Melanotan-II: History and Development

Origins: The Search for Photoprotection (1980s-1991)

The story of Melanotan-II begins in the 1980s at the University of Arizona, where researchers were investigating ways to prevent skin cancer through artificial tanning. The rationale was straightforward: melanin, the pigment responsible for skin color, provides natural protection against UV radiation. If a drug could stimulate melanin production without requiring UV exposure, it might offer photoprotection without the DNA damage that causes skin cancer.

The research team, led by Dr. Mac Hadley and Dr. Victor Hruby, focused on alpha-melanocyte-stimulating hormone (α-MSH), a naturally occurring peptide that triggers melanin production. However, natural α-MSH had significant limitations: it was rapidly degraded by enzymes (half-life of minutes), required high doses, and had poor bioavailability. The team set out to create synthetic analogs with improved properties.

Their first success was Melanotan-I (later named afamelanotide), a linear peptide analog of α-MSH with enhanced stability and potency. While Melanotan-I showed promise in early studies, the researchers continued exploring modifications to further improve efficacy and reduce the frequency of dosing required.

Synthesis of Melanotan-II (1991)

In 1991, the University of Arizona team synthesized Melanotan-II, a cyclic heptapeptide (seven amino acids) with a dramatically different structure from both natural α-MSH and Melanotan-I. The key innovation was creating a cyclic structure through a lactam bridge between aspartic acid and lysine residues, along with incorporating D-phenylalanine (an unnatural D-amino acid) and norleucine.

These modifications produced remarkable improvements:

• 1,000-fold increased potency compared to natural α-MSH
• Extended half-life of approximately 33 hours (vs. minutes for α-MSH)
• Broader receptor activity affecting MC1R, MC3R, MC4R, and MC5R
• Enhanced stability resistant to enzymatic degradation

Initial animal studies confirmed MT-II's ability to induce pigmentation without UV exposure. The peptide appeared to fulfill the original goal: providing photoprotection through artificial tanning. The University of Arizona filed patents on the compound, and plans were made for human clinical trials.

Early Clinical Trials (1996-2000)

Phase 1 Safety Studies

The first human trials of Melanotan-II began in the mid-1990s, focusing on safety and pharmacokinetics. These small studies (typically 10-30 participants) administered MT-II via subcutaneous injection to healthy volunteers and assessed side effects, blood levels, and tanning effects.

The trials confirmed MT-II's tanning efficacy: participants developed noticeable skin darkening within days, with full pigmentation achieved in 2-4 weeks. The tan quality differed from UV-induced tanning—more uniform but sometimes described as more "golden" or "orange" rather than brown, particularly in fair-skinned individuals.

However, the trials also revealed significant side effects: nausea (60-80% of participants), facial flushing, increased blood pressure, and—unexpectedly—sexual effects including spontaneous erections in men and increased libido in both sexes. These sexual effects were initially considered problematic side effects that complicated the drug's development for photoprotection.

The Unexpected Discovery: Sexual Enhancement (1998)

By 1998, it became clear that MT-II's sexual effects were not minor side effects but profound pharmacological actions. Male participants reported spontaneous erections lasting hours, increased sexual thoughts, and enhanced erectile function. Female participants reported increased desire, improved arousal, and enhanced sexual satisfaction.

This discovery was both exciting and problematic. On one hand, it suggested a novel mechanism for treating sexual dysfunction—working through central nervous system pathways rather than the peripheral vascular mechanisms of existing ED drugs like Viagra (approved in 1998). On the other hand, it complicated MT-II's development for photoprotection, as regulators would be concerned about a tanning drug causing unpredictable sexual effects.

The research team and their commercial partners faced a decision: continue developing MT-II for tanning despite the sexual side effects, pivot to developing it for sexual dysfunction, or pursue both indications simultaneously. The complexity of this situation, combined with safety concerns and the availability of alternative approaches, ultimately led to MT-II's development being discontinued by the original developers.

