F-MARC Fight against Doping in Football

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2 F-MARC Fight against Doping in Football A comprehensive introduction and overview FIFA s strategy, the relevant substances, their effects and detection Fédération Internationale de Football Association President General Secretary Address Joseph S. Blatter Urs Linsi Fédération Internationale de Football Association FIFA-Strasse 20 P.O. Box 8044 Zurich Switzerland Tel: +41-(0) Fax: +41-(0)

3 SPORTS MEDICAL COMMITTEE FIGHT AGAINST DOPING IN FOOTBALL FIGHT AGAINST DOPING IN FOOTBALL FIFA MEDICAL ASSESSMENT AND RESEARCH CENTRE Sports Medical Committee Chairman D HOOGHE Michel, Dr Belgium Deputy Chairman DIAKITE Amadou Mali Members PETERSON Lars, Prof. Dr Sweden O HATA Nozomu, Prof. Japan DVORAK Jiri, Prof. Dr Switzerland GITTENS Rudy, Dr Canada ZERGUINI Abdelmadjid Yacine, Dr Algeria MADERO Raul, Dr Argentina GRAF-BAUMANN Toni, Prof. Dr Germany TOLEDO Lidio, Dr Brazil YOON Young Sul, Dr Korea Republic ABDEL-RAHMAN Hosny, Prof. Egypt BABWAH Terence, Dr Trinidad and Tobago SINGH Gurcharan, Dr Malaysia EDWARDS Tony, Dr New Zealand FIFA Medical Assessment and Research Centre (F-MARC) President D HOOGHE Michel, Dr Belgium Chairman DVORAK Jiri, Prof. Dr Switzerland Members PETERSON Lars, Prof. Dr Sweden GRAF-BAUMANN Toni, Prof. Dr Germany JUNGE Astrid, Dr Germany O HATA Nozomu, Prof. Japan GITTENS Rudy, Dr Canada MADERO Raul, Dr Argentina ZERGUINI Abdelmadjid Yacine, Dr Algeria FULLER Colin, Dr England ROUX Constant-Antoine, Prof. Côte d Ivoire EDWARDS Tony, Dr New Zealand MANDELBAUM Bert, Dr USA ABDEL-RAHMAN Hosny, Prof. Egypt CHOMIAK Jiri, Dr Czech Republic ROSNOVSKY Mark, Dr Israel Doping Control Sub-Committee President D HOOGHE Michel, Dr Belgium Chairman GRAF-BAUMANN Toni, Prof. Dr Germany Members DVORAK Jiri, Prof. Dr Switzerland PETERSON Lars, Prof. Dr Sweden GUILLEN MONTENEGRO Jorge, Dr Spain SAUGY Martial, Dr Switzerland

4 TABLE OF CONTENTS FIGHT AGAINST DOPING IN FOOTBALL FIGHT AGAINST DOPING IN FOOTBALL TABLE OF CONTENTS Table of Contents Fight against Doping in Football Editorial 2 J. S. Blatter Introduction to FIFA/F-MARC Update on Doping 4 J. Dvorak, M. D Hooghe FIFA s Approach to Doping in Football 6 J. Dvorak, T. Graf-Baumann, M. D Hooghe, M. Saugy, H. Tännler Social Drugs: Cannabis 28 M. Saugy Stimulants 32 L. Mateus-Avois, N. Robinson, Ch. Saudan, N. Baume, M. Saugy Testosterone and Synthetic Anabolic Steroids 42 Ch. Saudan, N. Baume, L. Mateus-Avois, N. Robinson, M. Saugy Nandrolone 48 N. Baume, L. Mateus-Avois, Ch. Saudan, N. Robinson, M. Saugy Erythropoietin Blood Doping 54 N. Robinson, Ch. Saudan, N. Baume, L. Mateus-Avois, M. Saugy Human Growth Hormone 62 M. Saugy, N. Robinson, Ch. Saudan, N. Baume, L. Mateus-Avois Therapeutical Use Exemption 70 J. Dvorak, D. Kirkendall, M. Vouillamoz Beta-2 Agonists and Asthma 76 W. Kindermann Glucocorticosteroids 80 W. Kindermann Medical Legal Aspects 86 T. Graf-Baumann FIFA s Future Activities in the Fight against Doping 94 J. Dvorak, P. McCrory, M. D Hooghe Glossary and Abbreviations 100 Note: Please refer to the Glossary at the end for explanation of medical terms and abbreviations.

