Melanotan II

Melanotan II is a synthetic cyclic heptapeptide analogue of α-melanocyte-stimulating hormone, acting as a non-selective melanocortin receptor agonist. Of the five melanocortin receptors, MC1R governs pigmentation, MC3R and MC4R govern appetite and energy balance, and MC4R additionally governs sexual function; MT-2 activates all of these simultaneously, which is why melanogenesis, anorexigenic and pro-sexual effects arrive as a package.

Developed in the 1980s at the University of Arizona as a photoprotective agent intended to induce a tan without UV-related DNA damage, it completed Phase 1 work but was abandoned before Phase 3 on safety grounds. It has never been submitted for FDA approval. PT-141 (bremelanotide), an MC4R-preferring derivative, was developed from it and went on to approval for female sexual dysfunction; Melanotan I (afamelanotide) is the more MC1R-selective sibling, available only as a prescription implant for a rare photosensitivity disorder.

Pharmacokinetics: plasma half-life approximately 1 hour after subcutaneous injection, cleared by enzymatic degradation and renal excretion. Biological effects far outlast plasma exposure because melanin, once deposited, persists, and the central effects also extend well beyond clearance.

Supplied as lyophilised powder for reconstitution in bacteriostatic water and subcutaneous administration.

Melanogenesis (MC1R). MT-2 activates MC1R on cutaneous melanocytes, driving conversion of tyrosine to melanin independently of UV exposure; concurrent UV accelerates and deepens the response. Phase 1 data showed visible darkening within 3 to 5 days and full effect over 2 to 3 weeks, persisting for weeks after cessation because deposited melanin is cleared only through epidermal turnover. Response scales with available melanocyte reserve, so constitutively fair, non-tanning phototypes respond poorly.

Anorexigenic (MC3R/MC4R). Hypothalamic MC3R and MC4R activation generates a satiety signal, reducing appetite and, in many users, caloric intake without conscious restriction.

Pro-sexual (MC4R, central). Central MC4R activation increases dopamine release in the medial preoptic area of the hypothalamus, driving desire and arousal. In a double-blind, placebo-controlled crossover study of 20 men with psychogenic erectile dysfunction, subcutaneous MT-2 at 0.025 mg/kg produced clinical erections in 17 of 20, with mean tip rigidity exceeding 80% and mean duration exceeding 40 minutes; sexual desire increased in 68% versus 19% on placebo. The mechanism is central rather than the vascular PDE5 inhibition of sildenafil and tadalafil. The pro-sexual effect was found serendipitously when a University of Arizona researcher self-administered twice the intended dose and experienced an 8-hour erection, an observation that led to PT-141.

Pharmacokinetics. Plasma half-life approximately 1 hour after subcutaneous injection, enzymatic degradation, renal excretion. Pharmacodynamic duration substantially exceeds plasma exposure across all three effect domains.

Three effect domains, inseparable because receptor selectivity is poor.

Melanogenic (MC1R). Increased cutaneous melanin, producing progressive pigmentation over 2 to 3 weeks with an associated degree of UV photoprotection and more uniform tone. A pilot Phase 1 study at 0.01 to 0.03 mg/kg produced significant darkening over a 10-day period without UV exposure, across all skin types. Existing naevi and freckles darken; new freckles may appear; injection sites may pigment locally.

Anorexigenic (MC3R/MC4R). Reduced appetite and often reduced intake, compounding with GLP-1 agonists.

Pro-sexual (MC4R). Increased desire and arousal, improved erection quality and duration in men with psychogenic erectile dysfunction, and spontaneous erections 1 to 5 hours post-dose.

The existing entry additionally records symptomatic benefit in rosacea and studied application in erythropoietic protoporphyria and vitiligo; afamelanotide, not MT-2, holds approval in the former.

On melanoma: a 2013 review found no conclusive causal evidence; a 2021 review reported increased incidence among users, attributed to UV-seeking behaviour; a 2020 report found MT-2 suppressed melanoma progression in a preclinical model. Case reports of melanoma in users exist without established causation. The operative concern is that pigmentary change masks early malignant change. A 2024 review in the British Journal of Dermatology of real-world use confirmed nausea, flushing, naevus darkening and pro-sexual effects consistent with trial data.

Serious rare events from case reports — renal infarction, rhabdomyolysis with renal dysfunction, and priapism — were documented at excessive doses, including rhabdomyolysis after injection at 6 times the standard dose, and contributed to abandonment of development.

Loading, weeks 1 to 2. Nausea onsets 10 to 60 minutes post-injection, is dose-dependent and is the principal early tolerability barrier; pre-bed dosing is the standard mitigation. Facial flushing and warmth persist 30 to 60 minutes. Stretching and yawning are documented. Visible darkening from day 3 to 5. Pro-sexual effects within the first doses, with spontaneous erections 1 to 5 hours post-dose in men. Appetite suppression within the first week. Users less commonly report fatigue or flu-like malaise in the first days, feeling cold, stomach cramping and headache.

