Melanotan II Safety Research: Comprehensive Review

From early Phase I trials at the University of Arizona to dozens of post-market case reports across three continents, the safety profile of Melanotan II has been assembled piece by piece over thirty years. This article examines the full body of evidence -- what clinical studies found, what case reports revealed, and what remains unknown.

What Is Melanotan II?
The Phase I Clinical Trial (Dorr et al., 1996)
Short-Term Side Effects From Controlled Studies
Cardiovascular and Hemodynamic Effects
Dermatological Concerns: Nevi, Moles, and Pigmentation Changes
Melanoma Case Reports
Systemic Toxicity: Rhabdomyolysis and Organ Damage
Sexual Side Effects and the PT-141 Connection
Product Quality and Contamination Risks
Regulatory Status Worldwide
Summary of Evidence by Category
FAQ
The Bottom Line
References

What Is Melanotan II?

Melanotan II (MT-II) is a synthetic cyclic peptide analog of alpha-melanocyte-stimulating hormone (alpha-MSH). Developed at the University of Arizona in the late 1980s and early 1990s, it was originally designed to trigger melanogenesis -- the process by which skin produces the pigment melanin -- without UV exposure.

Unlike Melanotan I (afamelanotide), which is a linear peptide that binds primarily to the MC1 receptor, Melanotan II is a shorter, cyclized peptide that binds non-selectively across multiple melanocortin receptors (MC1R through MC5R). This broader receptor activity explains both its potency and its wider range of side effects, including appetite suppression, sexual arousal, and cardiovascular changes.

MT-II has never been approved by any regulatory body for human use. Despite this, it has been widely available through online vendors since the early 2000s, sold as a research chemical for self-injection.

The Phase I Clinical Trial (Dorr et al., 1996)

The foundational safety data for Melanotan II comes from a pilot Phase I study published by Dorr et al. in Life Sciences in 1996. This was a small, double-blind, placebo-controlled crossover trial conducted at the University of Arizona.

Study design:

Parameter	Detail
Subjects	10 healthy male volunteers
Design	Double-blind, placebo-controlled crossover
Dose	0.025 mg/kg subcutaneous injection
Schedule	5 doses administered every other day
Primary outcome	Change in skin pigmentation

The study found that five low-dose subcutaneous injections of MT-II produced measurable tanning activity, confirming the peptide's melanogenic effect in humans at a fraction of the dose required for Melanotan I.

Observed adverse events:

Nausea was the most common side effect, reported at doses above 0.025 mg/kg
Facial flushing occurred shortly after injection
Yawning and stretching were noted
Spontaneous penile erections occurred in several subjects, lasting 1-5 hours post-injection
No serious adverse events were documented at the recommended dose

The study concluded that 0.025 mg/kg/day represented a safe single dose for future Phase I/II investigation, and recommended slower dose escalation protocols to limit nausea (Dorr et al., 1996).

This trial was small and short-term. It was never followed by the larger Phase II and Phase III trials that would be needed for regulatory approval, leaving a significant gap in the formal safety record.

Short-Term Side Effects From Controlled Studies

Beyond Dorr et al., a handful of small controlled studies examined MT-II in humans during the late 1990s and early 2000s. These studies, combined with clinical trial data from the related compound PT-141 (bremelanotide, which was derived from MT-II), provide the most reliable data on short-term side effects.

Side Effect	Frequency	Notes
Nausea	Very common (reported in most subjects at therapeutic doses)	Dose-dependent; severe in approximately 20% of subjects at higher doses
Facial flushing	Common	Typically resolves within 1-2 hours
Yawning/stretching	Common	Possibly CNS-mediated
Decreased appetite	Common	Related to MC4R activation
Spontaneous erections	Common in males	Led to PT-141 development
Fatigue	Occasional	Reported in post-market case reports
Headache	Occasional	Reported at various doses
Dizziness	Occasional	Reported in some case series

The 2017 review by Habbema et al. in the International Journal of Dermatology, which remains the most comprehensive safety review of alpha-MSH analogs in the literature, noted that "side effects of MT-II include nausea, vomiting, yawning, and reduced appetite" and that the compound's non-selective receptor binding creates risks not seen with the more receptor-specific Melanotan I (Habbema et al., 2017).