5 2 EDITORIAL FIGHT AGAINST DOPING IN FOOTBALL FIGHT AGAINST DOPING IN FOOTBALL EDITORIAL 3 Since we are dealing with ambitious and independent professionals, FIFA s anti-doping strategy relies on education and prevention... Editorial Dear Members of the International Football Family FIFA has a clear vision for its anti-doping strategy in football: to make the game free of doping. It is our duty to protect the players from harm and ensure that they can compete on a level playing field. Since we are dealing with ambitious and independent professionals, FIFA s anti-doping strategy relies on education and prevention, thereby ensuring their support in our fight against doping. Naturally, FIFA aims at interfering as little as possible in the normal course of matches and tournaments and the recuperation of players after a game. At the same time, we demonstrate our respect for the dignity and privacy of each player who is subjected to testing. A worldwide network of specially trained physicians therefore ensures the correct implementation of FIFA s doping control procedure, which is straightforward and leaves no room for cheating or wrong doing. As far as we can judge from current data, the incidence of doping in football appears to be very low, and we have no scientific evidence for systematic doping in football. As abuse still occasionally occurs, much closer collaboration with other antidoping organisations such as WADA, the IOC and international federations is required regarding banned substances, detection methods and data collection. At the same time, a firm stand must be made against the suppression of symptoms through medication with the sole objective of meeting the ever-increasing demands on professional football players. FIFA actively acknowledges its responsibility in the fight against doping through stringent doping control regulations, data collection of positive samples and active support of research in the field, complemented by large-scale prevention promoted by the FIFA Medical Assessment and Research Centre (F-MARC). FIFA has proved to be a reliable and supportive partner in the much-needed worldwide collaboration of all parties involved in the fight against doping to safeguard the health of athletes and the spirit of fair competition. However, the increasing use of recreational drugs such as marihuana and cocaine is outside the scope of doping and reveals the need for collaboration far beyond the capacity of anti-doping agencies and sports organisations. FIFA is ready to play an active role in this challenge to the worldwide community and to reach out to the billions of young people linked to us through their passion for the game. By acknowledging this responsibility, we will not only make the game better, but also contribute to making the world a better place! Joseph S. Blatter FIFA President

6 4 INTRODUCTION FIGHT AGAINST DOPING IN FOOTBALL FIGHT AGAINST DOPING IN FOOTBALL INTRODUCTION 5 Introduction Prof. Jiri Dvorak and Dr. Michel D Hooghe Fight against Doping in Football The ongoing debate and controversy surrounding doping has raised public awareness of a problem that has not been fully appreciated during the rapid development of various sports disciplines. FIFA introduced doping controls in 1970 to ensure that the results of national and international matches were a fair reflection of the ability of those taking part. Over the past twelve years, the FIFA Medical Assessment and Research Centre (F-MARC) has developed a worldwide network of specialists who are involved in the educational process within the confederations and associations as well as in conducting doping controls at national, international and FIFA competitions. Over the years, FIFA has developed a close collaboration not only with the confederations and member associations, but also with other team sports federations and particularly with the accredited laboratories. It has also established its own database. Consequently, FIFA is able to understand the problems based on facts, figures and a statistical analysis of the test results, and draw conclusions for developing a global, harmonised strategy in the fight against doping in football. Over 20,000 doping controls are performed each year on football players worldwide in fact, in football, more tests are performed than in any other sport. Based on that number, the incidence of positive doping cases is 0.4%. The FIFA database shows that the most common doping cases are on account of so-called recreational or social drugs, such as cannabis and cocaine. Only 0.07% are linked to the abuse of anabolic steroids. Analysing this data in detail, including the distribution of positive cases among the confederations, has determined the content of this FIFA/F-MARC update on the strategy in the fight against doping. In fact, in football, more doping tests are performed than in any other sport The first part describes the background, historical perspectives and development of the FIFA strategy in the fight against doping over the past twelve years. The articles that follow are in an order