Inside the body with Melanotan II

In the human studies MT-II was given subcutaneously, and effects (nausea, yawning and stretching, intermittent spontaneous erections over 1-5 hours, later skin darkening) followed dosing, indicating systemic exposure. The lactam ring, D-Phe7 and Nle4 came from a design programme aimed at high potency; in frog and lizard skin bioassays the 23-membered-ring analogues showed prolonged residual activity. No published human pharmacokinetic study (absorption, half-life, clearance) was found.[src][src]

MT-II activates MC1R on melanocytes, increasing eumelanin synthesis. In the pilot phase 1 study, two of three men had increased facial, upper-body and buttock pigmentation, measured by reflectance, after a short course of injections. The pigment change is not a substitute for sun protection: the TGA states it does not protect against UV in the way a suitable sunscreen does.[src][src][src]

Intracerebroventricular MT-II, a potent agonist at neural MC3R and MC4R, inhibited feeding in four mouse hyperphagia models (fasted, ob/ob, agouti A(Y), and neuropeptide-Y-injected mice); co-administration of the antagonist SHU9119 blocked the effect. This is animal-only evidence from central injection. It does not establish an effect on body weight in humans, and MT-II is not an approved or trialled weight-loss drug.[src]

In a double-blind, placebo-controlled crossover study of 10 men with psychogenic erectile dysfunction, 8 of 10 developed clinically apparent erections; mean duration of tip rigidity above 80% was 38.0 minutes with MT-II versus 3.0 with placebo (p=0.0045). In men with organic risk factors, erections were reported after 12 of 19 injections versus 1 of 21 placebo doses, and desire scores were higher after MT-II. The authors describe MT-II as a centrally acting melanocortin agonist; these studies did not isolate which receptor subtype drives the effect in humans.[src][src][src]

MT-II is non-selective across melanocortin receptors. Nausea (severe after 4 of 19 injections in one crossover study), stretching-and-yawning, decreased appetite, fatigue and somnolence (WHO grade II in one volunteer at the highest dose) were reported in the clinical studies; nausea, yawning, stretching and reduced appetite occurred more often than with placebo.[src][src][src][src]

Case reports describe multiple new atypical naevi within a week of two melanotan injections, a melanoma in a user, and a mucosal melanoma after nasal-spray use. Whether chronic MC1R stimulation of melanocytes causes malignant change has not been established in controlled studies, and single case reports cannot establish causation or rule out other factors such as sun exposure. FDA's compounding safety page lists melanoma among serious adverse events in published case reports.[src][src][src][src]

Case reports include a sympathomimetic toxidrome with rhabdomyolysis and kidney injury after injection of a product confirmed by mass spectrometry to be MT-II, renal infarction, posterior reversible encephalopathy syndrome, and priapism requiring aspiration and irrigation of the penis. Mechanisms are not established; for the renal infarction, the authors suggested a thrombotic effect or direct kidney toxicity. Incidence cannot be estimated from case reports.[src][src][src][src]