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Melanotan II

Melanotan II is a synthetic cyclic peptide analogue of the endogenous hormone alpha-melanocyte-stimulating hormone (α-MSH), with the chemical structure Ac-Nle⁴-Asp⁵-His⁶-D-Phe⁷-Arg⁸-Trp⁹-Lys¹⁰-α-MSH⁴⁻¹⁰-NH₂, designed to act as a non-selective agonist at melanocortin receptors to stimulate melanogenesis and induce skin pigmentation.^[1]^[2] Originally developed in the 1980s at the University of Arizona as a potential preventive agent against skin cancer by promoting tanning without UV exposure, it has since been investigated for its erectogenic properties in treating psychogenic erectile dysfunction.^[2]^[3] Clinical studies have demonstrated that subcutaneous doses of Melanotan II, such as 0.025 mg/kg, can produce tanning effects in humans after just five alternate-day administrations, alongside spontaneous penile erections lasting up to five hours.^[1] In a double-blind, placebo-controlled crossover trial involving men with psychogenic erectile dysfunction, eight out of ten participants achieved erections with greater than 80% rigidity for an average of 38 minutes following administration, significantly outperforming placebo.^[3] Despite these findings, Melanotan II is not approved by the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for any medical use and is classified as an unapproved new drug, often distributed illicitly online as a research chemical or supplement.^[4]^[2]^[5] Common side effects include nausea, facial flushing, fatigue, somnolence, decreased appetite, yawning, and spontaneous erections, which are generally manageable at low doses but can be more pronounced at higher levels.^[1]^[3] More serious risks encompass hyperpigmentation of existing moles, development of new melanocytic lesions, and potential associations with melanoma, renal infarction, and systemic toxicity, though long-term safety data remain limited due to unregulated use.^[6]^[7]^[2] Health authorities worldwide, including the FDA and Australia's Therapeutic Goods Administration (TGA), warn against its use owing to contamination risks, lack of quality control, and unverified efficacy beyond preliminary trials.^[4]^[8]

Chemical Properties

Structure

Melanotan II is a synthetic cyclic peptide analog of α-melanocyte-stimulating hormone (α-MSH), characterized by the molecular formula C50H69N15O9 and a molecular weight of approximately 1,024.18 g/mol. This heptapeptide features an N-terminal acetylation and a C-terminal amidation, contributing to its compact structure and resistance to enzymatic degradation.^[9] The primary sequence of Melanotan II is represented as Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH2, where the cyclic portion encompasses a heptapeptide constrained by a lactam bridge between the side-chain carboxyl group of the aspartic acid (Asp) residue and the side-chain amino group of the lysine (Lys) residue within the cycle. This cyclization, specifically an i-to-i+5 lactam linkage, constrains the peptide backbone into a more rigid conformation, mimicking the bioactive core of α-MSH while enhancing its potency and duration of action.^[1] Relative to the native α-MSH sequence (Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2), Melanotan II incorporates targeted modifications to improve stability and receptor affinity, including the substitution of norleucine (Nle) for methionine at the fourth position to prevent oxidative degradation, replacement of the L-phenylalanine at the seventh position with its D-enantiomer (D-Phe) to alter stereochemistry and reduce proteolysis, and retention of N-terminal acetylation for proteolytic protection. These alterations focus on the pharmacologically active "message" sequence (residues 4–10 of α-MSH), resulting in a truncated, cyclized structure that maintains essential binding elements while eliminating less critical flanking residues.^[1]