that reflects the frequency of the substances in positive cases, i.e. cannabis, cocaine, testosterone and synthetic anabolic steroids as well as nandrolone. The latter is a case deserving of special attention, as many of the food supplements sold over-the-counter are contaminated by undeclared nandrolone or its precursors. As a result, they might be taken by footballers without their knowledge, leading to a positive doping test. However, it is clear that any footballer is responsible for his or her diet, including the intake of food supplements and vitamins. The papers on erythropoietin, blood doping and human growth hormone offer in-depth information about substances that are frequently discussed in the media. However, over the past three years, there has not been a single positive test for abuse of erythropoietin and/or blood doping in football. Football players who suffer from acute or chronic diseases or physical symptoms and signs following injury may require specific medication for treatment that might be on the prohibited list. In these cases, a therapeutical use exemption (TUE) may be granted if clinically justified. The most common applications for TUE in FIFA and the confederations are for the use of beta-2-agonists to treat asthma and for corticosteroids to treat acute injuries. Both groups of medications are presented in separate chapters. In its management of positive samples, FIFA follows the rule of separation of power. Medical doctors analyse the medical circumstances and laboratory results, and estimate the severity of violation of the FIFA doping control regulations. It is the duty of the FIFA Doping Control Sub-Committee to present the medical aspects of a positive case with background information for further individual case management in the FIFA Disciplinary Committee. The last chapter therefore deals with these particular medical legal aspects of positive cases. Even though, according to WADA statistics for 2004, the incidence of positive doping cases among football players is low in comparison with other sports, FIFA is convinced that a stringent system of doping controls adhered to by all member associations is important. However, the education of players, coaches, paramedical and medical personnel surrounding the football players might be even more important. It helps to underline that doping has no place in football and FIFA, but also that there is no rational reason to believe that such abuse would transform a good footballer into an excellent footballer or even into a star. This update on FIFA s strategy in the fight against doping should contribute to a better understanding of the problem and it will be an integral part of the concerted action in the long-term educational programme of FIFA. Prof. Jiri Dvorak FIFA Chief Medical Officer F-MARC Chairman Michel D Hooghe, MD Chairman of FIFA Sports Medical Committee FIFA Executive Committee Member

7 FIFA s Approach to Doping in Football

8 8 FIFA S APPROACH TO DOPING IN FOOTBALL F-MARC DOPING UPDATE 2006 F-MARC DOPING UPDATE 2006 FIFA S APPROACH TO DOPING IN FOOTBALL 9 FIFA s Approach to Doping in Football Introduction The ongoing debate and controversy concerning doping (i.e. the list of prohibited substances, the procedures and the sanctions used in amateur and professional sport) has raised public awareness of a problem that has not been fully appreciated during the rapid development of various sports disciplines. It is only 38 years since drug testing was first introduced at the1968 Olympic Games in Mexico City following the amphetamine and nicotinyl tartrate-related deaths of a number of cyclists at the 1960 summer Olympic Games in Rome and during the 1967 Tour de France. Regular doping controls have been conducted since, but these controls have failed to prevent sportsmen and women from taking performance enhancing drugs both during and out of competition. Regrettably, banned and harmful substances are openly available even without prescription. Drugs such as nandrolone and others can be ordered over the internet in unlimited quantities. In recent years, an increasing number of positive samples and cases of so-called recreational drugs like marijuana and cocaine have been observed and need to be addressed accordingly. In addition, media reports may encourage those competing at lower levels of sport to experiment in the use of such substances without considering the possible side-effects and medical complications, let alone the legal consequences of their actions. Sporting associations, including FIFA, have stated that the fundamental aims of doping controls and antidoping policies are: to uphold and preserve the ethics of sport; to safeguard the physical health and mental integrity of the player; to ensure that all competitors have an equal chance. FIFA introduced doping controls in 1970 to ensure that the results of national and international matches were a fair reflection of the ability of those taking part. The FIFA Sports Medical Committee has the responsibility for implementing doping controls at all FIFA competitions and