Limited · human
This case report describes a single patient who self-administered Melanotan II (an unlicensed synthetic melanocortin peptide analog) over 64 days to achieve a tanning effect, with a three-month follow-up period after discontinuation. At the initial intraoral examination, clinicians observed brown pigmentation on the attached gingiva of both the maxillary and mandibular arches, distributed in a near-symmetrical pattern with greater intensity in the anterior mandibular region. Additional irregularly shaped, poorly defined pigmented lesions were noted on both left and right buccal mucosa. Following cessation of injections, the buccal mucosal pigmentation had nearly resolved by the one-month follow-up. However, gingival pigmentation persisted at three months, albeit with noticeably reduced intensity. The authors note that Melanotan II acts primarily via melanocortin 1 receptor activation on melanocytes, stimulating eumelanin production independently of UV exposure. The report highlights a gap in the published literature regarding the timeline for resolution of oral pigmentation associated with Melanotan II use, positioning this case as a contribution to a sparse evidence base. Key limitations include the single-patient design, absence of histological confirmation, and inability to control for confounding factors.
Life (Basel, Switzerland) · Feb 2026DOI ↗ Review
This systematic review, conducted following PRISMA guidelines, synthesizes findings from 68 peer-reviewed studies examining the mechanisms, clinical applications, formulations, and adverse effects of four major sunless tanning agents: dihydroxyacetone (DHA), melanotan (I and II), forskolin, and carotenoids. The authors found that DHA produces skin pigmentation through the Maillard reaction (a non-enzymatic browning of amino acids in the stratum corneum) and has shown additional dermatologic utility in vitiligo and erythropoietic protoporphyria, as well as potential antifungal properties—though concerns about cytotoxicity, genotoxicity, and systemic absorption were noted. Melanotan I and II, which act on melanocortin receptors, were associated with serious adverse effects in unregulated use, including rhabdomyolysis, renal infarction, and priapism. Forskolin was reported to stimulate melanin production independently of melanocortin receptors, with efficacy demonstrated primarily in animal models. Orally ingested carotenoids were found to accumulate in skin and subcutaneous fat, producing a yellow-orange hue. The review acknowledges significant limitations: lack of standardized reporting, heterogeneous outcomes across studies, and insufficient long-term human safety data, particularly for forskolin and carotenoids. The authors conclude that further rigorous clinical research and updated regulatory guidance are needed.
The Journal of clinical and aesthetic dermatology · Feb 2026Source ↗ In vitro
This study investigated the chemical and physical stability of afamelanotide (melanotan-1), a synthetic 13-amino acid peptidomimetic of α-melanocyte stimulating hormone (α-MSH) approved as an orphan drug for erythropoietic protoporphyria. Researchers subjected the compound to a range of stress conditions — acidic, basic, neutral, oxidative, UV light exposure, and elevated temperature (60°C) — following International Council for Harmonisation (ICH) guidelines Q1A(R2) and Q5C. Using gradient reversed-phase HPLC coupled with ultra-high-performance liquid chromatography–high resolution tandem mass spectrometry (UHPLC-HRMS/MS), the team identified and structurally characterized 14 distinct degradation products. Collision-induced dissociation fragmentation patterns enabled detailed elucidation of each product's structure. Key degradation pathways identified included truncation, methylation, deacetylation, and oxidation. The analytical method was validated per ICH Q2(R1) guidelines. This work is purely analytical and pharmaceutical in nature — it does not involve human subjects, animals, or cell-based experiments. Its primary value lies in establishing a comprehensive stability profile of afamelanotide to inform rational drug formulation design. No clinical outcomes, efficacy, or safety data in biological systems were assessed.
Journal of pharmaceutical and biomedical analysis · Jan 2026DOI ↗ Limited · human
This case report describes a 65-year-old woman who developed pyoderma gangrenosum (PG) — a rare, rapidly progressing neutrophilic skin ulceration — at abdominal injection sites following use of the synthetic peptide melanotan. Four ulcerated wounds with erythematous borders were observed, clinically correlating with the injection sites. A diagnosis of PG was established based on wound appearance and progression, failure to respond to multiple antibiotic courses, and negative bacteriology (including negative Panton-Valentine leukocidin Staphylococcus aureus testing). The patient was treated with topical betamethasone, steroid occlusion tape, and oral prednisolone, with the prednisolone subsequently tapered and topical Dermovate initiated. The wounds healed over several months, leaving characteristic cribriform scarring. The authors acknowledge that while drug-induced PG has rarely been documented, this appears to be the first reported case of melanotan-induced PG in the literature. Key limitations include the inherent constraints of a single case report: no causal mechanism is established, there is no control or comparator, and generalizability is very limited. The report serves primarily to raise clinical awareness of a potentially serious and previously unreported adverse effect of melanotan use.