Divergent Paths: Afamelanotide vs. Bremelanotide (2000-2010)

Afamelanotide (Melanotan-I): The Approved Path

While MT-II's development stalled, its predecessor Melanotan-I (afamelanotide) continued through clinical trials. Afamelanotide is selective for MC1R, producing tanning effects without the sexual or appetite effects associated with MC4R activation. This selectivity made it more suitable for regulatory approval.

Clinuvel Pharmaceuticals acquired rights to afamelanotide and developed it as an implant formulation for treating erythropoietic protoporphyria (EPP), a rare genetic disorder causing severe photosensitivity. After extensive clinical trials demonstrating safety and efficacy, afamelanotide received:

• European approval (2014): Under the brand name Scenesse
• US FDA approval (2019): For EPP in adults
• Australian approval (2020): For EPP

Afamelanotide's success validated the melanocortin approach to photoprotection but highlighted the importance of receptor selectivity for regulatory approval. The drug is administered as a subcutaneous implant every 2 months and costs approximately $100,000+ per year, limiting its use to the approved rare disease indication.

Bremelanotide (PT-141): From MT-II to FDA Approval

Recognizing MT-II's potent sexual effects, Palatin Technologies developed bremelanotide (PT-141), a derivative of MT-II with modifications aimed at reducing tanning effects while maintaining sexual enhancement properties. The development process was lengthy and faced multiple setbacks:

2000-2007: Initial Development

• Early trials focused on intranasal administration
• Showed efficacy for erectile dysfunction in men
• Also showed promise for female sexual dysfunction
• Development halted in 2007 due to blood pressure concerns

2008-2015: Reformulation and Refocus

• Switched to subcutaneous injection to reduce blood pressure effects
• Pivoted to focus on female sexual dysfunction (larger unmet need)
• Conducted phase 2 and phase 3 trials in premenopausal women
• Trials showed significant improvements in sexual desire and satisfying sexual events

2019: FDA Approval

• Approved for hypoactive sexual desire disorder (HSDD) in premenopausal women
• Marketed as Vyleesi
• Administered as on-demand subcutaneous injection 45 minutes before sexual activity
• Carries black box warning for transient blood pressure increases
• Expensive (~$1,000+ per month) and requires prescription

Bremelanotide's approval validated melanocortin receptor agonists as a legitimate approach to treating sexual dysfunction, though the drug's high cost, injection requirement, and side effect profile have limited its commercial success.

Underground Market and Internet Distribution (2000-Present)

Emergence of Research Chemical Market

As pharmaceutical companies abandoned MT-II development, the peptide found a second life in the underground research chemical market. Beginning in the early 2000s, Chinese chemical manufacturers began producing MT-II for sale through internet suppliers, marketed as "research chemicals" or "not for human consumption" to skirt regulatory restrictions.

The internet enabled direct-to-consumer sales, with websites offering MT-II alongside other research peptides, SARMs, and experimental compounds. Online forums and bodybuilding communities shared information about sourcing, dosing, and effects, creating a grassroots knowledge base that substituted for the absent clinical research.

This underground market grew substantially through the 2000s and 2010s, driven by:

• Tanning demand: Individuals seeking cosmetic tanning without UV exposure
• Sexual enhancement: Men and women seeking alternatives to conventional ED treatments
• Weight loss: Recognition of MT-II's appetite-suppressing effects
• Bodybuilding: Pre-competition tanning and potential metabolic benefits
• Biohacking: Experimentation with novel compounds for self-optimization

Quality Control Crisis

The unregulated nature of the MT-II market created serious quality control issues. Third-party testing conducted by independent laboratories and user groups revealed alarming problems:

• Purity variations: Products containing 50-95% actual peptide, with remainder being unknown impurities
• Dosing inaccuracies: Vials labeled "10 mg" containing anywhere from 5-15 mg
• Contamination: Bacterial endotoxins, heavy metals, or other peptides
• Degradation: Improper storage during shipping causing peptide breakdown
• Wrong compounds: Some products sold as MT-II actually containing Melanotan-I or other substances

These quality issues made accurate dosing impossible and introduced additional health risks beyond those inherent to the peptide itself. Users had no way to verify what they were actually injecting, creating a dangerous situation where adverse events could result from the peptide, contaminants, or incorrect dosing.

