Melanotan II was invented at the University of Arizona Cancer Center in an effort to develop an “internal sunscreen” to prevent UV radiation-induced damage, which is a growing problem especially in the American Southwest. It was immediately clear that MT2 supplementation induced a long-lasting tan response in human volunteers, thus fulfilling its initial goal. Intriguingly, a series of unexpected findings have led to an incredibly broad profile of physiological effects which has encouraged ongoing preclinical research that spans different fields of biology.
Despite the current lack of clinical progress, an enormous number of people have taken MT2 during clinical trials and in parallel with academic studies. In a recent observational survey conducted by the Boston Medical Center, over 93% of respondents who have taken MT2 reported a desire to continue using it .
It is essential to address the side effect profile of MT2, which is especially relevant when MT2 is dosed improperly. Research participants are advised that there is a lag time to developing a tan, and impatience amongst participants can lead to increased incidence of side effects when dose limits are not respected. In very rare cases, MT2 overdose has been shown to cause adverse reactions, so care should be taken in designing research studies to strictly limit doses to avoid such outcomes. However, such findings are detailed in case reports, which are not controlled studies, thus limiting the ability to draw conclusions about causation.
On the other hand, more recent research from controlled studies have shown promising results for a number of new potential indications. For instance, the Institute for Biomedical Science in Taiwan demonstrates that MT2 can actually prevent the spread of melanoma, the deadliest type of skin cancer, using well-established preclinical models .
Excitingly, MT2 has now been verified to be bioavailable by nasal spray administration, so injection is no longer necessary.
PubChem CID: 92432
Main Research Findings for MT2 (controlled studies):
Inducing melanin production for UV protection and preventing photoaging –
Suppressing melanoma spread 
Reversing autistic features 
Increasing libido in men and women –
Suppressing appetite and reducing body mass –
Selected Preclinical Data
“Activation of the central melanocortin system chronically reduces body mass without the necessity of long-term caloric restriction”
“Topical MTII Therapy Suppresses Melanoma Through PTEN Upregulation and Cyclooxygenase II Inhibition”
“Melanocortin receptor agonists in the treatment of male and female sexual dysfunctions: results from basic research and clinical studies”
Melanotan II (MT2) is a potent appetite suppressor that rapidly reduces body mass. MTII causes an immediate decrease in food intake, which last for 2-5 days, which then reverts to normal. However, despite appetite normalizing, body weight remains lower on average. As of yet, most investigations have focused only on the initial physiological adaptations that occur in the first 5 days. However, since other evidence supports MT2 as a long-term modulator of energy balance, this evidence needs to be further explored and quantified. Therefore, researchers examined the chronic effects of MT2on energy homeostasis. MT2 (high or low dose) or artificial cerebrospinal fluid (aCSF) was infused into the lateral ventricle of the brain of 6-month-old rats (6–7/group) over 40 days. MT2 suppressed appetite in a dose-dependent manner. Although food intake promptly rose back to control level, body mass was persistently reduced in both MT2 groups. At day 40, both MTII groups displayed lower adiposity (ie. fatty tissue) than the aCSF control animals. These results show that MT2 chronically reduces body mass without the requirement of long-term caloric restriction.This study proposes that food restriction helps initiate mass loss; however, combined with MT2 preserving a negative energy balance state over time may help combat obesity.
The central melanocortin system is a critical regulator of energy homeostasis . Pharmacological and genetic studies have revealed crucial roles for the central melanocortin pathway in the regulation of hunger and energy expenditure . The optimal function of the central melanocortin system requires 2 receptors expressed in the brain: the melanocortin receptors 3 and 4 (MC3/4 receptors) which are both targeted by MT2. These receptors modulate the activity of a broad neural network regulating appetite along with numerous metabolic pathways, including thermogenesis (heat production) and lipolysis (fat burning) . The α-melanocyte-stimulating hormone (α-MSH) is the natural activator for the MC3/4 receptors. Given the very short half-life of α-MSH (~10 min), more stable synthetic peptides have been invented to clarify the biological roles of MC3/4 receptor signaling. One of the best suitable analogs is melanotan II (MT2), a nonselective agonist of MC receptors. Intriguingly, MT2 reduces body mass and robustly suppresses appetite . Indeed, central administration of MT2 induces a 30% to 50% reduction in food intake, considered a primary mechanism of MT2-induced body mass loss.