also for coordinating with confederations and member associations. The overall management of doping controls is done by the FIFA administration (medical department and the FIFA Sports Medical Committee). Over the past twelve years, the FIFA Medical Assessment and Research Centre (F-MARC) has developed a worldwide network of specialists who are involved in the educational process within the confederations and member associations as well as in conducting doping controls at national, international and FIFA competitions. The medical doctors/sports physicians, following their Hippocratic Oath as well as their professional and ethical values, play key roles in FIFA s long-term strategy in the fight against doping. Many of the doctors are also team physicians within their associations. The fight against doping in football focuses on education and prevention with regular in- and out-of-competition controls. In years gone by, approximately 15,000 doping controls were performed annually on footballers, with over 20,000 performed in both 2004 and FIFA has articulated its unyielding position in the fight against doping prior to the World Cups in 1998 and 2002 (FIFA magazine May 2002) and reinforced its strategy in FIFA magazine in March The physicians demonstrated their strong support of FIFA s long-term strategy in the fight against doping prior to the 2002 FIFA World Cup Korea/ Japan when the team physicians of all 32 finalists unanimously signed a joint declaration in the fight against doping, supporting FIFA s decision to introduce routine blood sampling to analyse for blood doping and erythropoietin. This was a firm message to the football community and demonstrated the excellent collaboration and cooperation between the FIFA Sports Medical Committee with the team physicians taking care of the players prior to and during the competition. The team physicians of all the finalists of the 2006 FIFA World Cup Germany again reinforced the fight against doping with a joint declaration signed on 5 March 2006 to keep this unique event free of doping. Definition Doping constitutes an acute or chronic health hazard for players Doping is defined as any attempt either by the player, or at the instigation of another person such as manager, coach, trainer, doctor, physiotherapist or masseur, to enhance mental and physical performance unphysiologically or to treat ailments or injury when this is medically unjustified for the sole purpose of taking part in a competition. This includes using (taking or injecting), administering or prescribing prohibited substances prior to or during a competition. These stipulations also apply to out-of-competition testing for anabolic steroids and peptide hormones as well as to substances producing similar effects. Other prohibited methods (e.g. blood doping) or manipulation of collected samples is likewise classified as doping. The detailed definition as related to the anti-doping rule violations is presented in the current FIFA Doping Control Regulations (January 2006). Doping contravenes the ethics of sport, constitutes an acute or chronic health hazard for players and may have fatal consequences. The fight against doping in football focuses on education and prevention with regular in- and out-of-competition controls.

9 10 FIFA S APPROACH TO DOPING IN FOOTBALL F-MARC DOPING UPDATE 2006 F-MARC DOPING UPDATE 2006 FIFA S APPROACH TO DOPING IN FOOTBALL 11 The Extent and Scope of Doping in Football FIFA is a global organisation that unifies over 250 million footballers in 207 countries with around 40 million of these players being female. Currently, confederations, members associations or both that fall under FIFA s management carry out their own doping controls at competitions that they stage. Urine, blood samples or both must, however, be analysed at FIFA/WADA-accredited laboratories. These laboratories send reports on any chemically positive A samples to the member associations, as well as to FIFA headquarters for management and to WADA for information. Once the FIFA medical department has received a positive A sample report, follow up information is required by the member association, the confederation in question, or both to receive the results of the possible B sample and the particular disciplinary committee decision. If the information is not provided, the FIFA Disciplinary Committee takes appropriate action. Since the 1994 FIFA World Cup in the United States, the FIFA medical department has been stringently registering all performed samples. The true extent of the problem is unknown A new doping control policy for FIFA competitions was introduced at the FIFA U-17 World Championship in New Zealand in Ever since, during tournaments, two players from each team have been randomly selected to undergo doping tests after each match. Between 1994 and 2005, 3,327 doping controls (men and women) were performed during three consecutive FIFA World Cup competitions (USA, France, Korea/ Japan), two consecutive Olympic Games (Sydney, Athens) as well as at the most recent Women s World Cup, the FIFA U-19 