Synthesis

Melanotan II is produced through a multi-step solid-phase peptide synthesis (SPPS) utilizing the Fmoc (9-fluorenylmethoxycarbonyl) protection strategy, starting from resin-bound C-terminal amino acids such as on Rink amide resin. The linear heptapeptide sequence, Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-NH₂, is assembled via sequential Fmoc deprotection with piperidine in DMF and coupling of protected amino acids using reagents like HBTU/HOBt or HATU with DIPEA in DMF, typically requiring approximately 12 cycles of deprotection and coupling to incorporate the full sequence, including the orthogonally protected side chains of Asp (e.g., OAllyl) and Lys (e.g., Alloc) for later cyclization.^[10] The defining reaction is the on-resin lactamization, achieved by selective deprotection of the Asp and Lys side chains (using Pd-catalyzed removal for Alloc/OAllyl groups) followed by intramolecular cyclization between the γ-carboxyl of aspartic acid and the ε-amino of lysine, mediated by coupling agents such as HBTU/HOBt or PyBOP in the presence of a base, often under microwave assistance to enhance efficiency and yield >85% for the cyclization step. This side-chain to side-chain bridge stabilizes the α-helical conformation essential for bioactivity. After cyclization, the N-terminal norleucine is acetylated if not pre-incorporated, and the peptide is cleaved from the resin using TFA-based cocktails with scavengers to prevent side reactions.^[10] Purification involves reverse-phase HPLC on C18 columns with acetonitrile-water gradients containing TFA, routinely achieving >90% purity without prior chromatography in optimized protocols, though crude yields prior to purification are typically low (e.g., overall process yields around 2.6% in benchmark syntheses, with solid-phase variants often exceeding 25% depending on scale). The final attachment of the N-acetylnorleucine moiety, if performed post-cyclization, uses standard acylation conditions to cap the N-terminus.^[11]^[10] Synthesis challenges center on maintaining stereochemical integrity, particularly avoiding racemization during D-phenylalanine incorporation, which is mitigated by conducting couplings at low temperatures (0-5°C) and using additives like HOBt to suppress epimerization; additionally, side reactions such as aspartimide formation from the Asp residue are minimized through careful Fmoc handling and orthogonal protections.^[10]

Pharmacology

Mechanism of Action

Melanotan II acts as a non-selective agonist at melanocortin receptors (MCRs), a family of G-protein-coupled receptors that mediate diverse physiological responses. It exhibits high binding affinity for the MC1R, MC3R, MC4R, and MC5R subtypes, with reported Ki values of 0.27 nM at human MC1R, 24 nM at MC3R, 2.66 nM at MC4R, and 23.1 nM at MC5R.^[12] These affinities enable Melanotan II to activate multiple MCRs, contributing to its broad effects on pigmentation, appetite regulation, sexual function, and sebum production.^[12] Upon binding, Melanotan II stimulates the Gs-coupled signaling pathway across these receptors, leading to activation of adenylyl cyclase and subsequent elevation of intracellular cyclic adenosine monophosphate (cAMP) levels. In melanocytes, MC1R agonism by Melanotan II enhances cAMP signaling, which upregulates the expression and activity of tyrosinase, the rate-limiting enzyme in melanogenesis, thereby promoting the synthesis of eumelanin over pheomelanin for increased skin pigmentation.^[13] This cAMP-dependent pathway also influences MC3R and MC4R in the central nervous system, where activation suppresses appetite and facilitates sexual arousal through hypothalamic signaling.^[12] Additionally, MC5R stimulation correlates with enhanced sebaceous gland activity and sebum secretion.^[12] The peptide's ability to cross the blood-brain barrier allows central penetration, amplifying MC4R-mediated effects in the hypothalamus that contribute to libido enhancement and erectile function, independent of peripheral vascular mechanisms.^[14]

Pharmacokinetics

Melanotan II is primarily administered via subcutaneous injection, which is the preferred route due to its favorable bioavailability compared to other methods. Oral administration demonstrates poor bioavailability of approximately 4.6% in preclinical rat models, rendering it ineffective for therapeutic purposes.^[15] Nasal spray formulations have been used in non-medical contexts but with variable efficacy.^[2] Following subcutaneous administration, Melanotan II is rapidly absorbed, with onset of effects observable within hours. However, detailed human pharmacokinetic parameters, including precise time to peak plasma concentrations and elimination half-life, are not well-established, with most information derived from preclinical studies. In rats, the elimination half-life is approximately 1.5 hours.^[16] The drug distributes widely, with partial penetration of the blood-brain barrier enabling central effects, as evidenced by detectable concentrations in brain tissue following systemic administration in animal models.^[17] The volume of distribution remains incompletely characterized. As a synthetic peptide analog of α-melanocyte-stimulating hormone, Melanotan II undergoes proteolytic degradation primarily by endogenous peptidases. Excretion occurs mainly via renal clearance, with no prominent metabolites identified in available pharmacokinetic assessments from limited preclinical and early clinical evaluations.^[18]

