Melanotan: An Unhealthy Glow? Rebekah Brennan Prof. John S.G Wells Dr. Marie Claire Van Hout Melanotan: An Unhealthy Glow? What is currently known on tanning peptide melanotan use and associated clinical outcomes

Background A range of image and performance enhancing drugs (IPED) are now available, to include enhancement of muscle, skin tone, facial features and to boost longevity Amongst these are tanning injectables, of which three main formulations, Melanotan I (afamelanotide), Melanotan II, and bremelanotide exist These agents are synthetic analogues of the endogenous melanocortin peptide hormone alpha- melanocyte stimulating hormone (α-MSH) These analogues were first synthesised in the 1980s for photo protective effects Synthetic analogues of α-MSH are not illegal to use, possess or import, but domestic sale and supply outside of clinical trials is legislated in the UK and other countries. The image and performance enhancement drug (IPED) market has become increasingly accessible through online sellers Of concern is that these products sold to the public are unregulated and untested, sold without prescription, potentially contaminated, counterfeit and with contents unverified

Identified Concerns Sourcing of melanotan largely occurs through web retailing by unregulated vendors (Evans Brown et al, 2012). Very little is known around long term outcomes of use (Mahiques-Santos, 2012) Online normalisation of unsupervised use and self-experimentation (Van Hout, 2014) supports the adaptation of risk behaviours

User Profiling Clinical case report literature describes both male and female use. Use of melanotan by bodybuilding or weighttraining males was reported in three case reports (Schulze et al.2012, Cardones & Grichnik, 2009, Shelly, Husain & Lawrence, 2009). This is further evidenced by melanotan use in AAS users accessing needle exchange services (Chandler & McVeigh, 2013, Hope et al.2013). Body dysmorphia has been indicated as a possible motivator for melanotan use, particularly in users of AAS who may have muscle dysmorphia (Affleck, 2010)

Motivators for Use Studies on melanotan users also describe motivation for use as grounded in appearance. An internet study of forum posts found descriptions of desired side effects listing benefits such as being slimmer, enhanced eye colour and clearing skin with acne (Van Hout 2014). The surveyed site was found to contain messages such as “melanotan will make you tan, slim and hot” Appearance enhancement was also described as increased occupational functioning in a case study, as the case described melanotan as more effective than topical tanners when working as a dancer under hot lights (Van Hout & Brennan, 2013)

Patterns of Use – empirical research Polypharming A single case study of an exotic dancer using melanotan found that the case used benzodiazepines to induce sleep once she had taken melanotan, in order to avoid experiencing the nauseous feeling that followed injection (Van Hout & Brennan, 2013). In Van Hout’s internet study (2014) melanotan users also disclosed smoking marijuana to combat feelings of nausea

Patterns of Use – empirical research Injecting Behaviours Melanotan injection technique is described in Van Hout’s (2014) study of internet forum melanotanforum.org, Subcutaneous injection in the abdominal region Darting, using a short needle, pinching the skin and angling the needle advised. Site rotation common in order to avoid track marks, swelling and scar tissue. High level harm reduction awareness amongst users to include sterile needle use and correct storage of product. Dependence Participant disclosures which indicate possible dependence have been reported in melanotan users (Van Hout, 2014, Brennan & Van Hout, 2013)

Patterns of use - clinical case presentations Findings from Brennan, Wells & Van Hout (2015) No information on injecting risk behaviours Polypharming with AAS (Shelley et al, 2012) ecstasy(Kaski et al, 2010) alcohol use (Kjaergaard& Dalhoff, 2009) and “pain pill” (Nelson, Bryant & Aks, 2012) Out of 21 clinical case presentations reviewed, 11 reported concurrent use of solariums. The remainder did not specify whether use of solariums had occurred or not Patients sourced melanotan online and from ‘cosmetic physicians’ Melanotan II most common product used Varying dosages with some patients administering far more than what is recommended (Nelson, Bryant & Aks, 2012; Devlin & Pomerleau, 2012)

Clinical Trial Results Phase I, II and III clinical trials have found several potential benefits of afamelanotide to include treatment of a range of skin conditions, carcinoma (Harms et al, 2009) and improved sexual functioning (Dorr et al, 2000; Hadley & Dorr, 2006) Side effects observed in clinical trials are largely minor, and include nausea, facial flushing, darkening of existing naevi, penile erection, gastrointestinal upset, yawning, stretching and fatigue (Haylett et al 2011; Barnetson et al, 2006; Harms et al, 2009).