Limited · human
This prospective qualitative study surveyed 104 consecutive patients attending a pigmented lesion clinic at a tertiary referral dermatology centre in Ireland to examine the characteristics, attitudes, and behaviours of sunbed users. Using an anonymous self-reported questionnaire, researchers collected data on demographics, frequency of sunbed use, motivations, and use of unregulated tan-enhancing agents such as Melanotan I and II. The study found that sunbed users were predominantly younger women living in urban areas, consistent with prior literature. Regulatory non-compliance was widespread: over half of sunbed premises reportedly did not provide protective goggles, and nearly half offered no health risk information to customers. Key motivations for use included improving appearance and self-confidence. Notably, greater awareness of health risks did not correlate with reduced sunbed use, suggesting a potentially compulsive or addictive behavioural pattern. Users of tan-enhancing agents also used sunbeds more frequently than non-users. The authors suggest psychological interventions such as cognitive behavioural therapy may be beneficial and call for stricter regulatory enforcement. Limitations include the single-centre design, small sample size, self-reported data susceptible to bias, and a clinic-based population that may not represent the general public.
Skin health and disease · May 2025DOI ↗ Limited · human
This paper reports the case of a 22-year-old female who developed a mucosal malignant melanoma of the anterior maxilla following use of Melanotan II, an unlicensed synthetic analogue of melanocyte-stimulating hormone (α-MSH) administered as a nasal spray for cosmetic tanning purposes. Histological analysis confirmed the malignant melanoma diagnosis, and the patient was subsequently treated with surgical resection followed by immunotherapy. The authors conducted a supporting literature review examining the potential association between Melanotan II use and malignant melanoma development. They note that Melanotan II is illegal to sell in the United Kingdom and many other countries due to its unlicensed status and safety concerns. The paper highlights awareness of serious potential adverse effects linked to Melanotan II use. As a single case report, it cannot establish causation between Melanotan II use and oral mucosal melanoma; the temporal association is notable but confounding factors and the rarity of the event limit broader conclusions. The authors call for greater public and clinical awareness of risks associated with unregulated tanning peptides.
International journal of oral and maxillofacial surgery · Apr 2025DOI ↗ Animal only
This animal study investigated whether two synthetic analogs of the ACTH(4-10) peptide fragment — Semax (ACTH(4-7)-Pro-Gly-Pro) and Melanotan II (MTII), a melanocortin receptor agonist — possess antidepressant-like and antistress properties in a chronic unpredictable stress (CUS) rat model of depression. Male adult Sprague-Dawley rats were subjected to CUS and received daily intraperitoneal injections of either saline or a low dose of Semax or MTII. Outcomes assessed included body weight, hedonic status via the sucrose preference test, adrenal gland weight, hippocampal BDNF levels, and immobility in the forced swim test. The study found that both Semax and MTII reversed or substantially reduced CUS-induced anhedonia, suppressed body weight gain, adrenal hypertrophy, and decreased hippocampal BDNF levels. Neither the CUS procedure nor the peptide treatments produced significant effects on immobility in the forced swim test. The authors concluded that systemically administered ACTH(4-10) analogs may have therapeutic potential for depression and stress-related conditions. Key limitations include the exclusive use of male rats, an animal-only design with no human data, and restriction to a single dose level.
European journal of pharmacology · Oct 2024DOI ↗ Insufficient
This forensic laboratory study describes the analytical challenges encountered when identifying Melanotan II — a synthetic peptide informally nicknamed the "Barbie drug" — in suspected illicit drug samples submitted for analysis. Researchers used HPLC-DAD, UHPLC-TOF-MS, and UPLC-MS/MS to characterize a powder found in pharmaceutical-appearing vials labeled "Melanotan II." Standard library searches via HPLC-DAD yielded no match, partly because the UV spectrum for Melanotan II was not available in the reference library at the time. Mass spectrometric identification was further complicated by the peptide's relatively high molecular weight (~1024 Da), which exceeded the typical detection ceiling of instruments configured for classical small-molecule drugs of abuse, and by the compound's multi-charged ionization behavior. Using a reference standard, the team ultimately confirmed the identity of Melanotan II and estimated a purity of approximately 30%. The study highlights that Melanotan II is not approved for market use due to safety concerns and is sold illicitly primarily for skin tanning. The authors suggest that the significant analytical hurdles involved in detecting this peptide may partly explain its growing presence on the illicit market. This study is a descriptive forensic case report with no clinical outcome data or human subject testing.