Potential Uses

Skin Tanning and Photoprotection

Melanotan II promotes skin tanning through stimulation of melanogenesis, increasing the synthesis of eumelanin—the dark, photoprotective form of melanin—primarily in melanocytes, with subsequent transfer to adjacent keratinocytes, thereby darkening the skin without requiring ultraviolet (UV) exposure.^[19]^[2] This results in a gradual, sunless tan that develops over days to weeks, depending on dosage and individual skin type.^[1] The elevated eumelanin levels confer photoprotective benefits by absorbing UV radiation, scattering photons, and scavenging reactive oxygen species, which collectively diminish UV penetration into deeper skin layers and reduce associated DNA damage.^[20] Early studies on related melanotropic peptides, such as afamelanotide (Melanotan I), have demonstrated photoprotective effects, including a reduction in sunburn cells by approximately 47% following UV exposure, suggesting analogous protective potential for Melanotan II-induced pigmentation.^[21] In a pilot phase I clinical trial, subcutaneous doses of Melanotan II ranging from 0.01 to 0.025 mg/kg administered every other day for 10 days (five doses total) produced measurable increases in skin pigmentation, as assessed by reflectance spectrophotometry and visual evaluation, in two of three healthy male volunteers one week post-treatment.^[1] Common non-clinical usage protocols, derived from user reports in medical case studies, involve initial daily subcutaneous injections of 0.25-1 mg until the desired tan level is reached, followed by maintenance doses of 0.5-1 mg once or twice weekly to sustain pigmentation.^[22] Despite these effects, Melanotan II-induced tanning has limitations, including the potential for uneven pigmentation, such as darkening of existing moles, freckles, or scars, which may exacerbate cosmetic concerns or complicate dermatological monitoring.^[2]^[22] Furthermore, while eumelanin provides inherent UV absorption equivalent to a sun protection factor of approximately 2-3, it does not fully replace topical sunscreens or other photoprotective measures, as the induced melanin offers only partial shielding against erythema and long-term UV damage.^[23]^[20]

Sexual Arousal and Dysfunction

Melanotan II, a synthetic analog of α-melanocyte-stimulating hormone, enhances libido through activation of melanocortin-4 receptors (MC4R) located in the hypothalamus, which modulates sexual desire in both males and females.^[24] This central nervous system action promotes increased sexual motivation and can induce spontaneous erections in males without external stimulation, as observed in clinical studies where subcutaneous administration led to penile rigidity in a majority of participants.^[25] The compound shows potential in treating erectile dysfunction by improving penile blood flow through the neuronal release of nitric oxide, a key mediator in cavernosal smooth muscle relaxation.^[26] This mechanism parallels that of bremelanotide, a derived analog of Melanotan II lacking the C-terminal amide group, which has been developed and approved for enhancing erectile function.^[27] In females, Melanotan II has been associated with increased sexual arousal and genital lubrication, based on findings from early clinical trials, though systematic investigation remains limited compared to male effects.^[28] Its role in addressing hypoactive sexual desire disorder (HSDD) is under exploration, building on the melanocortin pathway's influence on female sexual response, as evidenced by related agonists.^[29] Sexual effects of Melanotan II typically onset within hours of administration and persist for 24-72 hours, with repeated dosing leading to cumulative increases in sensitivity over time.^[28] This duration aligns with its pharmacokinetic profile, enabling sustained central receptor activation.^[14]

Other Investigated Applications

Melanotan II has been investigated for its potential in appetite suppression due to its agonism at melanocortin-3 (MC3R) and melanocortin-4 (MC4R) receptors, which play key roles in regulating food intake and energy balance. In rodent models, central or peripheral administration of Melanotan II dose-dependently reduced food consumption and led to sustained weight loss, with effects comparable to those of selective MC4R agonists like setmelanotide, though its broader receptor profile may contribute to transient suppression followed by adaptation.^[30]^[31]^[32] Through activation of the melanocortin-1 receptor (MC1R), Melanotan II exhibits potential anti-inflammatory effects that may benefit inflammatory skin conditions. Activation of MC1R by melanocortin agonists like Melanotan II promotes resolution of inflammation by inhibiting pro-inflammatory cytokine production and enhancing anti-inflammatory pathways in keratinocytes and immune cells, suggesting therapeutic utility in modulating skin inflammation.^[33]^[13] Preliminary animal studies have explored Melanotan II's neuroprotective properties, including promotion of peripheral nerve regeneration following injury and partial protection against toxic neuropathy. Additionally, in rodent models of substance use, Melanotan II reduced binge-like ethanol consumption and reinstatement of alcohol-seeking behaviors, indicating potential modulation of addiction-related neural circuits via melanocortin receptor signaling.^[34]^[35]^[36] In cancer research, a 2020 in vitro and in vivo study using the B16-F10 melanoma model found that topical Melanotan II suppressed tumor cell migration, invasion, and proliferation while attenuating tumor growth in mice, primarily through upregulation of the tumor suppressor PTEN and inhibition of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) pathways, with MC1R mediation confirmed via neutralization experiments.^[37]