A key distinction: nausea tends to diminish with repeated dosing. Forum-based research by Gilhooley et al. (2021) in Dermatology found that MT-II users commonly reported nausea with initial doses that subsided over time, a pattern consistent with receptor desensitization.

Cardiovascular and Hemodynamic Effects

Because MT-II activates multiple melanocortin receptors including MC4R, which plays a role in sympathetic nervous system regulation, cardiovascular effects have been a consistent safety concern.

Data from controlled studies:

Transient blood pressure increases have been documented in clinical research on both MT-II and the related compound bremelanotide
The FDA prescribing information for bremelanotide (Vyleesi) -- which shares the same receptor activity profile as MT-II -- reports mean systolic increases of up to 6 mmHg and diastolic increases of up to 3 mmHg, peaking 2-4 hours post-dose and returning to baseline within 12 hours
Heart rate decreases of up to 5 beats per minute have been observed

Data from case reports:

The most alarming cardiovascular data comes from the case report by Nelson et al. (2012) published in Clinical Toxicology. A patient who injected an excessive dose of MT-II presented with:

Heart rate of 146 bpm (tachycardia)
Hypertension
Diaphoresis (excessive sweating)
Anxiety and restlessness
Symptoms consistent with sympathomimetic toxicity

This case demonstrated that MT-II overdose can produce a clinical picture resembling sympathomimetic drug toxicity, with significant cardiovascular stress. The patient required hospital monitoring but recovered without lasting harm.

The Vyleesi label contraindicates the drug in patients with uncontrolled hypertension or known cardiovascular disease -- a warning that applies equally to MT-II given its shared mechanism.

Dermatological Concerns: Nevi, Moles, and Pigmentation Changes

The dermatological effects of MT-II extend beyond the desired tanning response. Changes to moles and nevi represent one of the most documented and potentially serious safety concerns.

Documented pigmentation effects:

Darkening of existing moles: Reported consistently across case reports and user surveys
New mole formation: Multiple studies document appearance of new nevi during MT-II use
Atypical/dysplastic nevi: Concerning changes in mole appearance, including irregular borders and color variation (Ferrandez-Pulido, 2011; Hjuler & Lorentzen, 2014)
Melanonychia: Darkening of nail beds, reported in some cases
Oral mucosal pigmentation: A 2026 case report by Bonchev in Life documented changes in oral mucosa associated with MT-II injections

The Habbema et al. (2017) review concluded that MT-II use is "strongly associated with melanocytic changes in existing moles and the emergence of atypical/dysplastic nevi." The mechanism is straightforward: MT-II activates melanocyte-stimulating pathways, and melanocytes within nevi respond to this stimulation just as skin melanocytes do.

A 2025 study published in JAAD by McKenzie et al. surveyed MT-II users and found that participants were "generally unconcerned with long-term adverse effects" despite evidence of pigmentary changes -- a finding that worried the researchers given the potential implications.

Reversibility:

Data on whether pigmentation changes reverse after stopping MT-II is limited. The Vyleesi prescribing information notes that focal hyperpigmentation was not confirmed to resolve in all patients after discontinuation. With daily dosing for 8 days, 38% of participants developed hyperpigmentation changes, compared to just 1% with less frequent use (up to 8 doses per month).

Melanoma Case Reports

The relationship between MT-II and melanoma is the most serious safety question in the literature. Several published case reports have documented melanoma diagnoses in MT-II users:

Hjuler & Lorentzen (2014), Dermatology: A 20-year-old woman with Fitzpatrick skin type II was diagnosed with melanoma after using MT-II in combination with tanning beds. The researchers noted that MT-II could "promote growth of subclinical melanoma" in the context of UV exposure.