Journal of forensic sciences · Sep 2024DOI ↗ Review
This review paper examines the history, development, and scientific utility of key synthetic tool compounds used to study the melanocortin receptor (MCR) family — a group of five Class A G protein-coupled receptors (GPCRs) involved in diverse physiological processes including pigmentation, steroidogenesis, and energy homeostasis. The authors trace how synthetic derivatives of the endogenous agonist α-MSH, including NDP-MSH (melanotan I), melanotan II (MTII), and SHU9119, have become essential pharmacological tools for the field. The review discusses how these compounds are used to validate cell lines stably expressing melanocortin receptors, serve as reference ligands in high-throughput screening, inform structure-activity relationship (SAR) studies, and act as core ligands in cryo-EM structural investigations of active and inactive receptor complexes. The paper also notes that these tool compounds have served as scaffolds for FDA-approved drugs. Limitations of the review include its descriptive, non-experimental nature and its focus on synthesizing existing literature rather than presenting new empirical data. It provides important context for researchers working on MCR pharmacology but does not itself generate clinical or mechanistic evidence.
ACS pharmacology & translational science · Aug 2024DOI ↗ Animal only
This mouse study investigated therapeutic strategies for hyperphagia, hyperglycemia, and obesity caused by a loss-of-function mutation in the Htr2c gene (Htr2cF327L/Y), which encodes the serotonin 2C receptor (5-HT2CR). Researchers tested three main approaches in male mice fed a high-fat diet. First, they used viral re-expression of functional 5-HT2CR specifically in hypothalamic POMC neurons, finding this was sufficient to reduce food intake and body weight, and restored neuronal responsiveness to lorcaserin (a selective 5-HT2CR agonist). Second, they administered melanotan II, an MC4R agonist, which effectively suppressed feeding and weight gain. Third, they promoted voluntary wheel-running exercise, which reduced high-fat diet consumption and improved glucose homeostasis. The study highlights the importance of the 5-HT2CR–melanocortin pathway in energy balance regulation and suggests MC4R agonists and physical activity may be relevant strategies for individuals carrying rare Htr2c variants. Key limitations include exclusive use of a single male mouse model, a specific engineered mutation, and the gap between rodent models and human metabolic disease.
Endocrinology · May 2024DOI ↗ Animal only
This animal study investigated whether AMP-activated protein kinase (AMPK) in the central nucleus of the amygdala (CeA) serves as an intracellular signaling mediator linking metabolic cues—ghrelin, fasting, and glucoprivation—to food intake regulation. Male Wistar rats were surgically implanted with cannulas in the CeA and received intra-CeA injections of various modulators, including glucose, 2-deoxy-D-glucose (2DG), ghrelin, and Melanotan II (MTII). The study measured AMPK phosphorylation at Thr172 (AMPKThr172) alongside food intake and body weight. Key findings attributed to the study include: fasting increased and refeeding reduced CeA AMPKThr172; intra-CeA glucose reduced food intake while 2DG (a glucoprivation inducer) increased food intake and blood glucose with modest AMPKThr172 elevation; intra-CeA ghrelin increased both food intake and AMPKThr172; and chronic intra-CeA MTII injection reduced body mass and food intake over seven days alongside a slight reduction in AMPKThr172. Limitations include use of a single rodent model, small and unspecified sample sizes per group, and the inability to establish direct causality between AMPK activation and feeding behavior. No human data were collected.
Molecular and cellular endocrinology · Apr 2024DOI ↗ In vitro
This study explores novel peptide stapling strategies inspired by natural product motifs found in fungal toxins (amatoxins, phallotoxins) and the alkaloid staurosporine. The researchers developed a chemical method using a 5-hydroxypyrroloindoline building block that can react with either a cysteine thiol (forming a tryptathionine staple) or a tryptophan indole (forming a 2,2'-bis-indole staple) to create constrained macrocyclic peptide structures. The authors applied these two stapling approaches to α-melanocyte-stimulating hormone (α-MSH), using the Melanotan-II scaffold as a model, with careful protecting group strategies to achieve chemoselectivity between the two staple types. Both classes of stapled peptides were evaluated for binding affinity at the melanocortin receptor, and the study reports that both series achieved nanomolar inhibition constants (Ki values), with at least one compound reaching sub-nanomolar Ki. Limitations include that all work is conducted in vitro (binding assays and synthetic chemistry), with no cell-based functional data, animal studies, or human data reported. The study is primarily a proof-of-concept for expanding the chemical toolbox of peptide stapling using underexplored natural product-derived cross-links.