Research and Development

Historical Development

The development of Melanotan II traces its roots to research on alpha-melanocyte-stimulating hormone (α-MSH), a naturally occurring peptide first identified in the 1960s for its role in regulating skin pigmentation through melanogenesis.^[38] Early studies demonstrated that α-MSH injections could enhance skin darkening in humans, prompting interest in synthetic analogs to mimic these effects for potential photoprotective applications.^[38] In the late 1980s, researchers at the University of Arizona, led by Victor J. Hruby, synthesized Melanotan II (MT-II) as a cyclic lactam-bridged analog of α-MSH, specifically Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-NH2, aiming to create a more stable and potent version resistant to enzymatic degradation.^[39] This compound was designed to bind more effectively to melanocortin receptors, exhibiting up to 1,000 times greater potency than native α-MSH in stimulating melanin production.^[40] During the 1990s, preclinical studies at the University of Arizona focused on MT-II's potential for inducing tanning without ultraviolet exposure, initially as a strategy to reduce skin cancer risk in fair-skinned individuals.^[41] These efforts built on earlier work with Melanotan I (MT-I, afamelanotide), a linear analog, but shifted toward MT-II in the early 2000s due to its superior potency and efficacy in pigmentation assays, despite noted central nervous system effects.^[42] By this time, MT-II had demonstrated robust melanogenic activity in animal models, prompting exploration beyond cosmetics into therapeutic areas like erectile dysfunction after incidental observations of pro-erectile side effects in early trials. Key milestones in the 2000s included licensing agreements that diverged development paths for MT-I and MT-II. In the early 2000s, Palatin Technologies acquired rights to MT-II from Competitive Technologies and advanced it for sexual dysfunction, eventually modifying it into bremelanotide (a deaminated metabolite) to mitigate side effects while retaining melanocortin agonism.^[43] Concurrently, Clinuvel Pharmaceuticals prioritized MT-I (afamelanotide) for medical applications, particularly in treating erythropoietic protoporphyria, a condition causing severe photosensitivity, leading to its approval as Scenesse in Europe in 2014.^[44] Regulatory interest in MT-II for cosmetic tanning waned by the mid-2000s due to concerns over adverse effects such as nausea, flushing, and unintended erections, resulting in its abandonment for non-medical pigmentation uses.^[41] Post-2010, renewed research has explored MT-II analogs for targeted applications like melanoma suppression and anti-inflammatory effects, though without regulatory approval for cosmetics.^[45]

Clinical Studies and Trials

Early clinical trials of Melanotan II in the 1990s focused primarily on its potential for inducing skin pigmentation. A pilot phase I study involving three male volunteers administered subcutaneous doses starting at 0.01 mg/kg daily, escalating to 0.025-0.03 mg/kg over two weeks, resulted in visible increased pigmentation on the face, upper body, and buttocks in two subjects, as assessed by visual evaluation and skin reflectance analysis one week post-dosing.^[1] These trials demonstrated tanning activity with only five low doses every other day, but development for photoprotection was limited due to frequent nausea and other side effects, leading to abandonment of further large-scale tanning investigations.^[1] Subsequent studies in the late 1990s and early 2000s shifted emphasis to erectile dysfunction (ED). A double-blind, placebo-controlled trial in 10 men with psychogenic ED using a 0.025 mg/kg subcutaneous dose induced clinically apparent erections in 8 of 10 participants, with mean tip rigidity exceeding 80% for 38 minutes. A follow-up 2000 study by Palatin Technologies and collaborators, involving 20 men, reported erections in 17 of 20 subjects (85% response rate) without sexual stimulation, with mean rigidity over 80% lasting 41 minutes and increased sexual desire after 68% of doses.^[25] These phase I/II efforts, however, highlighted persistent challenges with nausea (reported in up to 13% of cases at this dose) and yawning, prompting exploration of analogs like bremelanotide for ED applications.^[25] Preclinical animal models have corroborated these effects. Rodent studies confirmed Melanotan II's stimulation of melanogenesis, with subcutaneous administration leading to dose-dependent skin darkening in mice and rats via activation of melanocortin-1 receptors.^[46] Similarly, intracerebroventricular or peripheral dosing in male and female rats enhanced libido and proceptive sexual behaviors, including increased solicitation and reduced latency to mounting, independent of pigmentation changes.^[47] A 2020 study using the B16-F10 melanoma model demonstrated in vitro suppression of cell migration, invasion, and colony formation, alongside in vivo reduction in tumor growth in mice treated topically with Melanotan II, attributed to PTEN upregulation and cyclooxygenase-2 downregulation.^[37] Despite these findings, significant gaps persist in the clinical data for Melanotan II. Most human trials involved small cohorts (under 20 participants), with no large-scale, long-term phase III studies completed due to side effect profiles and regulatory hurdles.^[2] Much of the available evidence on sexual dysfunction derives from early analogs like bremelanotide, which underwent more extensive testing but differs in administration and selectivity.^[25] As of 2025, no new large-scale clinical trials have been reported, with research limited to preclinical models, such as a 2023 study demonstrating MT-II's potential to reverse memory impairment induced by a short-term high-fat diet in rats.^[48] Overall, the lack of robust, extended-duration human trials limits definitive assessments of efficacy and safety beyond short-term observations.

