Drug Testing and Analysis

Correspondence letter Received: 7 January 2014

Revised: 13 February 2014

Accepted: 14 February 2014

Published online in Wiley Online Library: 17 March 2014

(www.drugtestinganalysis.com) DOI 10.1002/dta.1636

Online marketing of synthetic peptide hormones: poor manufacturing, user safety, and challenges to public health To the Editor An increasing range of drugs that are being used to enhance the body have recently become available on the illicit market. Many of these products contain pharmacologically active substances that are untested or banned (after being licensed as a medicinal product) and they are widely subject to adulteration and misbranding.[1] While the existence of illicitly manufactured drugs containing anabolic steroids as the active substance has been known for decades,[2] new generation drugs for human enhancement include fibroblast growth factor 1,[3] mechano growth factor analogues,[4] and His-tagged Long-R3-IGF-I.[5] Forensic analysis of drugs seized by Norwegian law enforcement revealed the presence of the synthetic growth hormone secretagogue CJC-1295,[6] whereas analysis of drugs seized in Italy identified the synthetic growth-hormone-releasing peptide GHRP-2 as the active substance.[7] In addition, GHRP-2 has also been found in a product sold as a ‘nutritional supplement’.[8] Notable amongst novel drugs on the illicit market are the synthetic peptide hormones GHRP-6, taken to stimulate the secretion of natural growth hormone, as well as melanotan II, a synthetic analogue of the endogenous α-melanocyte stimulating hormone (α-MSH) which is predominantly used to achieve a skin tan.[6,9–11] Both of these drugs have wide appeal for those who want to enhance their physical performance and improve body satisfaction. Synthetic peptide hormones like GHRP-6 and melanotan II can supposedly be bought from traditional ‘street dealers’ or specific venues associated with a particular lifestyle or behaviour; for example, muscular enhancement drugs (GHRP-6) from a gym or skin darkening drugs (melanotan II) from a tanning salon.[1] These drugs also appear to be traded from unauthorized shops on the Internet offering at least some anonymity to consumers as well as protecting illicit suppliers from regulatory agencies. This is one of the barriers to obtaining a clear picture of what specific types of enhancement drugs are available online, along with their composition and quality.

Poor-quality drugs from online shops

396

Members of our research group were recently approached by an individual who said that he was using (enhancement) drugs while undertaking weight training in a ‘hardcore’ bodybuilding gym. He claimed he had bought a product purported to contain GHRP-6 from an Internet shop, and had it shipped to an address in Denmark. He was taking GHRP-6 because of its claimed

Drug Test. Analysis 2014, 6, 396–398

effects on the stimulation of growth hormone release in the body, which he believed would lower his body fat, reduce recovery time between workouts, decrease healing time after injury, and enhance the size and strength of his muscles. The user stated he had injected the substance for a period of time without experiencing any notable effects. He admitted to doubling his dosage in order to achieve results, but noticed that his skin colour started to get darker and ended his injections. He agreed to give us the vial. The contents of the vial were analyzed using a reference standard and liquid chromatographic-tandem mass spectrometry (LC-MS/MS). Although the vial was labelled ‘GHRP-6 (RECEPTOR)’ (Figure 1), we found that the product contained melanotan II as the only pharmacologically active substance (Supporting Information). This case illustrates the potential defects in drugs manufactured outside the scope of the formal regulation, bypassing production standards of licensed medicinal products that ensure their quality, safety, and efficacy. Given that adulteration and misbranding of illicit market drugs are commonplace, users of such products will often remain unaware of the active substance(s) in the drugs they have acquired, along with the amount of active substance and sterility of these compounds, exposing them to significant health risks.

The unauthorized use of synthetic peptide hormones Non-clinical and clinical testing have demonstrated that GHRP-6 increases peak levels of natural growth hormone.[12] This endogenous hormone, which is released in a pulsatile pattern from the anterior pituitary gland, binds to receptors in tissue throughout the body and is involved in the regulation of growth, fat metabolism, and physical performance.[13] Although GHRP-6 has not been granted a license for clinical use in Denmark, at the time of writing a simple Internet search – entering search terms like ‘buy GHRP-6’ or ‘buy peptides’ into Google – revealed a number of shops offering to ship products that claimed to contain GHRP-6 to users in Denmark. Data on GHRP-6 usage for enhancement purposes is severely limited, including information about the potential acute and long-term side effects of these drugs. Nonetheless, the use of GHRP-6, along with other types of growth hormone secretagogues can be associated with two groups of

* Correspondence to: Andreas Kimergård, Centre for Public Health, Liverpool John Moores University, 15-21 Webster Street, L3 2ET, Liverpool, United Kingdom. E-mail: [email protected]

Copyright © 2014 John Wiley & Sons, Ltd.

Drug Testing and Analysis

Online marketing of synthetic peptide hormones

chain the error could have occurred; from the delivery of the wrong raw ingredient to the manufacturer, to a mix-up of vials (before they were labelled), through to incorrect labelling of the vial.