Weeks 2 to 3. Full melanogenic effect. Darkening of existing naevi and freckles, appearance of new freckles or beauty marks, and localised injection-site hyperpigmentation. Pro-sexual effects consistent.

Maintenance, week 3 onwards. Frequency reduced from daily to 2 to 3 times weekly; some users dose only ahead of planned UV exposure.

Washout. Tan fades with epidermal turnover over 4 to 8 weeks after the last dose. Most pigmentary change reverses, some may be permanent. Response correlates with baseline tanning capacity; non-tanning phototypes are poor responders. Baseline dermatology review with full mole photography, regular follow-up, and immediate cessation with dermatological review on any asymmetric change in shape, border or colour are the recommended monitoring standard.

Reconstitution: 10 mg vial in 2 mL bacteriostatic water, giving 5 mg/mL, i.e. 500 mcg per 10 insulin units (50 mcg/unit). 0.25 mg = 5 units, 0.5 mg = 10 units, 1 mg = 20 units. Subcutaneous, abdomen or thigh, dosed before bed to sleep through nausea and flushing.

Loading: 0.25 to 0.5 mg daily for 7 to 14 days or until target pigmentation. Initiate at 0.1 to 0.25 mg to assess nausea tolerance. Body-weight tiers: under 150 lbs, 0.25 mg daily; 150 to 200 lbs, 0.25 to 0.5 mg daily; over 200 lbs, 0.5 mg daily. Some experienced users escalate to 1 to 1.5 mg daily during loading at the cost of markedly increased adverse effects.

Maintenance: 0.25 to 0.5 mg, 2 to 3 times weekly, indefinitely while maintenance is desired; some users dose only ahead of planned UV exposure.

Studied doses: 0.01 to 0.03 mg/kg subcutaneously daily, approximately 0.7 to 2.1 mg per dose at 70 kg; the erectile dysfunction study used 0.025 mg/kg. No published dose-finding work supports the loading and maintenance pattern, which reflects practice rather than trial data. The serious case-report toxicities occurred at excessive doses, including rhabdomyolysis at 6 times the standard dose.

The previous protocol on this site used 2.5 mL diluent (4 mg/mL, 40 mcg/unit) with a four-week titration — 250, 500, 750, then 1,000 mcg daily through week 8 — and 500 to 1,000 mcg 1 to 2 times weekly for weeks 9 to 16, in 8 to 16 week cycles with an 8 to 16 week washout. At that concentration 1,000 mcg is 25 units; the current protocol tables use the 2 mL standard and the lower practical doses.

Do not combine with PT-141: redundant MC4R agonism with increased nausea and blood pressure risk. Appetite suppression compounds with GLP-1 agonists, so watch for under-eating.

MT-2 has Phase 1 data only; development was abandoned before Phase 3 on safety grounds and it was never submitted for FDA approval.

Melanogenesis. A pilot Phase 1 study (Dorr et al., 1996) using subcutaneous MT-2 at 0.01 to 0.03 mg/kg produced significant darkening of constitutive skin colour over a 10-day period without UV exposure, across all skin types. Darkening was visible within 3 to 5 days with full effect at 2 to 3 weeks. Dorr et al. (2005) further characterised melanocortin agonist effects on human melanin production.

Erectile function. In a double-blind, placebo-controlled crossover study of 20 men with psychogenic erectile dysfunction (Wessells et al., 1998), subcutaneous MT-2 at 0.025 mg/kg produced clinical erections in 17 of 20 subjects. Mean tip rigidity exceeded 80% and mean duration exceeded 40 minutes. Sexual desire increased in 68% of recipients versus 19% on placebo. The mechanism is central MC4R agonism increasing dopamine release in the medial preoptic area, distinct from PDE5 inhibition.

Real-world data. A 2024 review in the British Journal of Dermatology examined user experiences and confirmed nausea, facial flushing, naevus darkening, and sexual effects consistent with trial data. Evans-Brown et al. (2009) documented general-population use.

Melanoma. A 2013 review found no conclusive evidence of causation. A 2021 review reported increased melanoma incidence among users but attributed it to UV-seeking behaviour. A 2020 preclinical report found MT-2 suppressed melanoma progression. Case reports exist (Hjuler and Lorentzen, 2014) without established causation. Brennan et al. (2025) review the risks and benefits of chronic MC1R activation. The practical hazard is masking of malignant change in darkened naevi.

Serious adverse events. Renal infarction likely attributable to MT-2 (Peters and Hadimeri, 2020) and systemic toxicity with rhabdomyolysis after injection at 6 times the standard dose (Nelson et al., 2012). No published dose-finding studies exist for the loading and maintenance protocols used in practice.