Safety Profile

Adverse Effects

Melanotan II administration is associated with several short-term adverse effects, primarily observed shortly after subcutaneous injection. Common side effects include nausea, facial flushing, spontaneous erections or priapism in males, and appetite suppression, which have been reported in clinical studies and user experiences.^[25]^[2] In one phase I trial, nausea occurred following 38% of Melanotan II injections, with severe cases in approximately 15% of instances, significantly higher than placebo. Yawning and lethargy are also frequently noted, occurring in up to 44% and 21% of doses in early trials, respectively, often linked to the drug's agonism at melanocortin receptors.^[25] Skin-related adverse effects encompass darkening of existing nevi, moles, and freckles, as well as potential injection site reactions such as pain, erythema, or infection, particularly with unregulated or contaminated products sourced online.^[6]^[2] These changes typically appear within days of use and may reverse upon discontinuation, though monitoring for atypical pigmentation is advised due to the risk of exacerbating pre-existing lesions.^[5] Systemic effects can include increased blood pressure, fatigue, and, in rare cases, severe complications such as renal infarction attributed to vasoconstriction, rhabdomyolysis, or posterior reversible encephalopathy syndrome (PRES).^[49]^[19]^[50] A case report documented renal infarction affecting 50% of one kidney in a user after cumulative dosing, highlighting potential sympathomimetic overstimulation.^[49] Priapism, a prolonged erection requiring medical intervention, has been reported in isolated instances, with one case resolving after aspiration but leading to temporary erectile dysfunction.^[51] These adverse effects exhibit dose-dependency, with higher doses exceeding 1 mg per injection intensifying gastrointestinal symptoms like nausea and vomiting, as well as cardiovascular responses such as flushing and hypertension.^[2]^[25] In trials, side effect incidence rose with escalating doses from 0.01 to 0.025 mg/kg, underscoring the need for careful dosing to mitigate acute reactions.^[52]

Long-Term Risks and Concerns

The long-term use of Melanotan II raises concerns about potential promotion of melanoma due to its stimulation of melanocytes, which could theoretically exacerbate neoplastic changes in susceptible individuals.^[53] However, a 2020 preclinical study in mice demonstrated that topical Melanotan II suppressed melanoma progression by upregulating PTEN expression and inhibiting cyclooxygenase-2 signaling, reducing tumor size by approximately 50% compared to controls.^[45] The interaction with ultraviolet (UV) exposure remains unclear, as case reports have linked combined Melanotan II use with sunbed tanning to the development of cutaneous melanoma, suggesting a possible synergistic risk.^[53] Prolonged activation of melanocortin receptors by Melanotan II may contribute to cardiovascular complications, including hypertension and renal infarction. Chronic administration of Melanotan II in animal models has been associated with elevated arterial pressure and heart rate through sustained melanocortin-3/4 receptor stimulation.^[54] A case report described a 45-year-old man who developed right-sided renal infarction affecting about 50% of his kidney after repeated injections totaling 27 mg over six months, with persistent hypertension (165/95 mmHg) post-event and no identifiable embolic source.^[49] Extended exposure to Melanotan II as an exogenous melanocortin agonist could lead to hormonal disruptions, particularly through receptor desensitization, potentially fostering dependency for effects like tanning or arousal. Studies indicate that chronic central infusion of Melanotan II results in rapid loss of anorexic response within 2-5 days, likely due to desensitization or trafficking of melanocortin-3/4 receptors, though body mass reduction persists without caloric restriction.^[55] The impacts on fertility remain unknown, with no long-term human data available, though avoidance is recommended during pregnancy or breastfeeding due to potential effects on reproductive signaling via melanocortin pathways.^[2] Unregulated Melanotan II products, often sourced online without pharmaceutical oversight, pose additional risks from impurities that may cause allergic reactions or facilitate infections. These formulations can contain toxic or counterfeit contaminants due to inconsistent manufacturing, leading to adverse effects such as facial flushing or systemic reactions.^[8] Improper injection practices with such products further heighten the chance of localized or systemic infections, compounded by the lack of sterility controls.^[56]