User safety and challenges to public health

Figure 1. Vial labelled ‘GHRP-6 (RECEPTOR)’ containing melanotan II as the only pharmacologically active substance. Photo taken by the Audio Visual Services at Vendsyssel Hospital.

Drug Test. Analysis 2014, 6, 396–398

Copyright © 2014 John Wiley & Sons, Ltd.

wileyonlinelibrary.com/journal/dta

397

people: competitive athletes and non-competing bodybuilders in gyms.[1,11] In this latter group, GHRP-6 is either taken alone or in combination with other drugs, such as anabolic steroids, to improve performance and body satisfaction. There is evidence that melanotan II increases skin pigmentation in humans, although it is no longer being pursued as a drug candidate due to adverse effects such as penile erection.[14] As a consequence, melanotan II has not been authorized for use in medical treatment and the Danish Health and Medicines Authority has issued repeated warnings against the use of ‘melanotan products’.[15] Data on the harm associated with melanotan II, when used in the general population, are limited, but a growing number of individual case reports of adverse reactions from the use of products claiming to contain melanotan II links this exogenous hormone to changes in pre-existing moles (stimulation of dysplastic naevi or malignant melanoma).[16–19] This information, along with accounts by users of melanotan II shared on the Internet, reports in the media, seizures by custom authorities, and observations of online shops,[10] suggest that these drugs have gained popularity over the years. In fact, the increasing demand for these drugs accounts for their presence on the illicit market. Because information about the function of the supply chain fuelling the online drug market is sparse, the operation of manufacturers, wholesalers, and retailers are, by and large, unknown. It is therefore difficult to determine why the active substance in the product we examined was melanotan II instead of GHRP-6 as purported on the vial and on the retailer’s website. However, given that these products are manufactured outside formal regulation of medical product manufacturing, it is easy to imagine a scenario where at some point in the supply

The dangers associated with the use of enhancement drugs are exacerbated by the practices employed by users such as self-experimentation with the effects of various products. The user who provided us the vial admitted to increasing his dosage because he did not experience the anticipated effects, highlighting the risk of suffering adverse reactions from using high and toxic doses of an unknown substance. Furthermore, individuals who use drugs where the active substance has been replaced without their knowledge may fail to recognize that adverse reactions are caused by the drug. This may result in a delay in attending an appropriate health facility or failure to accurately report the use of specific products, impacting negatively on diagnosis and prognosis. In turn, the lack of reliable information amongst national medicine regulatory authorities about the use of specific products impedes accurate estimations of the extent and severity of harm caused by these substances, severely limiting the development of public health and regulatory interventions. It is clear from our study that healthcare professionals who come in contact with patients reporting the use of enhancement drugs need to be cognisant of the potential for errors in users’ identification of the drugs they are taking. The manufacturing, distribution, and marketing of melanotan II is currently unlawful under the Danish Medicines Act. So is the unauthorized manufacturing, importation, marketing, distribution, and possession of substances capable of increasing the release of natural growth hormones in the body with possession being punishable by up to two years’ imprisonment and supply with up to six years’ (according to the Act on Prohibition of Certain Doping Substances). Tellingly for the increasing availability of novel products on the illicit market, GHRP-6 was recently added to the list of controlled ‘doping substances’ which now sits under the Act on Prohibition of Certain Doping Substances.[20] However, despite the existence of these drug control frameworks, it has proven difficult to put an end to the illicit supply of peptide hormones on the Internet. The ever expanding nature of the Internet, along with cheap and worldwide shipment options, means consumers in Denmark can easily order these products, and have them delivered in a matter of days. Determining how to respond effectively to the increasing accessibility and popularity of novel enhancement drugs, when there is typically little information available, is a major barrier to both criminal justice and healthcare professionals. Cooperation between researchers, healthcare professionals, and regulatory bodies is needed to monitor trends on the illicit market, the quality of products being sold, the prevalence of usage, and the health consequences for people who take them. The process of gathering information will, of course, not stop retailers who operate without an official license. However, acquiring more information is critical to policy development and decisions that will have to be made to address the challenges to public health from the supply and use of enhancement drugs.