Regulatory Actions and Warnings (2007-Present)

FDA Warnings (2007, 2009, 2016)

The FDA issued multiple warnings about Melanotan-II and related products:

2007 Warning: Initial alert about unapproved tanning products sold online, including MT-II. Emphasized lack of safety data and unknown long-term effects.

2009 Warning: More detailed consumer alert specifically naming Melanotan-II and warning about serious health risks including:

• Nausea, vomiting, and loss of appetite
• Flushing and cardiovascular effects
• Spontaneous erections and priapism
• Darkening of moles (potentially masking melanoma)
• Unknown long-term cancer risk

2016 Update: Reiterated warnings and noted continued availability despite previous alerts. Emphasized that products marketed as "Melanotan," "Melanotan-II," or similar names are unapproved drugs that should be avoided.

International Regulatory Actions

Other countries have taken various approaches to MT-II:

• United Kingdom: Medicines and Healthcare products Regulatory Agency (MHRA) issued warnings and seized products from suppliers
• Australia: Therapeutic Goods Administration (TGA) classified MT-II as a prescription-only medicine, making unauthorized sale illegal
• European Union: Various member states have issued warnings or banned sales
• Canada: Health Canada warned consumers about health risks and illegal status

Despite these regulatory actions, MT-II remains widely available through international suppliers, with enforcement complicated by internet sales and international shipping.

Legal Cases and Enforcement

Several high-profile cases have involved MT-II distribution:

• 2009: UK man died after using MT-II, leading to increased regulatory scrutiny
• 2012: Multiple suppliers in UK and Australia prosecuted for selling unapproved medicines
• 2015: FDA warning letters sent to US-based websites selling MT-II
• 2018: Australian man sentenced for importing and selling MT-II

These cases demonstrate regulatory authorities' concerns about MT-II but also highlight the difficulty of controlling internet-based sales of research chemicals.

Current Status and Future Outlook (2020-Present)

Ongoing Underground Use

Despite regulatory warnings and legal actions, MT-II use continues and may be increasing, driven by:

• Social media influence: Instagram, TikTok, and YouTube content promoting tanning and body modification
• Biohacking movement: Interest in experimental compounds for self-optimization
• COVID-19 pandemic: Increased online shopping and reduced in-person social scrutiny
• Cryptocurrency: Enabling anonymous purchases that evade traditional payment monitoring
• Peptide therapy trend: Growing interest in peptides for anti-aging, performance, and wellness

Online communities continue to share information, experiences, and sources, creating a parallel knowledge ecosystem outside traditional medical channels. This creates both benefits (harm reduction information, quality testing initiatives) and risks (normalization of unregulated drug use, misinformation).

Research Developments

While MT-II itself is not being developed by pharmaceutical companies, research on melanocortin receptor agonists continues:

• Setmelanotide: MC4R-selective agonist approved for genetic obesity (2020)
• New analogs: Research into melanocortin agonists with improved selectivity and safety
• Combination therapies: Exploring melanocortin agonists combined with other weight loss or sexual dysfunction treatments
• Melanoma research: Investigating whether melanocortin receptor activation affects cancer risk

These developments may eventually lead to safer, regulated alternatives to MT-II for its various applications, though such products would likely be expensive and require prescriptions.

Future Possibilities

Several scenarios could change MT-II's status:

Increased regulation: Stricter enforcement, scheduling as controlled substance, or international cooperation to reduce availability

Pharmaceutical development: New company acquiring rights and pursuing FDA approval for specific indication (unlikely given bremelanotide's limited success)

Alternative technologies: Development of safer tanning methods (topical melanocortin agonists, genetic approaches) or better sexual dysfunction treatments reducing MT-II demand

Long-term safety data: If serious adverse events (particularly melanoma) emerge in long-term users, could dramatically reduce use

Normalization: Continued underground use becoming more accepted, similar to other research chemicals and performance-enhancing drugs