Overview
Melanotan II is a synthetic cyclic peptide analog of alpha-melanocyte-stimulating hormone (α-MSH), a naturally occurring hormone involved in pigmentation and other physiological processes in the body. It belongs to the melanocortin peptide family and was originally developed through research aimed at understanding how melanocortin receptors function and respond to chemical signaling. With a molecular weight of approximately 1024.2 Da, it has a cyclic structure that distinguishes it from its linear natural counterpart and influences how it interacts with melanocortin receptor subtypes. Melanotan II is an unlicensed compound that is not approved for human use, and it is studied strictly in research settings to explore the role of melanocortin receptors in various biological processes. Published research involving this peptide has examined topics ranging from its effects on stress-related pathways in animal models to case observations documenting physiological changes associated with its unsanctioned use outside of controlled research environments.
Research & Bioactivity
Melanotan II is a synthetic analog of alpha-melanocyte-stimulating hormone (α-MSH) that researchers have studied primarily in relation to its activity at melanocortin receptors, a family of G protein-coupled receptors expressed both centrally and peripherally. Studies have investigated its role as an agonist at multiple melanocortin receptor subtypes — particularly MC1R, MC3R, MC4R, and MC5R — which are associated with physiological processes including pigmentation, energy homeostasis, and steroidogenesis. In animal models, research has examined Melanotan II in the context of stress response and mood-related behavior, including studies using chronic unpredictable stress paradigms in rats to explore its interactions with the hypothalamic-pituitary-adrenal (HPA) axis. Researchers have also used Melanotan II as a tool compound in pharmacological studies aimed at characterizing melanocortin receptor binding and signaling properties. Additionally, case reports in the published literature have documented observations related to pigmentation changes in oral mucosal tissues following self-administration, contributing to a broader body of safety-relevant research. The melanocortin receptor system that Melanotan II engages continues to be an active area of investigation due to its wide-ranging roles in mammalian physiology.
Published Research
Changes in Oral Mucosa Associated with Melanotan II Injections: A Case Report.
Bonchev A — 2026
This case report presents a three-month follow-up of a patient who self-administered Melanotan II injections over a period of 64 days with the goal of achieving a deeper tanning effect. Melanotan II is an unlicensed synthetic peptide analog belonging to the melanocortin hormone family. It acts primarily by activating melanocortin 1 receptors on melanocytes, stimulating eumelanin production and resulting in skin pigmentation independent of sun exposure. Despite its popularity, particularly through promotion on social media, Melanotan II remains unregulated, and its use is associated with a range of potential adverse effects. During the initial intraoral examination, brown pigmentation was observed on the attached gingiva in both the maxillary and mandibular arches. The lesions were almost symmetrically distributed, with a more intense coloration in the anterior region of the lower jaw. Additional pigmented areas with irregular shapes and poorly defined borders were noted on the left and right buccal mucosa. At the one-month follow-up after discontinuation of the injections, the buccal mucosal pigmentation had nearly disappeared. However, at the three-month follow-up, gingival pigmentation persisted, though with visibly reduced intensity. To date, there is a lack of published data specifically addressing the timeline for resolution of oral pigmentation associated with Melanotan II use, making this case a valuable contribution to the limited existing literature on the subject.
Melanotan II nasal spray: a possible risk factor for oral mucosal malignant melanoma?
Yassin Alsabbagh A, Bhujel N, Singh RP — 2025
The case of a 22-year-old female who developed a mass in the anterior maxilla after using Melanotan II, a nasal spray containing a synthetic analogue of melanocyte-stimulating hormone, is reported. The patient had used the nasal spray for tanning purposes. Melanotan II is unlicensed, and its sale is illegal in the United Kingdom and in many other countries around the world. Histological analysis confirmed the diagnosis of a mucosal malignant melanoma. The patient subsequently underwent surgical resection followed by ongoing immunotherapy. The clinical presentation and initial management of the patient, along with a literature review on the potential association between Melanotan use and the development of malignant melanoma, is provided. This report highlights the need for awareness of the possible serious side effects associated with Melanotan II nasal spray.
Antidepressant-like and antistress effects of the ACTH(4-10) synthetic analogs Semax and Melanotan II on male rats in a model of chronic unpredictable stress.