Women s World Championship in Thailand, the FIFA U-17 World Championship in Peru, the FIFA Confederations Cup in Germany, the FIFA Club World Championship in Japan, the FIFA Beach Soccer World Cup in Brazil, the FIFA U-20 World Championship in Netherlands and the FIFA Futsal World Championship in Chinese Taipei as well as at the 2006 FIFA World Cup preliminaries. Only four samples tested positive during this period: one for ephedrine and pseudoephedrine in 1994, one for cannabis and one for nandrolone during the 2003 FIFA World Youth Championship in the United Arab Emirates, and one for ephedrine in Angola. This reflects an overall incidence of 0.12% positive cases over the past eleven years. The extremely low incidence of positive cases during FIFA competitions indirectly confirms FIFA s long-term strategy in the fight against doping, that education and prevention are key issues in keeping high-profile competitions free of doping. It can only be assumed that team sports such as football are not as prone to abuse of performance enhancing substances in comparison to individual sports. When looking at positive doping cases during the 2004 Olympic Games in Athens, 27 positive cases were detected; all in individual athletes and none in any team sport participants. It might be claimed that the close collaboration of the team sport medical committees has, since the 2000 Olympic Games in Sydney, positively influenced the team sports fair play attitude during the Olympic Games in Athens. Close collaboration with accredited laboratories, the reporting system and the central control system are important tools to continue to statistically record the extent of doping in football in the future. Although several prominent footballers have tested positive for drugs in recent decades, the true extent of the problem is unknown. Even if we assume that doping is still not a major issue in team sports such as football, any estimation of the problem can be considered to be merely an unscientific hypothesis or speculation. To meet the challenge brought about by this situation, FIFA has taken action to develop closer collaboration between the medical committees of the various confederations. In October 1999, the FIFA Sports Medical Committee and the UEFA Medical Committee met to discuss the latest sports medicine issues, not only with the aim of combating doping, but also to develop educational programmes designed to meet the fundamental aims and objectives outlined above. Similar meetings have been conducted between a representative of the FIFA Sports Medical Committee and the medical committees of CONCACAF (North, Central America and the Caribbean in 2000, 2001), AFC (Asia, 2001, 2002, 2005) and CAF (Africa, 2003, 2004). During 2005, meetings with the newly established OFC (Oceania) Sports Medical Committee and CONMEBOL (South America) were held with the aim of harmonising doping control procedures, improving the understanding of the scientific background of doping and enhancing the FIFA network of doping control officers (DCOs) who fulfil educational duties as a part of their responsibilities. According to IOC statistics (until 2003) and WADAaccredited laboratories (as of 2004), approximately 20,750 doping controls are performed annually on football players. The majority of tests are performed in Europe, North and South America. The number of doping controls continues to increase in the other confederations. In this respect, FIFA has developed its own database to keep records on the substances reported as positive to allow an online control of the management of these samples within the different confederations and member associations. During 2004 and 2005, there were 88 (0.42% based on the assumption of 20,750 samples per year) and 78 (0.37%) positive samples respectively registered at FIFA (see Figure 1). This increase is probably a result of improved reporting systems by the laboratories as a result of the implemented World Anti- Doping Code (March 2004). Most of these cases were detected or reported by the European Laboratories that receive most of their samples from European associations (see Figures 2 and 3) Number of Cases Cannabis Cocaine Anabolic Steroids Stimulants Miscellaneous Figure 1: FIFA doping statistics per substance for 2004 and 2005 (excl. T/E)

10 12 FIFA S APPROACH TO DOPING IN FOOTBALL F-MARC DOPING UPDATE 2006 F-MARC DOPING UPDATE 2006 FIFA S APPROACH TO DOPING IN FOOTBALL 13 Number of Cases AFC 2 7 CAF 0 CONCACAF CONMEBOL Figure 2: FIFA positive doping samples per confederation in 2004 and 2005 (excl. T/E) Following FIFA s meeting in Zurich with medical representatives of the Olympic Team Sports Federations and representatives from the WADA accredited laboratories in 2003, it has been possible to receive reliable data on performed analyses of doping samples from the WADA-accredited laboratories (Figure 4). It was observed that samples performed for football (FIFA) showed quite a discrepancy between laboratories in Seoul (42 analyses) and Rome (4,159 analyses). The analysis of this data might influence the