Ongoing Clinical Trials Afamelanotide has undergone and continues to undergo clinical trials for the treatment of skin conditions such as erythropoietic protoporphyria (Biolcati et al, 2014; Harms et al, 2009) Hailey-Hailey disease (Biolcati et al, 2013) solar urticarial (Haylett et al, 2011) . No serious harms were noted in these clinical side effects have ever been noted in subjects in these trials, with one recent trial conducted over a period of eight years (Biolcati et al, 2014).

Clinical Outcomes – Clinical Trials & Clinical Case Presentations Desirable Skin tanning Enhanced appearance of muscle Sexual functioning? Minor patchy pigmentation of skin and nails Nausea Fatigue Headache

Clinical Outcomes – Clinical Trials & Clinical Case Presentations Chronic eruptive new naevi darkening/enlargement of existing naevi Melanoma Acute clonic seizure systemic toxicity or toxidrome refractory priapism Haematoma heart palpitations Hyperventilation dizziness and abdominal pain

Limitations of Clinical Case Presentations Findings are limited to melanotan users who presented to health services for treatment. Many of the wider population of Melanotan users may be experiencing additional effects currently undocumented Unknown and potentially complicating factors which hinder determinations of causality Shortcomings in reporting : - incomplete drug use histories, where dosages and cycles of Melanotan use are not well described -unclear whether product was Melanotan I or II -polypharming with other substances is not accounted for -whether the patient had used sunbeds was not described. - no sourcing route disclosed -no vial produced for analysis (Brennan, Wells & Van Hout, 2015)

Internet Sourcing Forum posts analysed by Van Hout (2014) indicated that melanotan users largely trusted their sources, and that this trust is built through recommendation swapping in discussion forums User attitudes towards the risks associated with purchasing potentially contaminated products online have seldom been studied. In one single case study, the case reported no concerns about potential contamination despite having some knowledge of the dangers (Van Hout & Brennan, 2013). Previous studies have evidenced incidences of mislabelling, understrength vial contents and presence of contaminants in IPED products purchased from websites (Breindahl et al.2014, Kimergard et al.2014). One identified concern is the online availability of a “peptide calculator” for melanotan users (Van Hout, 2014) where the user calculates their own doses. The potential for overdose has been indicated in a single clinical case report of systemic toxicity where the user self-administered six times the recommended dose (Nelson, Bryant & Aks, 2012).

Clinical Studies on Melanotan Products Sourced Online In one case, a user purchased what was sold as growth hormone and was found to be melanotan II (Kimergard et al, 2014) Breindahl et al (2014) study was the first attempt to quantitatively analyse the contents of melanotan vials online. Findings indicated that the majority of vials were understrength and contained impurities, although the study did not determine the characteristics of these impurities. It is clear from the findings of both these studies that the potential for harms associated with mislabeling of melanotan products, contamination and counterfeiting is significant.

Injecting Risk Traditionally, IPED injectors were seen as a group less likely to share needles, and to be less susceptible to bloodborne viruses (BBV). Of public health concern is a recent study which found HIV prevalence amongst IPED injectors to be equivalent to that found amongst opiate and psychoactive stimulant injectors (Hope et al., 2013). This is the first unequivocal evidence of blood borne viruses (BBV) within IPED injectors.

RESEARCH AGENDA There is notable contrast between what is documented on melanotan use in the scientific literature and what information is available online in discussion forums and internet sites Future work is needed to examine use of melanotan in bodybuilding cohorts and users of other IPED and should utilise online discussion fora as a research setting Body dysmorphics have also been indicated as at risk for pathological use. There is a lack of research on body image disorder in melanotan users No studies to identify vendor websites have been conducted for melanotan Observational studies to track health outcomes in melanotan users are needed as well as enhanced clinical responses