Societal Aspects

Legal Status

Melanotan II has not been approved by the U.S. Food and Drug Administration (FDA) for any medical use and is classified as an unapproved new drug, making it illegal to market or distribute for human consumption.^[57] Similarly, Melanotan II has not been authorized as a medicine in the European Union due to safety concerns, rendering its sale and use as a medicinal product prohibited across EU member states.^[58] In both regions, it is often categorized as a research chemical intended solely for laboratory use, with strict prohibitions on promotion for tanning, photoprotection, or sexual enhancement purposes.^[59] Regulatory bans on Melanotan II were established in several countries in the late 2000s. In Australia, the Therapeutic Goods Administration (TGA) prohibited its supply without a prescription in 2007, classifying it as an unapproved therapeutic good.^[8] The UK's Medicines and Healthcare products Regulatory Agency (MHRA) followed in 2008, deeming Melanotan II an unauthorized medicine and issuing warnings against its importation, sale, or advertising.^[60] These actions aligned with broader European restrictions, where unauthorized melanocortin peptides like Melanotan II have been subject to enforcement since around 2010 to prevent public health risks.^[58] Internationally, enforcement varies, but Melanotan II is frequently seized at customs worldwide due to its unapproved status. For instance, the FDA maintains an import alert for unapproved peptide drugs, leading to detentions of shipments containing Melanotan II.^[59] Similar seizures occur in Europe, such as by Swissmedic, which reported intercepting melanotan products in illegal imports.^[61] It remains available through online vendors as a "research peptide," though subject to regulatory scrutiny and import bans in many jurisdictions. Recent regulatory actions underscore ongoing concerns. In 2023, Australia's TGA issued public alerts warning against online sales of Melanotan II products, emphasizing their illegality and health dangers.^[41] As of January 2025, Australia's TGA reiterated warnings against melanotan products, highlighting risks from nasal sprays and injectables.^[8] In March 2025, UK health authorities reported cases of severe reactions, including hospitalizations, from illegal nasal tanning products containing Melanotan II.^[62] No approvals have been granted for Melanotan II or its direct analogs beyond bremelanotide, which received FDA approval in 2019 specifically for treating hypoactive sexual desire disorder in premenopausal women.^[63]

Non-Medical Use and Availability

Melanotan II is predominantly accessed through unregulated online marketplaces, where it is marketed and sold as a synthetic tanning agent without medical oversight. Products are typically offered as lyophilized powder in glass vials, intended for reconstitution with bacteriostatic water, and shipped discreetly from international vendors. These gray-market sites, along with informal networks in gyms and bodybuilding forums, facilitate easy purchase without prescriptions, often alongside other performance-enhancing substances.^[64]^[8] The primary users are fair-skinned individuals pursuing a cosmetic tan to achieve a bronzed appearance, particularly in preparation for vacations or social events, as well as members of bodybuilding and fitness communities seeking enhanced libido and sexual arousal. Online forum discussions reveal a user base motivated by aesthetic goals, with many reporting use to avoid traditional sun exposure while synergizing with UV light for deeper pigmentation. Younger demographics, including adolescents and young adults, are increasingly targeted through social media promotions that glamorize the product despite regulatory cautions.^[65]^[5] Administration commonly involves self-mixing the powder into injectable solutions for subcutaneous delivery using insulin syringes, or as nasal sprays for non-invasive absorption, with users following informal protocols such as initial "loading doses" of 0.25–1 mg daily for one to two weeks, followed by maintenance doses and controlled UV exposure to amplify tanning effects. These practices are shared via user-generated guides on forums, emphasizing sterile techniques but often lacking professional guidance.^[65]^[41] Public health concerns arise from the prevalence of counterfeit and substandard products, where vials labeled as 10 mg may contain only 4.32–8.84 mg of active substance, along with impurities, increasing risks of inconsistent dosing, overdoses, and contamination leading to infections. Social media influencers promote Melanotan II through visually appealing content, contributing to rising misuse among vulnerable groups, while authorities report adverse events including nausea, priapism, and potential melanoma exacerbation from unregulated use.^[64]^[8]^[5]