Fig. 1. Food intake is greatly decreased only in the first week of MT2 supplementation, yet the decrease in body mass is maintained long-term. aCSF is the control group that did not receive MT2. Adapted from Cote et al. Activation of the central melanocortin system chronically reduces body mass without the necessity of long-term caloric restriction. Can J Physiol Pharmacol. 2017 Feb; 95(2): 206–214
Fig. 2. Decreases in voluntary food intake in MT2 treated animals is more pronounced in older vs younger individuals. Adapted from Zhang et al. Aged-obese rats exhibit robust responses to a melanocortin agonist and antagonist despite leptin resistance. Neurobiology of Aging (2004) pp1349–1360.
Fig. 3. MT2 supplementation increases oxygen consumption, in both young and old individuals, which is part of the mechanism for weight loss coming from “burning calories”. Adapted from Zhang et al. Aged-obese rats exhibit robust responses to a melanocortin agonist and antagonist despite leptin resistance. Neurobiology of Aging (2004) pp1349–1360.
Currently, more than two-thirds of Americans are overweight with a body mass index (BMI) > 25, of which half are considered obese (BMI > 30). Because of obesity-associated health issues and morbidity, novel strategies to treat or prevent obesity have become a high priority. Feeding restriction is one of the most commonly employed methods to generate a negative energy balance and achieve body mass loss. However, more than 75% of the dieters regain their initial body mass within 5 years . Therefore, alternative approaches to caloric restriction are attractive strategies to combat obesity. From this perspective, these studies uncovered the role of the melanocortin system for long-term body mass loss without the necessity of chronic caloric restriction. The authors found MT2 transiently affects food intake yet also supports long-term body mass loss. It is also very interesting that older individuals seemed to benefit more than younger individuals when it comes to decreasing food intake (Fig 2). Additionally, this was reflected in oxygen consumption, which partially explains the maintenance of weight loss over the long-term.
From a clinical point of view, these studies suggests that caloric restriction effectively initiates body mass loss despite normalization of food intake; however, a combination with secondary actions that preserve a negative energy balance state over time, such as targeting melanocortin receptors with MT2, may be a valuable tool to combat obesity. Given the complexity of targeting neural receptors, future studies need to examine whether long-term peripheral administration of MT2, a more translational approach for humans, will yield similar physiological responses. Additional experiments could also assess whether intermittent peripheral administration may extend MT2 efficacy over a longer period of time.
Melanotan II (MTII or MT2), a synthetic analogue of the alpha-melanocyte stimulating hormone (α-MSH), has been applied for skin tanning in humans. However, the carcinogenic consequence of topical MT2 has been equivocal. This study aims to delineate the anti-neoplastic efficacy and mechanism of MT2 using the B16-F10 melanoma model in vitro and in vivo. It was found that, despite a lack of influence on proliferation, MT2 potently inhibited the migration and invasion of melanoma cells.Moreover, topical MT2 application significantly reduced tumor progression in mice bearing established melanoma. Histological analysis revealed that MT2 therapy induced tumor cell death while inhibiting neovascularization (ie. new blood vessel formation) in melanoma tissues. Consistently, MT2 treatment inhibited COX-2 and PGE2 production in melanoma cells, thus demonstrating a decrease in inflammation. Together, these results indicate that MT2 suppressing melanoma progression through downregulating inflammatory COX-2/PGE2 signaling. Hence, MT2 therapy may facilitate a novel therapeutic strategy against melanoma.
Fig 1. MT2 reduces the growth of melanoma tumors. Adapted from Wu et al. Topical MTII Therapy Suppresses Melanoma Through PTEN Upregulation and Cyclooxygenase II Inhibition. International Journal of Molecular Science. 2020 Jan; 21(2): 681.
Fig 2. MT2 does not influence cell viability (panel A), yet it does reduce cell migration into a gap which is located between the red lines (panel B). MT2 also reduces 3D invasion of melanoma cells as determined by staining for cells that can pass through tiny pores in a membrane and then be stained purple to visualize them (panel D). Lastly, MT2 reduces colony forming ability of melanoma cells (panel E).Adapted from Wu et al. Topical MTII Therapy Suppresses Melanoma Through PTEN Upregulation and Cyclooxygenase II Inhibition. International Journal of Molecular Science. 2020 Jan; 21(2): 681.
Melanoma is a frequently diagnosed skin cancer, with an estimated 91,270 new cases in the United States in 2018 . Early stage melanoma is usually curable by surgical resection and radiotherapy, with a five-year survival rate around 90%. However, once developed into malignant melanoma that spreads, the prognosis becomes poor, so that the five-year survival rate drops to only 17% .