Mallalieu (2021), Clinical Case Reports: A case of melanoma in-situ diagnosed four weeks after beginning MT-II from a regulated compounding pharmacy. The author noted that "case reports of eruptive nevi, dysplastic nevi and melanoma in-situ" have been linked to even short-term MT-II use.

Alsabbagh et al. (2025), International Journal of Oral and Maxillofacial Surgery: A case of oral mucosal malignant melanoma in a young, otherwise healthy patient was potentially linked to MT-II nasal spray use -- a unique case that expanded the concern beyond cutaneous melanoma.

Important context on causality:

Establishing a direct causal link between MT-II and melanoma is complicated by several factors:

Most MT-II users also use UV tanning beds, which are themselves a proven melanoma risk factor
Melanoma can take years to develop, and detection may be coincidental
By stimulating melanocytes, MT-II may make existing subclinical melanomas more visible rather than causing them
No controlled study has been powered or designed to measure melanoma incidence

That said, the biological plausibility of the concern is real. MT-II stimulates melanocyte proliferation. Melanoma is a cancer of melanocytes. The Habbema review (2017) stated that the risk "cannot be excluded" and called for heightened vigilance.

Systemic Toxicity: Rhabdomyolysis and Organ Damage

Beyond common side effects, rare but severe systemic reactions have been documented:

Rhabdomyolysis:

Nelson et al. (2012) in Clinical Toxicology reported a case where a patient presented with rhabdomyolysis after MT-II overdose. Creatine phosphokinase (CPK) levels reached 17,773 IU/L (normal range: 22-198 IU/L). The patient experienced intense muscle breakdown alongside the sympathomimetic symptoms described above. This was the first published case requiring hospitalization following MT-II use.

Renal injury:

A 2020 case report published in BMC Nephrology documented renal infarction potentially caused by MT-II. The Swedish Poisons Information Centre reported multiple contacts related to MT-II between 2008 and 2019, and the authors noted that "direct toxic effects of MT-II on renal parenchyma must be considered."

Pyoderma gangrenosum:

Dickson et al. (2025) in Cureus reported the first case of pyoderma gangrenosum (a painful skin ulceration) linked to melanotan use -- a 65-year-old woman who presented at a dermatology clinic with ulcerated lesions after using the peptide.

Encephalopathy:

The Australian Therapeutic Goods Administration (TGA) has reported cases of brain swelling associated with MT-II use, though detailed published case reports on this complication remain limited.

Sexual Side Effects and the PT-141 Connection

The sexual effects of MT-II were discovered accidentally during the early tanning trials at the University of Arizona. Researchers observed that male subjects experienced spontaneous erections 1-5 hours after injection, accompanied by increased sexual desire.

This observation led directly to the development of bremelanotide (PT-141), a metabolite of MT-II that was optimized for its sexual function effects. PT-141 was eventually approved by the FDA in 2019 as Vyleesi for the treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women.

The sexual effects of MT-II are mediated through MC3R and MC4R receptors in the central nervous system. Unlike phosphodiesterase inhibitors (such as sildenafil), which work on peripheral blood flow, MT-II and PT-141 act on brain pathways that influence sexual desire and arousal.

For a detailed analysis of this pathway from MT-II to FDA-approved drug, see our guide on best peptides for sexual health.

Priapism risk:

Mallory et al. (2021) in Sexual Medicine reported cases of priapism (prolonged, painful erection) associated with melanotan injections. While rare, priapism is a medical emergency that can result in permanent tissue damage if not treated promptly. This risk is not unique to MT-II -- it has also been noted with PT-141 -- but the uncontrolled dosing associated with self-administered MT-II likely increases the probability.

Product Quality and Contamination Risks

Because MT-II is sold outside regulated pharmaceutical channels, product quality represents a major safety variable that formal clinical trials cannot account for.

Analytical studies have found:

Significant variation in peptide purity among online vendors
Contamination with degradation products
Inaccurate labeling of peptide content
Potential bacterial contamination in reconstituted products

A 2014 study by van der Bijl et al. using LC-UV-MS/MS analysis characterized melanotan II products purchased online and identified concerning quality issues including impurities and incorrect concentrations.