Chemistry (Weinheim an der Bergstrasse, Germany) · Feb 2024DOI ↗ Animal only
This animal study investigated how the melanocortin receptor agonist Melanotan II (MTII) affects brain activity in prairie voles, with a focus on whether its effects depend on social context and the oxytocin system. Researchers administered MTII to male and female prairie voles either before social interactions or in non-social conditions, then used Fos expression (a marker of neuronal activation) to map brain activity. In non-social contexts, MTII activated only the hypothalamic paraventricular nucleus (PVN), the brain's primary site of oxytocin production. However, when MTII was given before social interactions, it selectively increased oxytocin-dependent activation in the nucleus accumbens — a region critical for social learning and reward. The authors propose this mechanism may explain how MTII accelerates partner preference formation (a model of social bonding) seen in earlier studies. The study frames these findings as supportive of a treatment model where endogenous oxytocin is pharmacologically stimulated during behavioral therapy, rather than via chronic exogenous oxytocin supplementation. Limitations include the use of a single animal species, an animal-only design, and the inherent challenges of translating prairie vole social bonding models to human psychiatric conditions such as autism.
Neuropharmacology · Jan 2024DOI ↗ Animal only
This study investigated whether a short-term high-fat (HF) diet could impair neurobehavioral outcomes in zebrafish (Danio rerio) and whether treatment with Melanotan-II (MT-II), a melanotropin receptor agonist, could reverse those effects. Zebrafish were fed an HF diet for approximately three weeks — roughly 1% of their lifespan — and then assessed for recognition memory, anxiety levels, and exploratory behavior. The researchers found that zebrafish on the HF diet showed measurable impairments in recognition memory, elevated anxiety, and reduced exploratory behavior compared to control-diet animals. Notably, HF-diet zebrafish that also received MT-II treatment demonstrated memory, anxiety, and exploratory behavior comparable to the control group, suggesting a reversal of HF diet-induced changes. The authors describe this as the first study demonstrating MT-II's ability to reverse short-term HF diet-induced neurobehavioral abnormalities. Key limitations include the use of a non-mammalian animal model (zebrafish), which limits direct translation to human neurology, and the absence of mechanistic data clarifying how MT-II acts on the relevant brain pathways. No human or clinical data are presented.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · Jul 2023DOI ↗ Animal only
This animal study investigated how the central nervous system melanocortin (CNS-MC) system influences feed intake, metabolic hormones, and insulin sensitivity in sheep. Ewes were surgically fitted with intracerebroventricular (ICV) cannulas and infused with artificial cerebrospinal fluid (aCSF), the α-MSH analog melanotan-I (MTI), or agouti-related peptide (AGRP) directly into the third ventricle. The study found that ICV MTI infusion significantly reduced voluntary feed intake, while AGRP infusion modestly increased it. MTI also elevated plasma triiodothyronine and thyroxine independently of changes in food intake, suggesting a direct central effect on thyroid hormone regulation. Notably, MTI did not affect plasma glucose, insulin, or cortisol under normal feeding conditions. However, during hyperinsulinemic-euglycemic clamp experiments in energy-restricted ewes, MTI impaired insulin's ability to suppress endogenous glucose production, indicating reduced hepatic insulin sensitivity. MTI also tended to lower plasma leptin in a feeding-level-dependent manner, with no effect on adiponectin. AGRP infusion did not significantly alter any measured plasma metabolic variables. The authors concluded that the CNS-MC system plays a role in regulating metabolic efficiency and peripheral insulin action in ruminants. Limitations include small sample sizes, a single non-human species, and the invasive ICV delivery route.
Journal of animal science · Jan 2023DOI ↗ Animal only
This preclinical study investigated the neurological mechanisms by which obesity medications suppress food intake, focusing on proglucagon (PPG)-expressing neurons in the nucleus of the solitary tract (PPG-NTS). Using single-nucleus RNA sequencing and histochemistry, researchers characterized gene expression profiles of PPG-NTS neurons in rodents, finding that serotonin 2C receptors (5-HT2CR) — the target of lorcaserin — were widely expressed in these neurons, while GLP-1 receptors and melanocortin-4 receptors were not. Lorcaserin was found to significantly activate PPG-NTS neurons. When PPG-NTS neurons were virally ablated, lorcaserin lost its ability to suppress food intake, whereas the MC4R agonist melanotan-II retained its effect, confirming the functional role of 5-HT2CR expression in these neurons. Additionally, combining lorcaserin with GLP-1R agonists liraglutide or exendin-4 produced greater food intake reduction than either drug alone. The study concludes that PPG-NTS neurons are a necessary mechanistic link for lorcaserin's appetite-suppressing effects and suggests that combining 5-HT2CR and GLP-1R agonists may enhance therapeutic outcomes. Key limitations include that all experiments were conducted in animals, and translational relevance to humans remains to be established.