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Melanocortin 4 receptor signaling in Sim1 neurons permits sexual ...
Mar 23, 2023 · The melanocortin system is a new treatment target for hypoactive sexual desire disorder (HSDD), but the neuronal pathways involved are unclear.Missing: penetration | Show results with:penetration<|control11|><|separator|>
[28]
The MC4 receptor and control of appetite - 2006 - Wiley Online Library
Jan 29, 2009 · Central administration of non-specific MC receptor agonists such as α-MSH and melanotan-II (MTII) results in decreased food intake and body ...<|separator|>
[29]
The effects of the melanocortin agonist (MT-II) on subcutaneous and ...
These results indicate that peripheral MT-II treatment leads to weight loss that affects both the visceral and subcutaneous fat compartments.Missing: suppression | Show results with:suppression
[30]
https://bpspubs.onlinelibrary.wiley.com/doi/10.1038/sj.bjp.0706929
[31]
An overview of benefits and risks of chronic melanocortin‐1 receptor ...
... 2. Melanotan II. Melanotan II is a synthetic cyclic α‐MSH analogue that is a nonselective MCR agonist and is not approved for use in any therapeutic indication.
[32]
The Potent Melanocortin Receptor Agonist melanotan-II Promotes ...
Melanotan-II significantly enhanced the recovery of sensory function following a crush lesion of the sciatic nerve in the rat at a dose of 20 microg kg(-1) per ...
[33]
Evidence that Melanocortin Receptor Agonist Melanotan-II ...
Methods: In the present report, a mouse model of binge EtOH drinking was employed to determine whether the MCR agonist, melanotan-II (MTII), would improve the ...
[34]
Lateral hypothalamic melanocortin receptor signaling modulates ...
Lateral hypothalamic melanocortin receptor signaling modulates binge-like ethanol drinking in C57BL/6J mice. Addict Biol. 2016 Jul;21(4):835-46. doi: 10.1111/ ...
[35]
Topical MTII Therapy Suppresses Melanoma Through PTEN ...
Jan 20, 2020 · Melanotan II (MTII), a synthetic analogue of the alpha-melanocyte stimulating hormone (α-MSH), has been applied for skin tanning in humans.
[36]
Journey through the spectacular landscape of melanocortin 1 receptor
Jun 10, 2024 · In the 1960's, Lerner and McGuire reported that injection of human subjects with dark complexion with α-MSH increased skin pigmentation (Lerner ...
[37]
Bench-Top to Clinical Therapies: A Review of Melanocortin Ligands ...
2 MTII (Melanotan-II). In 1989, a series of lactam cyclized α-MSH/NDP-MSH analogs were synthesized in order to develop more potent and prolonged-acting ...
[38]
What is Melanotan-II - the drug that the TGA urges ... - UNSW Sydney
Jan 30, 2023 · If injected or used as a nasal spray, Melanotan-II can cause dramatic skin darkening in just days. The drug can also suppress appetite and lead ...Missing: pharmacokinetics | Show results with:pharmacokinetics
[39]
Translational advances of melanocortin drugs: Integrating biology ...
Melanocortin (MC) drugs act by binding to five different melanocortin receptors. ... Although the affinities vary, all endogenous melanocortin peptides can bind ...
[40]
Bremelanotide: First Approval - PubMed
Initially developed by Palatin Technologies who sponsored the Phase 3 clinical trials, bremelanotide was subsequently out-licensed to AMAG Pharmaceuticals Inc.
[41]
Afamelanotide for Erythropoietic Protoporphyria
Jul 2, 2015 · Afamelanotide had an acceptable side-effect and adverse-event profile and was associated with an increased duration of sun exposure without pain and improved ...
[42]
Topical MTII Therapy Suppresses Melanoma Through PTEN ... - NIH
These results indicate that MTII elicits PTEN upregulation via MC1R, thereby suppressing melanoma progression through downregulating COX-2/PGE2 signaling.
[43]
The Effects of the Melanocortin Agonist (MT-II) on Subcutaneous ...
In this study, we analyzed the peripheral effects of the synthetic melanocortin agonist melanotan-II (MT-II) in rodents fed a low-fat or high-fat diet. MT-II- ...Missing: melanogenesis | Show results with:melanogenesis
[44]
The melanocortin agonist, melanotan II, enhances proceptive sexual ...