Drug Testing and Analysis

A. Kimergård et al.

Yours, Andreas Kimergård,a* Jim McVeigh,a Simon Knutsson,b Torben Breindahlc and Allan Stensballed a Centre for Public Health, Liverpool John Moores University, United Kingdom b Department of Biotechnology, Chemistry and Environmental Engineering, Aalborg University, Denmark c Department of Clinical Biochemistry, Vendsyssel Hospital (Aalborg University), Denmark d Department of Health Science and Technology, Aalborg University, Denmark

References [1] J. McVeigh, M. Evans-Brown, M.A. Bellis. Human enhancement drugs and the pursuit of perfection. Adicciones 2012, 24, 185. [2] M. Evans-Brown, A. Kimergård, J. McVeigh. Elephant in the room? The methodological implications for public health research of performance-enhancing drugs derived from the illicit market. Drug Test. Anal. 2009, 1, 323. [3] K. Walpurgis, A. Thomas, T. Laussmann, L. Horta, S. Metzger, W. Schänzer, M. Thevis. Identification of fibroblast growth factor 1 (FGF-1) in a black market product. Drug Test. Anal. 2011, 3, 791. [4] S. Esposito, K. Deventer, P. Van Eenoo. Characterization and identification of a C-terminal amidated mechano growth factor (MGF) analogue in black market products. Rapid Commun. Mass Spectrom. 2012, 26, 686. [5] M. Kohler, A. Thomas, K. Walpurgis, K. Terlouw, W. Schänzer, M. Thevis. Detection of His-tagged Long-R3-IGF-I in a black market product. Growth Horm. IGF Res. 2010, 20, 386. [6] J. Henninge, M. Pepaj, I. Hullstein, P. Hemmersbach. Identification of CJC-1295, a growth-hormone-releasing peptide, in an unknown pharmaceutical preparation. Drug Test. Anal. 2010, 2, 647. [7] M.C. Gaudiano, L. Valvo, A. Borioni. Identification and quantification of the doping agent GHRP-2 in seized unlabelled vials by NMR and MS: a case-report. Drug Test. Anal. 2014. DOI: 10.1002/dta.1603 [8] A. Thomas, M. Kohler, J. Mester, H. Geyer, W. Schänzer, M. Petrou, M. Thevis. Identification of the growth-hormone-releasing peptide-2 (GHRP-2) in a nutritional supplement. Drug Test. Anal. 2010, 2, 144.

[9] J. Henninge, I. Hullstein, G. Hagelin, P. Hemmersbach, in Recent Advances in Doping Analysis, (Eds: W. Schänzer, H. Geyer, A. Gotzmann, U. Mareck). Sportverlag Strauss, Cologne, 2008, pp. 351–353. [10] M. Evans-Brown, R.T. Dawson, M. Chandler, J. McVeigh. Use of melanotan I and II in the general population. Brit. Med. J. 2009, 338, b566. [11] Australian Crime Commission. Organised Crime and Drugs in Sport. Available at: http://www.crimecommission.gov.au/sites/default/files/files/organised-crime-and-drugs-in-sports-feb2013.pdf [13 February 2014]. [12] A. Cabrales, J. Gil, E. Fernández, C. Valenzuela, F. Hernández, I. García, A. Hernández, V. Besada, O. Reyes, G. Padrón, J. Berlanga, G. Guillén, L.J. González. Pharmacokinetic study of Growth Hormone-Releasing Peptide 6 (GHRP-6) in nine male healthy volunteers. Eur. J. Pharm. Sci. 2013, 48, 40. [13] M. Evans-Brown, J. McVeigh. Injecting human growth hormone as a performance-enhancing drug—perspectives from the United Kingdom. J. Subst. Use 2009, 14, 267. [14] M.E. Hadley, R.T. Dorr. Melanocortin peptide therapeutics: Historical milestones, clinical studies and commercialization. Peptides 2006, 27, 921. [15] Danish Medicines and Health Authority. Warning against the tanning product Melanotan. Available at: http://sundhedsstyrelsen. dk/en/news/2011/warning-against-the-tanning-product-melanotan [13 February 2014]. [16] K.F. Hjuler, H.F. Lorentzen. Melanoma associated with the use of melanotan-II. Dermatology 2013, 228, 34. [17] K. Thestrup-Pedersen, K. Søndergaard. Melatonin used for tanning induces and augments lentigines and naevi. Acta Derm-Venereol. 2010, 90, 643. [18] D. Paurobally, F. Jason, B. Dezfoulian, A.F. Nikkels. Melanotanassociated melanoma. Brit. J. Dermatol. 2011, 164, 1403. [19] C. Reid, T. Fitzgerald, A. Fabre, B. Kirby. Atypical melanocytic naevi following melanotan® injection. Irish Med. J. 2012, 125, 148. [20] Sundhedsstyrelsen [Danish Medicines and Health Authority]. Opdatering af den vejledende dopingliste [Renewal of the list of prohibited doping substances]. Available at: http:// laegemiddelstyrelsen.dk/da/service-menu/nyheder/opdatering-afden-vejledende-dopingliste [13 February 2014].

Supporting information Additional supporting information may be found in the online version of this article at the publisher's web site.

398 wileyonlinelibrary.com/journal/dta

Copyright © 2014 John Wiley & Sons, Ltd.

Drug Test. Analysis 2014, 6, 396–398

Online marketing of synthetic peptide hormones: poor manufacturing, user safety, and challenges to public health.

Online marketing of synthetic peptide hormones: poor manufacturing, user safety, and challenges to public health. - PDF Download Free
94KB Sizes 0 Downloads 3 Views