That selectivity is the entire point of the molecule, and it is also why nobody sells it to people who want the sexual effect.

For cosmetic users the most common disappointment is cost per shade. MT-I is a thirteen-residue peptide, much more expensive to synthesise than the seven-residue MT-II, and because injected free peptide clears in about an hour it needs daily loading rather than the twice-weekly maintenance MT-II tolerates. People buy one vial, dose it like MT-II, get almost no colour, and conclude they were sold a fake. Second, the pigment is generalised: it darkens palms, old scars, existing moles and the parts of you that were previously a different colour from the rest, and it is not a targeted tan. Third, and this is the serious one, it carries the same surveillance problem as MT-II. The approved label mandates skin checks every six months for a reason, and a cosmetic user with no dermatologist and no baseline photographs has taken on that risk with none of the monitoring. Implant-specific failures are procedural: nodule formation, implant migration and occasional difficulty retrieving a spent rod.

• MC1R — Roughly a thousandfold more potent than native alpha-MSH in the original characterisation of NDP-MSH; a specific Kd was not resolved here.

  Eumelanin synthesis through cyclic AMP, PKA, CREB and MITF, plus upregulated DNA repair and antioxidant response in melanocytes and keratinocytes. This is the therapeutic target.

• MC3R and MC4R

  Weak relative activity. Enough to explain the roughly one in five implant recipients who report nausea, not enough to produce the erections, appetite suppression or intense flushing seen with Melanotan II.

• MC5R

  Minor. Not clinically characterised in humans for this drug.

• CUV039 (NCT01605136) 3 · n=93 · 26 weeks · 2015

  Median hours spent in direct sunlight between 10am and 6pm on pain-free days over 180 days in adults with erythropoietic protoporphyria: 64.1 hours on afamelanotide versus 40.5 hours on vehicle implant.

• CUV029 (NCT00979745) 3 · n=74 · 39 weeks · 2015

  Median hours spent outdoors between 10am and 3pm in direct sunlight on pain-free days over 270 days: 6.0 hours on afamelanotide versus 0.75 hours on vehicle. The absolute numbers are small, which tells you how disabling untreated erythropoietic protoporphyria is.

After implant placement, visible darkening starts at two to five days and peaks around day ten to fourteen, holding for roughly two months, which is why the approved schedule is an implant every two months across the high-sunlight season. With daily grey-market injections the timeline is similar for pigment onset because the rate-limiting step is melanogenesis rather than drug exposure, but the colour begins to fade within one to two weeks of stopping unless maintenance dosing continues. Photoprotective benefit in erythropoietic protoporphyria tracks the pigment rather than the plasma level.

There is very little to stack here, which is the point of the molecule. Running MT-I alongside MT-II is redundant on pigmentation, though some people use MT-I to hold colour and a small MT-II dose separately for the sexual effect, which at least separates the two variables. The interaction worth naming is with anticoagulants, and it is procedural rather than pharmacological: the approved product is an implant placed with a wide-bore needle above the iliac crest, and that is a bleeding risk in anyone anticoagulated. UV exposure is the only true synergy, and the same caveat applies as with MT-II - the tan lowers the UV dose needed for colour, it does not raise the dose your DNA can absorb. Photosensitising drugs remain photosensitising.

Against Melanotan II, this is the clean version - the same MC1R pigmentation with essentially none of the nausea, flushing, erections or appetite suppression, because linear NDP-MSH simply does not engage central melanocortin receptors the way the cyclic analogue does. You pay for that in money and in injection frequency. Against a sunbed, afamelanotide is the only compound in this class with randomised controlled evidence of clinical benefit, but that evidence is about pain-free light exposure in a rare metabolic disease and says nothing about whether cosmetic pigment induction is net safe. Against PT-141, they are opposite solutions to the same problem: both were built to split alpha-MSH's tangled effects, PT-141 keeping the sex and dropping the tan, afamelanotide keeping the tan and dropping the sex.

$70–$250/month. Research-chemical 10 mg vials of Melanotan I typically run 70 to 180 dollars, and daily 500 to 1000 mcg loading burns through them far faster than MT-II, so a realistic loading month is one to two vials. The approved product is not comparable: Scenesse implants have been reported at roughly 20000 dollars each in the US, three implants a year, dispensed only through specialist centres. Figures are indicative and were not verified in this session.

• ?Volume of distribution, clearance and protein binding are absent from the Scenesse label and I could not source them elsewhere in this session.
• ?The metabolic profile is explicitly stated as not fully characterised in the label. Anyone claiming a specific elimination route for afamelanotide is going beyond the regulatory record.
• ?Free-peptide pharmacokinetics after ordinary subcutaneous injection - the way grey-market users actually take it - has not been formally published. The roughly one-hour clearance in the Core record is inference from alpha-MSH analogue behaviour rather than a measured value for this route.
• ?Blood-brain barrier penetration is marked as no on the basis of the absent central side effect profile rather than on direct measurement.
• ?The blood markers listed here are not drug-specific monitoring requirements from the label beyond the skin examination. There is no established bloodwork panel for afamelanotide.
• ?Scenesse pricing figures are widely reported but were not verified in this session.

• Afamelanotide for Erythropoietic Protoporphyria Langendonk JG, Balwani M, Anderson KE, Bonkovsky HL, Anstey AV, Bissell DM, Bloomer J, Edwards C, Neumann NJ, Parker C, Phillips JD, Lim HW, Hamzavi I, Deybach JC, Kauppinen R, Rhodes LE, Frank J, Murphy GM, Karstens FPJ, Sijbrands EJG, de Rooij FWM, Console-Bram L, Duffield J, Snyder R, Desnick RJ, New England Journal of Medicine, 2015 · PMID 26132941

  The pivotal randomised placebo-controlled evidence behind the approval, in the New England Journal. This is the highest-quality evidence anywhere in the melanocortin tanning space, and it is about a rare light-sensitivity disease, not cosmetics.

• Afamelanotide (CUV1647) in dermal phototoxicity of erythropoietic protoporphyria Minder EI, Barman-Aksoezen J, Schneider-Yin X, Expert Review of Clinical Pharmacology, 2015 · PMID 25470471

  A good review of the development programme and the mechanism, including why pigment is not the whole story.

• Investigation of the immunogenicity of the synthetic alpha-melanocyte-stimulating hormone analogue afamelanotide in patients with erythropoietic protoporphyria Lengweiler S, Kreim S, Barman-Aksoezen J, Maurer M, Minder EI, Skin Pharmacology and Physiology, 2015 · PMID 25402764

  Anti-drug antibody data on repeated implant exposure. Relevant to anyone dosing a peptide analogue of a human hormone long-term.

• SCENESSE (afamelanotide) implant - FDA prescribing information DailyMed / FDA, 2019

  Source of the 36-hour tmax, the roughly 15-hour apparent half-life from the implant, the 3.7 ng/mL peak concentration, the CUV029 and CUV039 results, and the twice-yearly skin examination requirement.