Melanotan II
A non-selective melanocortin agonist studied in small early-phase trials for tanning and erectile function. Never approved. Multiple published case reports of adverse events from unregulated use.
Sexual & Hormonal
Setmelanotide
An approved treatment for rare genetic obesity caused by defects in the leptin-melanocortin pathway. Highly effective in that narrow population and not a general weight-loss drug.
Overview
There is a chain of signals running from fat tissue to the brain that tells you how much energy you have stored. Leptin from fat starts it; the MC4 receptor in the hypothalamus is near the end of it. In a small number of people that chain is broken by a specific gene fault, and they experience relentless hunger from early childhood. Setmelanotide activates MC4R directly, restoring the "you have eaten enough" signal downstream of the break.
A cyclic octapeptide MC4R agonist with roughly 20-fold selectivity over MC1R and greater selectivity over MC3R and MC5R. Restores signalling downstream of loss-of-function variants in POMC, PCSK1 and LEPR, and in Bardet-Biedl syndrome. MC4R activation in the paraventricular nucleus reduces food intake and increases energy expenditure. Approval was based on open-label single-arm trials with a placebo-controlled withdrawal period, given the rarity of the genotypes involved.
Research areas
Genetic obesityMelanocortin signallingHyperphagia
Dosing reported in the literature
Every protocol below is reproduced from a published study or approved labelling, with its source named. These are records of what was studied — not recommendations, and not a suggestion that any of them is appropriate for any person.
| Protocol as reported | Source |
|---|---|
| 1 mg once daily for two weeks, increased to 2 mg, with a maximum of 3 mg in adults | Approved product labelling |
| Open-label treatment with a placebo-controlled withdrawal period in POMC and LEPR deficiency | Clément et al., The Lancet Diabetes & Endocrinology 2020 |
Trial status
Phase 3 completed in the approved genotypes. Trials in hypothalamic obesity have also been conducted.
Reported safety signals
- Skin hyperpigmentation and darkening of naevi are expected, from residual MC1R activity. Skin examination before and during treatment is part of the labelling.
- Spontaneous penile erections in males and sexual adverse reactions in females are labelled effects of melanocortin agonism.
- Depression and suicidal ideation have been reported; monitoring is required.
- It has no established role in common polygenic obesity and should not be treated as an alternative to GLP-1 therapy.
Common questions
Would setmelanotide work for ordinary obesity?
It was not designed for it and is not approved for it. The MC4 pathway is intact in most people with obesity, so activating it pharmacologically produces far less benefit than in someone whose pathway is genetically broken.
Primary sources
- 01
Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials
- 02
Setmelanotide for Bardet-Biedl syndrome and Alström syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
- 03
Imcivree (setmelanotide) prescribing information
Medical disclaimer
This page is for informational and research purposes only. Nothing here constitutes medical advice. The compounds discussed are research chemicals. Consult a qualified clinician before starting any protocol.
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