The Callaghan review (2018) published in the Dermatology Online Journal examined the underground melanotan market and found that "93% of users reported being unaware of the long-term side effects" and that the majority of products were sourced through unregulated online channels.

Users who self-administer injectable MT-II also face risks common to all self-injection of non-pharmaceutical products: injection site infections, abscess formation, and potential transmission of blood-borne pathogens when sharing injection equipment.

Regulatory Status Worldwide

No country has approved Melanotan II for human use. Several regulatory agencies have taken active enforcement steps:

Country/Region	Agency	Action
United States	FDA	Warning letter to Melanocorp Inc. (2007); classified as Category 2 Bulk Drug Substance (banned from compounding)
United Kingdom	MHRA	Issued safety warnings; classified as unauthorized medicinal product
Australia	TGA	Active warnings against use; reports of kidney dysfunction and brain swelling cited
European Union	EMA	Not authorized; various member states have issued individual warnings
Norway	Norwegian Medicines Agency	Published case studies documenting adverse effects in Norwegian users

The FDA's classification of MT-II as a Category 2 Bulk Drug Substance effectively prohibits pharmacies from compounding it. This is the most restrictive category, reserved for substances the FDA has determined present significant safety risks.

It is worth noting that Melanotan I (afamelanotide) followed a different regulatory path. It was approved in the EU in 2014 and in the US in 2019 as Scenesse for the treatment of erythropoietic protoporphyria (EPP), a rare condition causing extreme sun sensitivity. Afamelanotide's more selective receptor binding and its formal clinical development program distinguished it from MT-II's regulatory trajectory.

For more on the differences between these tanning peptides, see our guide on peptides for sunless tanning.

Summary of Evidence by Category

Safety Concern	Evidence Level	Key Findings
Nausea/GI effects	Strong (clinical trials + extensive case data)	Most common side effect; dose-dependent; diminishes with repeat use
Cardiovascular effects	Moderate (clinical data from related compound + case reports)	Transient BP increases; tachycardia in overdose; contraindicated in CV disease
Nevi/mole changes	Strong (multiple case series + review data)	Consistent darkening and new formation of nevi documented
Melanoma risk	Suggestive but unproven (case reports; no controlled studies)	Biological plausibility exists; confounded by UV exposure; requires monitoring
Rhabdomyolysis	Limited (single case report)	Documented with overdose; CPK levels reached 17,773 IU/L
Renal injury	Limited (case reports)	Renal infarction documented; mechanism unclear
Product quality	Moderate (analytical studies + market surveys)	Variable purity; contamination documented in online products
Long-term effects	Unknown	No long-term controlled studies exist

FAQ

Is Melanotan II safe to use?

There is no safety data from large controlled trials to support MT-II use. The limited clinical evidence, combined with case reports of melanoma, rhabdomyolysis, and renal injury, means the risk-benefit ratio cannot be properly assessed. No regulatory agency considers it safe for human use.

What is the difference between Melanotan I and Melanotan II?

Melanotan I is a linear peptide that binds primarily to the MC1 receptor and has been approved (as afamelanotide/Scenesse) for a rare disease. Melanotan II is a cyclic peptide that binds non-selectively across MC1-MC5 receptors, which produces a wider range of effects and side effects including sexual arousal, appetite suppression, and cardiovascular changes.

Does Melanotan II cause melanoma?

Multiple case reports have documented melanoma in MT-II users, but a direct causal link has not been established in controlled studies. The biological mechanism is plausible -- MT-II stimulates the same cells (melanocytes) that give rise to melanoma. Most documented cases involved concurrent UV/sunbed use, which makes isolating the contribution of MT-II difficult.

Can Melanotan II be prescribed by a doctor?

In the United States, the FDA has classified MT-II as a Category 2 Bulk Drug Substance, meaning compounding pharmacies cannot legally prepare it. It is not approved as a prescription medication in any country.

What happened to Melanotan II clinical trials?