References Affleck, A. (2010) Consider underlying body dysmorphia in users of melanotan, British Journal of Dermatology, 162(2), 452-268 Barnetson, R.S., Ooi, T.K.T., Zhuang, L., Halliday, G.M., Reid, C.M., Walker, P.C., Humphrey, S.M., et al. (2006). [Nle4-D- Phe7]-alpha-melanocyte stimulating hormonesignificantly increased pigmentation and decreased UV damage in fair-skinned Caucasian volunteers. The Journal of Investigative Dermatology, 126(8), 1869-78. Brennan, R., Van Hout, M.C., & 498 Wells, J. (2013). Heuristics of Human Enhancement Risk: A little chemical help? International Journal of Health Promotion and Education. 51(4), 317–500 Brennan, R. Wells, J., & Van Hout, M.C (2015) An unhealthy glow? A review of melanotan use and associated clinical outcomes, Performance Enhancement & Health, 3 (2), 78-92 Breindahl, T., Evans-Brown, M., Hindersson, P., McVeigh, J., Bellis, M., Stensballe, A., et al. (2015). Identification and characterization by LC-UVMS/2014 MS of Melanotan II skin tanning products sold illegally on the Internet. Drug Testing and Analysis , 7(2), 164-172 Devlin, J.J., & Pomerleau, A.C .(2013). Melanotan II overdose associated with priapism, Clinical Toxicology, 51(4), 383 Dorr, R.T., Dvorakova, K., Brooks, C., Lines, R., Levine, N., Schram, K., et al. (2000). Increased eumelanin expression and tanning is induced by a super potent melanotropin [[Nle4516 ,D-Phe7517 ]-α-MSH in humans, Photochemistry and Photobiology 72 (4),526–32 Evans-Brown, M., Dawson, R.T., Chandler, M., & McVeigh, J. (2009). Use of Melanotan I and II in the General Population. British Medical Journal, 338, b566.

References Evans-Brown, M., McVeigh, J., Perkins, C., & Bellis, M.A. (2012). Human enhancement drugs: The emerging challenges to public health. Liverpool: Public Health Observatories in England. Hadley, M.E., & Dorr, D.T. (2006) Melanocortin Peptide Therapeutics: Historical Milestones. Clinical Studies and Commercialization. Peptides, 27(4), 921–930. Harms, J. , Lautenshlager, S., Minder, C. E & Minder, E. I .(2009). An α-Melanocyte– Stimulating Hormone Analogue in Erythropoietic Protoporphyria. New England Journal of Medicine, 360(3), 306–307 Haylett, A.K., Nie, Z., Brownrigg, M., Taylor, R & Rhodes, L.E .(2011). Systemic photo protection in solar urticaria with α-melanocyte-stimulating hormone analogue [Nle4563 -d-Phe7564 ]-α-MSH, British Journal of Dermatology, 164(2), 407-414. Kjærgaard, C.T & Dalhoff , K .(2010). Melanotan - a Skin-tanning Product with Potentially Harmful Effects. A Case Series, Clinical Toxicology, 48, 3 Kaski, D., Stafford, N., Mehta, A., Jenkins, I.H., & Malhotra, P. (2013). Melanotan and the posterior reversible encephalopathy syndrome. Annals of Internal Medicine, 158(9), 707-708

References Kimergård, A., McVeigh, J., Knutsson, S., Breindahl, T., & Stensballe, A. (2014). Online marketing of synthetic peptide hormones: poor manufacturing, user safety, and challenges to public health. Drug Testing and Analysis, 6(4), 396-398 Mahiques-Santos, L. (2012). Melanotan. Actas Dermo-Sifiliograficas, 103 (4), 257-259. Mataix, J. (2012). Cult of the Body Beautiful: At What Cost? Culto al cuerpo: ¿ cuáles el precio de la belleza? Actas Dermo-Sifiliograficas, 103(8), 655-660. Nelson, M. E., Bryant, S. M & Aks, S. E. (2012). Melanotan II injection resulting in systemic toxicity and rhabdomyolysis. Clinical Toxicology, 50(10), 1169–1173. Shelley, J., Husain, A & Lawrence, C.A. (2009). Helios meets Priapus: Melanotan II-induced eruptive naevi and generalized hyperpigmentation, British Journal of Dermatology, 161(1),13–20 Van Hout, M.C., & Brennan, R. (2013). An in-depth case examination of an exotic dancer's experience of Melanotan. The International Journal on Drug policy. 25(3), 444-450. Van Hout, M.C. (2014). SMART: an Internet study of 685 users experiences of synthetic tanning. Performance Enhancement and Health. 3(1), 3-14