Inozemtseva LS, Yatsenko KA, Glazova NY, Kamensky AA, Myasoedov NF, et al. — 2024
Current antidepressant therapy shows substantial limitations, and there is an urgent need for the development of new treatment strategies for depression. Stressful events and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis play an important role in the pathogenesis of depression. HPA axis activity is self-regulated by negative feedback at several levels including adrenocorticotropic hormone (ACTH)-mediated feedback. Here, we investigated whether noncorticotropic synthetic analogs of the ACTH(4-10) fragment, ACTH(4-7)-Pro-Gly-Pro (Semax) and Ac-Nle4-cyclo[Asp5-His6-D-Phe7-Arg8-Trp9-Lys10]ACTH(4-10)-NH2 (Melanotan II (MTII), a potent agonist of melanocortin receptors), have potential antidepressant activity in a chronic unpredictable stress (CUS) rat model of depression. Stressed and control male adult Sprague-Dawley rats received daily intraperitoneal injections of saline or a low dose (60 nmol/kg of body weight (BW)) of Semax or MTII. Rats were monitored for BW and hedonic status, as measured in the sucrose preference test. We found that chronic treatment with Semax and MTII reversed or substantially attenuated CUS-induced anhedonia, BW gain suppression, adrenal hypertrophy and a decrease in the hippocampal levels of BDNF. In the forced swim test, no effects of the CUS procedure or peptides on the duration of rat immobility were detected. Our findings show that in the CUS paradigm, systemically administered ACTH(4-10) analogs Semax and MTII exert antidepressant-like effects on anhedonia and hippocampal BDNF levels, and attenuate markers of chronic stress load, at least in male rats. The results support the argument that ACTH(4-10) analogs and other noncorticotropic melanocortins may have promising therapeutic potential for the treatment and prevention of depression and other stress-related pathologies.
Barbie drug identification: Not a child's play.
Deville M, Charlier C — 2024
Various samples-including two vials with a pharmaceutical appearance-were submitted to the laboratory for identification. The aim of this work was to describe the unique characteristics observed during the analysis of the powder contained in the vial. Samples were submitted to HPLC-DAD, UHPLC-TOF-MS, and/or UPLC-MS-MS analysis. The majority of the samples were easily identified as standard drugs of abuse. The main difficulty lay in identifying the powder in the vials. No match was found in the library through HPLC-DAD analysis. Fortunately, the vials were labeled as "Melanotan II", although the UV spectrum was not available. Mass spectrometric analysis of melanotan II was challenging, as it is a small peptide with a molecular weight of 1024 Da, which is significantly heavier than classical drugs that the laboratory usually handles. As a result, mass spectrometer's parameters can be limited to detect masses up to 1000 Da. Additionally, melanotan II is multi-charged which is also unusual for compounds typically targeted in our daily work. Finally, the reference standard allowed us to confirm the identification with both instruments, and determine the purity of 30%. Melanotan II is not approved on the market due to safety concerns. It is used illegally mainly for tanning, explaining its nickname "Barbie drug". To conclude, analysis of melanotan II was challenging as it is heavy and doubly charged. Moreover, its UV spectrum was initially not available in the literature. The difficulties faced by forensic scientists in detecting this drug may explain its popularity on the illicit market.
Recommended Tool Compounds for the Melanocortin Receptor (MCR) G Protein-Coupled Receptors (GPCRs).
Weirath NA, Haskell-Luevano C — 2024
The melanocortin receptors are a centrally and peripherally expressed family of Class A GPCRs with physiological roles, including pigmentation, steroidogenesis, energy homeostasis, and others yet to be fully characterized. There are five melanocortin receptor subtypes that, apart from the melanocortin-2 receptor (MC2R), are stimulated by a shared set of endogenous agonists. Until 2020, X-ray crystallographic and cryo-electron microscopic (cryo-EM) structures of these receptors were unavailable, and the investigation of their mechanisms of action and putative ligand-receptor interactions was driven by site-directed mutagenesis studies of the receptors and targeted structure-activity relationship (SAR) studies of the endogenous and derivative synthetic ligands. Synthetic derivatives of the endogenous agonist ligand α-MSH have evolved into a suite of powerful ligands such as NDP-MSH (melanotan I), melanotan II (MTII), and SHU9119. This suite of tool compounds now enables the study of the melanocortin receptors and serves as scaffolds for FDA-approved drugs, means of validating stably expressing melanocortin receptor cell lines, core ligands in assessing cryo-EM structures of active and inactive receptor complexes, and essential references for high-throughput discovery and mechanism of action studies. Herein, we review the history and significance of a finite set of these essential tool compounds and discuss how they are being utilized to further the field's understanding of melanocortin receptor physiology and greater druggability.