Cyclooxygenases (COXs) are a family of enzymes that catalyze the rate-limiting step in the conversion of arachidonic acid to prostaglandins which are crucial for inflammation reactions. COX-2 is frequently responsible for promoting various tumors including malignant melanomas and its level is correlated with poor prognosis and tumor progression . Prostaglandin E2 (PGE2) is one of the major products of COX-2, which is known to modulate cell proliferation, cell death, and cell migration in many types of tumors. A growing body of evidence reveals that COX-2 inhibition is efficient to elicit the inhibition of proliferation, migration, and invasiveness of melanoma cells Previous studies have demonstrated that the precursor of alpha-melanocyte stimulating hormone (α-MSH) can effectively suppresses the progression and metastasis of melanoma though the inhibition of COX-2/PGE2 signaling. Thus, researchers wanted to know if MT2 could perform the same way and suppress melanoma.
Chronic inflammation is a key component in the progression of tumors. This is in line with the present study which shows that MT2 reduced melanoma progression through COX-2 reduction and PGE2 reduction in melanoma cells as well as in melanoma tissues. Furthermore, the application of COX-2 inhibitor celecoxib is capable of affecting immune signaling in human melanoma cell lines. Therefore, the COX-2-modulating function of MT2 implicates its potential to serve in combination with immunotherapy for the control of advanced melanoma.
In summary, MT2 exhibits beneficial effects against melanoma in vitro and in vivo. The anti-cancer mechanism of MT2 is clearly detailed through the activation of melanocortin signaling and the subsequent inhibition of the cancer promoting inflammatory gene COX-2. Hence, MT2 may serve as a novel therapeutic adjuvant for the control of malignant melanoma.
Sexual activity is an essential component of both male and female general health and well-being. According to epidemiological surveys conducted in westernized countries, disorders of sexual function are extremely common in the population of all ages and ethnicities and are associated with a significant burden of the illness and a poor quality of life. Among these dysfunctions, male erectile dysfunction (ED) as well as female arousal and orgasmic disorders are the most common afflictions presented for treatment –
Melanocortin receptor activators in male erectile dysfunction
The efficacy and safety of the synthetic peptides MT2 and PT-141 in the treatment of male ED have been investigated in a few clinical settings with enrolment of large variations in total numbers of subjects (10 - 342), presenting with different underlying causes of their ED. In a small study of 10 patients with psychological ED, subcutaneous injection of the peptide in stomach fat (0.025 mg/kg body weight) led to clinically significant erections in 8 men with regard to penile rigidity and the duration of erection, as assessed by real-time RigiScan monitoring during a 6 h time period. Average duration of rigidity of the tip of the penis greater than 80% was 38 min following supplementation with MT2 versus merely 3 min with placebo. The most frequent side effects reported were yawning and decreased appetite .
These findings were later confirmed in a double-blind, placebo-controlled crossover study. Administration of MT2 to 20 men with ED resulted in penile erection in 17 of the 20 men in the absence of visual sexual stimulation. The initiation of erections without sexual stimulation distinguishes the mechanism of action of MT2 compared to Cialis or Viagra which both require sexual stimulation in order to be effective. Eighty percent (80%) of the subjects reached tip rigidity within 41 min. The level of sexual desire was also assessed in the patients and an increase was reported in 68% of the subjects (versus 19% in the placebo group). It should be noted that, at a dose of 0.025 mg/kg MT2, 13% experienced nausea .
Melanotan II and Bremelanotide (PT-141) are over 99% identical and they activate the same receptors in the brain responsible for sexual arousal in both men and women. The difference is that Bremelanotide does not activate the receptor variant that causes skin tanning.
Melanocortin receptor activators in female sexual arousal
According to the clinical studies conducted in the field of ED, bremelanotide (PT-141) has also been evaluated for its effects on the physiological and subjective measurements of sexual arousal and desire in women with sexual arousal disorders. Such disorders affect an estimated 30% of women in North America and Europe, with etiologies based on several factors such as psychological/personal/interpersonal and physiological causes. In contrast to trials conducted in male patients with ED, bremelanotide is the only agent that has been investigated clinically in females. In a double-blind, placebo-controlled Phase II setting enrolling 18 premenopausal women (22 - 44 years) with sexual arousal deficiency, the intranasal administration of PT-141 resulted in an enhancement in sexual desire while viewing sexually explicit video sequences. A trend toward more enhanced feelings of genital arousal was also registered. Among those women who attempted sexual intercourse within 24 h after intake of the drug, significantly more females reported satisfaction with their level of sexual arousal in comparison to placebo. These preliminary observations indicated that the drug would be a promising candidate for further clinical evaluation .