PT-141 is the deaminated metabolite of melanotan-II (MT-II) (Diamond et al., 2004). Like PT-141, MT-II has a high affinity for MC1, MC3, MC4 and MC5 receptors.
[45]
Melanotan II: a possible cause of renal infarction - PubMed Central
We present a review of Melanotan II and the possible effects of this drug on the kidneys by including a case of a renal infarction most likely attributed to ...
[46]
Melanotan-induced priapism: a hard-earned tan - PMC
Further studies have reported the role of melanotan II in modulating both male and female sexual arousal. They also reported it as a centrally acting drug ...
[47]
Melanocortin receptor agonists, penile erection, and sexual motivation
Oct 2, 2000 · We review our experience with Melanotan II, a non-selective melanocortin receptor agonist, in human subjects with erectile dysfunction (ED).
[48]
Melanoma associated with the use of melanotan-II - PubMed
Background: Unlicensed use of melanotan-II (MT-II) to promote skin pigmentation has become prevalent amongst young people attending fitness centres.
[49]
Endogenous Melanocortin System Activity Contributes to the ...
Feb 19, 2008 · Chronic activation of the MC3/4R using a synthetic agonist, Melanotan II (MTII), increased arterial pressure and heart rate,10 and this effect ...Missing: MC | Show results with:MC
[50]
Activation of the central melanocortin system chronically reduces ...
One of the best suitable analogs is melanotan II (MTII), a nonselective agonist of MC receptors. When specifically administered in the brain, MTII reduces ...Missing: post- | Show results with:post-
[51]
Risks of unregulated use of alpha-melanocyte-stimulating hormone ...
Mar 7, 2017 · Recently, the unregulated use of untested synthetic alpha-melanocyte-stimulating hormone (α-MSH) analogues, commonly known as melanotan I ...
[52]
Notice of Opportunity for Hearing (NOOH) Manookian, Edward 8/5/16
Sep 16, 2016 · This letter also stated that Melanocorp did not disagree that FDA considered Melanotan II to be an unapproved new drug and that FDA had ...Missing: EMA | Show results with:EMA
[53]
Melanotan 2 | Watch-out database - COSlaw.eu
Melanotan 2 (MT2) is not a cosmetic ingredient. MT2 is a medicine and, at the moment, it is not authorized because of the adverse effects linked to its use.
[54]
Import Alert 66-41 - accessdata.fda.gov
Detention Without Physical Examination of Unapproved New Drugs Promoted In The U.S.. Reason for Alert: NOTE: The revision of this Import Alert, dated 09/21/2023 ...
[55]
Melanotan injections are sold illegally and possibly unsafe
Jan 28, 2009 · The MHRA has currently contacted 18 different companies explaining that any supplying or advertising of Melanotan is illegal and any websites ...
[56]
Commission's response to increasing melanotan abuse in the EU
Jul 12, 2011 · In the Commission's view, is it appropriate that a substance such as melanotan II, which is harmful to health, can be obtained by EU citizens ...Missing: 2010 | Show results with:2010
[57]
Statistics illegally imported medicinal products 2017 - Swissmedic
Feb 8, 2018 · Several shipments from the UK and Poland also contained melanotan. Allegedly a tanning agent, this substance produces primary side effects that ...
[58]
The Safety and Legality of Melanotan II in Modern Health
The legal status of Melanotan II varies. In countries like the United States and many in the EU, it is generally considered an unregulated substance, making ...
[59]
[PDF] Multi-Discipline Review - accessdata.fda.gov
Jun 25, 2019 · ... (melanotan II, BMT is the free acid form with no amide at the carboxyl terminus) of a 39-year-old Caucasian male who injected 6 mg of melanotan ...
[60]
Identification and characterization by LC‐UV‐MS/MS of melanotan II ...
Apr 25, 2014 · The present study aimed at developing, validating, and applying analytical methods for melanotan II products, based on liquid chromatography ...
[61]
Melanotan II User Experience: A Qualitative Study of Online ...
Aug 31, 2021 · Objectives: The aim of this study was to qualitatively examine MT II use, as portrayed on online forums, and to explore the motivations for its ...