Molecular metabolism · Dec 2022DOI ↗ Animal only
This study investigated the role of melanocortin signaling in the nucleus accumbens (NAcc) on food intake and motivation to eat in mice. Male C57BL/6J mice received bilateral microinjections of melanotan-II (MT-II), a melanocortin receptor 3/4 agonist, directly into the NAcc, and researchers measured effects on food consumption and operant responding for food. The study found that MT-II microinjected into the NAcc significantly reduced both the amount of food consumed (measured in home cage settings) and appetitive responding (measured by operant self-administration tasks requiring effort to obtain food). Importantly, these effects appeared to occur without inducing conditioned taste avoidance—suggesting the reductions were not due to nausea or aversion—and without measurable changes in metabolic rate. The authors concluded that melanocortin signaling in the NAcc may selectively regulate appetite and satiety independent of metabolism or aversive side effects. Key limitations include that this was an animal-only study conducted exclusively in male mice of a single inbred strain, limiting generalizability to other sexes, species, or humans. The microinjection approach is also not clinically translatable in its current form.
Neuropeptides · Sep 2022DOI ↗ Limited · human
This paper presents a case report of a 27-year-old male with no relevant medical history who attended an emergency department two hours after self-administering Melanotan II (also marketed as a "Barbie drug") subcutaneously. Melanotan II is a synthetic analogue of alpha-melanocyte-stimulating hormone (α-MSH) that stimulates eumelanin production to induce skin pigmentation without sun exposure. It is readily available for purchase online and in gyms, despite not being approved for clinical use. Following self-administration, the patient developed sympathomimetic symptoms requiring treatment with lorazepam, supplemental potassium, and intravenous fluid resuscitation. The authors also note that prior research has associated Melanotan II use with the development of new pigmented and dysplastic naevi, raising additional dermatological safety concerns. The paper concludes that despite its easy accessibility, Melanotan II carries real and potentially serious risks. Key limitations include its single-patient case design, which precludes generalization about incidence or severity of adverse effects across the broader population of users.
Nederlands tijdschrift voor geneeskunde · May 2022Source ↗ Limited · human
This case report by Mallory, Lopategui, and Cordon (Sexual Medicine, 2021) describes a single patient who developed acute ischemic priapism following subcutaneous self-administration of Melanotan II, a synthetic melanocortin analog that is illicitly sold online and used in unlicensed clinics as a sunless tanning agent and sexual stimulant. The authors note that Melanotan II has also been investigated as a potential treatment for erectile dysfunction. In this case, standard first-line management — including cavernosal aspiration, irrigation, and intracavernous phenylephrine injection — failed to achieve detumescence. The patient ultimately required surgical intervention via penoscrotal decompression, which the authors describe as a promising technique for refractory ischemic priapism. The report notes that priapism associated with Melanotan II had only been documented twice previously in the literature. The authors conclude that priapism should be recognized as a possible adverse effect of Melanotan II and that future therapeutic investigations and clinical guidelines should account for this risk. Key limitations include the inherent constraints of a single case report: findings cannot be generalized, causality cannot be definitively established, and no controlled comparison is possible.
Sexual medicine · Jan 2021DOI ↗ Limited · human
This paper presents a case report combined with a literature review examining a possible association between Melanotan II (MTII) — a non-selective melanocortin-receptor agonist commonly used illicitly for skin tanning, penile erection, and sexual stimulation — and renal infarction. The authors describe a patient who experienced renal infarction most likely attributed to MTII use. Renal infarction, an uncommon and potentially life-threatening condition caused by acute disruption of renal blood flow, is noted to be frequently misdiagnosed or diagnosed late. The paper reviews prior literature documenting MTII-associated rhabdomyolysis and renal failure, and proposes two potential mechanisms of renal injury: a thrombotic pharmacological effect and possible direct toxic effects on renal parenchyma. Limitations are significant: evidence rests on a single case and a narrative review of prior case-level reports, meaning causality cannot be formally established. No controlled data are available, and the condition's rarity makes systematic study difficult. The authors conclude that MTII's thrombotic and potentially nephrotoxic properties warrant clinical awareness, particularly given the compound's widespread unregulated use.
CEN case reports · Jan 2020DOI ↗