Another study in 2008 evaluated the efficacy of PT-141 in adult women with female sexual arousal disorder (FSAD). A total of 80 women (married, average age 31 years) were randomly assigned to receive either bremelanotide as an intranasal spray or a similar regimen of placebo on an as required basis 45 - 60 min before attempting sexual intercourse. The efficacy of the treatments was assessed after every fourth intercourse attempt and at the very end of the study protocol, using the Female Sexual Function Index (FSFI) and total number of sexual events and orgasms. At the end of the treatment, the average arousal score in the PT-141 group showed a greater increase compared to placebo. In addition, women in the PT-141 group reported significantly greater intercourse satisfaction than those who had received the placebo regimen. In conclusion, the drug was proved effective and well tolerated in adult women 
MT2 has enormous clinical potential for a variety of indications aside from its proven ability to cause tanning to prevent UV damage, as it has already informed a high volume of preclinical data that has improved our understanding of melanocortin receptor biology. This is especially true considering the capacity of MT2 to reduce body weight and suppress appetite. More recent discoveries such as the ability of MT2 to reduce autism features, as well as preventing the spread of melanoma, are sure to energize further efforts at clinical translation. However, it is essential to note that there are a handful of case reports detailing that MT2 overdoses (much higher than is proven safe) are linked to adverse reactions. Thus, it is essential that researchers limit MT2 doses to 0.5 mg per day or less in order to avoid adverse reactions.
This information is for educational purposes only. THE PRODUCTS DESCRIBED HEREIN ARE FOR RESEARCH USE ONLY. All clinical research must be conducted with oversight from the appropriate Institutional Review Board (IRB). All preclinical research must be conducted with oversight from the appropriate Institutional Animal Care and Use Committee (IACUC) following the guidelines of the Animal Welfare Act (AWA).
 D. J. Callaghan Iii, “A glimpse into the underground market of melanotan,” Dermatol. Online J., 2018.
 J. C. Wu, H. E. Tsai, Y. H. Hsiao, J. S. Wu, C. S. Wu, and M. H. Tai, “Topical MTII therapy suppresses melanoma through PTEN upregulation and cyclooxygenase II inhibition,” Int. J. Mol. Sci., 2020.
 H. Chen, Q. Y. Weng, and D. E. Fisher, “UV signaling pathways within the skin,” Journal of Investigative Dermatology. 2014.
 N. G. Jablonski and G. Chaplin, “Human skin pigmentation as an adaptation to UV radiation,” Proc. Natl. Acad. Sci. U. S. A., 2010.
 M. Yaar and B. A. Gilchrest, “Photoageing: Mechanism, prevention and therapy,” British Journal of Dermatology. 2007.
 J. M. Jeter et al., “Chemoprevention agents for melanoma: A path forward into phase 3 clinical trials,” Cancer. 2019.
 E. Minakova et al., “Melanotan-II reverses autistic features in a maternal immune activation mouse model of autism,” PLoS One, 2019.
 F. Giuliano, P. Clément, S. Droupy, L. Alexandre, and J. Bernabé, “Melanotan-II: Investigation of the inducer and facilitator effects on penile erection in anaesthetized rat,” Neuroscience, 2006.
 M. E. Hadley, “Discovery that a melanocortin regulates sexual functions in male and female humans,” Peptides. 2005.
 Trevor J. Hallam, Carl Spana, Dennis C. Earle, Annette M. Shadiack, and Shubh D. Sharma, “Melanocortins in the Treatment of Male and Female Sexual Dysfunction,” Curr. Top. Med. Chem., 2007.
 S. Ückert, A. Bannowsky, K. Albrecht, and M. A. Kuczyk, “Melanocortin receptor agonists in the treatment of male and female sexual dysfunctions: Results from basic research and clinical studies,” Expert Opinion on Investigational Drugs. 2014.
 G. M. Sutton, B. Duos, L. M. Patterson, and H. R. Berthoud, “Melanocortinergic modulation of cholecystokinin-induced suppression of feeding through ERK signaling in rat solitary nucleus,” Endocrinology, 2005.
 E. Keen-Rhinehart and T. J. Bartness, “MTII attenuates ghrelin- and food deprivation-induced increases in food hoarding and food intake,” Horm. Behav., 2007.
 S. Boghossian, M. Park, and D. A. York, “Melanocortin activity in the amygdala controls appetite for dietary fat,” Am. J. Physiol. - Regul. Integr. Comp. Physiol., 2010.