After the initial Phase I study by Dorr et al. in 1996, the research focus shifted to bremelanotide (PT-141), a derivative of MT-II with a more targeted therapeutic application. PT-141 completed full clinical development and received FDA approval in 2019 for HSDD. MT-II itself was never pursued through the standard drug development pipeline.

Is it safe to combine Melanotan II with other peptides?

No controlled studies have examined MT-II in combination with other peptides. Given its non-selective receptor activity and cardiovascular effects, combining it with other compounds adds unpredictable risk. See our peptide stacking guide for general principles.

The Bottom Line

Thirty years after the first human trial, the safety profile of Melanotan II remains poorly defined by the standards applied to approved pharmaceuticals. The Phase I trial that started it all enrolled just 10 men. No Phase II or III trials followed. Everything we know beyond that small study comes from case reports, user surveys, analytical chemistry studies, and data borrowed from the related compound bremelanotide.

What the evidence consistently shows: MT-II works for tanning, produces predictable short-term side effects (nausea, flushing, sexual arousal), and changes moles in ways that worry dermatologists. What the evidence cannot answer: whether long-term use increases melanoma risk, what cumulative effects look like over years, or how the unregulated products people actually inject compare to the pharmaceutical-grade compound used in the 1996 trial.

Every major regulatory agency has reached the same conclusion -- the unknowns outweigh the knowns, and the risks are not justified for a cosmetic application. That assessment is unlikely to change unless someone invests in the large-scale, long-term clinical trials that have never been done.

References

Dorr RT, Lines R, Levine N, et al. Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study. Life Sciences. 1996;58(20):1777-1784. PubMed
Habbema L, Halk AB, Neumann M, Bergman W. Risks of unregulated use of alpha-melanocyte-stimulating hormone analogues: a review. International Journal of Dermatology. 2017;56(10):975-980. Wiley
Nelson ME, Bryant SM, Aks SE. Melanotan II injection resulting in systemic toxicity and rhabdomyolysis. Clinical Toxicology. 2012;50(10):1169-1173. Taylor & Francis
Hjuler KF, Lorentzen HF. Melanoma associated with the use of melanotan-II. Dermatology. 2014;228(1):34-36. Karger
Brennan R, Wells JG, Van Hout MC. An unhealthy glow? A review of melanotan use and associated clinical outcomes. Performance Enhancement & Health. 2014;3(2):78-92. ScienceDirect
Gilhooley E, Daly S, McKenna D. Melanotan II user experience: a qualitative study of online discussion forums. Dermatology. 2021;237(6):995-1001. Karger
Mallalieu JE. Melanoma in-situ associated with Melanotan II use. Clinical Case Reports and Clinical Study. 2021;2(4). Aditum
Evans-Brown M, Dawson RT, Chandler M, McVeigh J. Use of melanotan I and II in the general population. BMJ. 2009;338:b566. BMJ
Alsabbagh AY, Bhujel N, Singh RP. Melanotan II nasal spray: a possible risk factor for oral mucosal malignant melanoma? International Journal of Oral and Maxillofacial Surgery. 2025;54(4):512-515. ScienceDirect
Callaghan DJ III. A glimpse into the underground market of melanotan. Dermatology Online Journal. 2018;24(10). eScholarship
Mallory CW, Lopategui DM, Cordon BH. Melanotan tanning injection: a rare cause of priapism. Sexual Medicine. 2021;9(1):100298. Oxford Academic
Bonchev A. Changes in oral mucosa associated with Melanotan II injections: a case report. Life. 2026;16(2):265. MDPI
Ferrandez-Pulido C, et al. An eruptive pigmented lesion after melanotan injection. Clinical and Experimental Dermatology. 2011;36(7):801-802. Oxford Academic
Dickson D, Htwe SH, Htwe SH. Pyoderma gangrenosum secondary to melanotan. Cureus. 2025;17(2). Cureus
McKenzie N, Gonzalez N, Huang C, et al. Beliefs, attitudes, and experiences of individuals using Melanotan II. Journal of the American Academy of Dermatology. 2025;92(5):AB206. JAAD

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