 C. A. Campos and R. C. Ritter, “Nmda-type glutamate receptors participate in reduction of food intake following hindbrain melanocortin receptor activation,” Am. J. Physiol. - Regul. Integr. Comp. Physiol., 2015.
 H. R. Berthoud, G. M. Sutton, R. L. Townsend, L. M. Patterson, and H. Zheng, “Brainstem mechanisms integrating gut-derived satiety signals and descending forebrain information in the control of meal size,” Physiol. Behav., 2006.
 S. M. Luckman, “Brainstem-hypothalamic neuropeptides and the regulation of feeding,” in Appetite and Body Weight, 2007.
 I. Côté et al., “Activation of the central melanocortin system chronically reduces body mass without the necessity of long-term caloric restriction,” Can. J. Physiol. Pharmacol., 2017.
 A. A. Butler and R. D. Cone, “The melanocortin receptors: Lessons from knockout models,” Neuropeptides, 2002.
 A. A. Butler, “The melanocortin system and energy balance,” Peptides. 2006.
 B. Monge-Roffarello et al., “The medial preoptic nucleus as a site of the thermogenic and metabolic actions of melanotan II in male rats,” Am. J. Physiol. - Regul. Integr. Comp. Physiol., 2014.
 D. D. Pierroz, M. Ziotopoulou, L. Ungsunan, S. Moschos, J. S. Flier, and C. S. Mantzoros, “Effects of acute and chronic administration of the melanocortin agonist MTII in mice with diet-induced obesity,” Diabetes, 2002.
 J. W. Anderson, E. C. Konz, R. C. Frederich, and C. L. Wood, “Long-term weight-loss maintenance: A meta-analysis of US studies,” Am. J. Clin. Nutr., 2001.
 R. L. Siegel, K. D. Miller, and A. Jemal, “Cancer statistics, 2018,” CA. Cancer J. Clin., 2018.
 Q. Liu, M. Das, Y. Liu, and L. Huang, “Targeted drug delivery to melanoma,” Advanced Drug Delivery Reviews. 2018.
 C. Lee, J. A. Ramirez, J. Guitart, and L. K. Diaz, “Expression of cyclooxygenase-2 and peroxisome proliferator-activated receptor gamma during malignant melanoma progression,” J. Cutan. Pathol., 2008.
 R. Basson, M. E. Wierman, J. van Lankveld, and L. Brotto, “Summary of the recommendations on sexual dysfunctions in women,” J. Sex. Med., 2010.
 F. Montorsi et al., “Summary of the recommendations on sexual dysfunctions in men,” J. Sex. Med., 2010.
 D. Hatzichristou et al., “Recommendations for the clinical evaluation of men and women with sexual dysfunction,” J. Sex. Med., 2010.
 D. Hatzichristou et al., “Diagnosing Sexual Dysfunction in Men and Women: Sexual History Taking and the Role of Symptom Scales and Questionnaires,” J. Sex. Med., 2016.
 H. Wessells et al., “Synthetic melanotropic peptide initiates erections in men with psychogenic erectile dysfunction: Double-blind, placebo controlled crossover study,” J. Urol., 1998.
 H. Wessells, N. Levine, M. E. Hadley, R. Dorr, and V. Hruby, “Melanocortin receptor agonists, penile erection, and sexual motivation: Human studies with Melanotan II,” Int. J. Impot. Res., 2000.
 L. E. Diamond, D. C. Earle, J. R. Heiman, R. C. Rosen, M. A. Perelman, and R. Harning, “An effect on the subjective sexual response in premenopausal women with sexual arousal disorder by Bremelanotide (PT-141), a melanocortin receptor agonist,” J. Sex. Med., 2006.
 M. R. Safarinejad, “Evaluation of the safety and efficacy of bremelanotide, a melanocortin receptor agonist, in female subjects with arousal disorder: A double-blind placebo-controlled, fixed dose, randomized study,” J. Sex. Med., 2008.
*The information herein is for educational and informational purposes only. THIS PRODUCT IS FOR RESEARCH USE ONLY. For use in animal studies, all research must be conducted with oversight from the appropriate Institutional Animal Care and Use Committee (IACUC) following the guidelines of the Animal Welfare Act (AWA).
Storage: Lyophilized peptide should be stored at -20°C (freezer), and the reconstituted peptide solution at 4°C (refrigerated). Use within 24 months. Once reconstituted use within 30 days. Do not freeze once reconstituted.