future strategy of the distribution of the samples to the laboratories. The total number of football samples analysed during the year 2004 allows the calculation of incidents for the positive samples in total (0.42%), the distribution and OFC 64 UEFA 58 calculation of incidents in the different confederations (Table 1), and the calculation for the most commonly detected prohibited substances (Table 2). It should be stated that these statistical analyses do not include the applications for Therapeutic Use Exemption (TUE) or the pending T/E (Testosterone/Epitestosterone) ratio cases. These cases are extremely difficult to manage and have motivated F-MARC to develop a new research study in collaboration with the WADA-accredited laboratory in Lausanne for direct proof of testosterone in urine. This study is currently on the way. The relatively low incidence of positive doping samples, especially for the true performance enhancing drugs such as anabolic steroids and stimulants, support the assumption that there is no evidence of systematic doping. Other important support for the assumption for no evidence of systematic doping was provided by UEFA during the 2005/2006 Champions League competition. All 32 participating teams underwent unannounced doping controls in their training camps. Ten players per team were tested by UEFA medical doctors. All 320 samples were declared negative. The newly developed FIFA database for management of all samples collected worldwide allows doping control officers records to be tracked and it has proven to be an extremely useful tool for following up on cases, particularly for less experienced FIFA member associations. As of January 2006, this database has Samples Positive Incidence% AFC CAF CONCACAF CONMEBOL OFC UEFA Total Table 1: WADA-accredited laboratories doping statistics for 2004 per confederation (excl. T/E) Samples 38 Cannabis Cocaine Anabolic Steroids Stimulants Miscellaneous Total 0.42 Incidence% Table 2: Substance per positive sample of WADA-accredited laboratories in 2004 allowed each positive sample to be tracked, with the aim of having the final decision of the member association s disciplinary committee no later than 90 days after the analysis of the B sample. The FIFA database will allow a continuous cross-check with the WADA database (ADAMS Anti-Doping and Management System) once operational, not only in order to control the reporting system of the WADA-accredited laboratories, but also to allow prospective studies on sanctions related to the different substances, the severity of the violation, or both. List of Prohibited Substances Like most major sports governing bodies and the IOC, FIFA has drawn up a list of prohibited doping substances and methods. The categories of prohibited substances and methods have been approved by the FIFA Sports Medical Committee and follows the Prohibited List International Standards in the World Anti-Doping Code. The most recent Doping Control Regulations and list of banned substances (Jan 2006) are divided into three main sections containing different categories of prohibited drugs and methods (table 3). Additional substances and methods such as stimulants, narcotics, cannabinoids and glucocorticosteroids are included for in-competition testing. The 2006 list includes specific Positive Doping Samples Belgium Croatia England 13 France 1 0 Greece 13 8 Italy 2 0 Malta 3 5 Netherlands 8 2 Norway 9 12 Portugal 2 0 Spain 2 3 Turkey Doping Samples Seoul Havanna Prague Barcelona Penang Los Angeles Bangkok Helsinki Montral Seibersdorf Bloemfontain Sydney Moscow Tokyo Lausanne Ankara Beijing Oslo Stockholm Tunis Genf Athens Kreischa Bogota 994 Paris Lisbon London Cologne Rio de Janeiro Rome Figure 3: FIFA positive doping samples for Europe in 2004 and 2005 (excl. T/E) Figure 4: Samples analysed in 2004 per WADA-accredited laboratory

11 14 FIFA S APPROACH TO DOPING IN FOOTBALL F-MARC DOPING UPDATE 2006 F-MARC DOPING UPDATE 2006 FIFA S APPROACH TO DOPING IN FOOTBALL 15 substances that are examined for monitoring purposes and are particularly susceptible to unintentional antidoping violations because of their general availability in medical products or because they are less likely to be successfully abused as doping agents. A doping violation involving such substances may result in a reduced sanction provided that the athlete can establish that the use of such specified substances was not intended to enhance sports performance (FIFA Doping Control Regulations p. 33). An extensive list of examples for each category of prohibited substances is provided by FIFA in the annual Doping Control Regulations. These lists are always followed by the words and other substances to include all related substances with a similar chemical structurr or biological effect. Even though the majority of the drugs described are banned in football, some categories are more capable of enhancing a player s performance than others and, as such, may well be used within our sport. Two categories are not commonly used by players: narcotic analgesics and diuretics. Narcotic analgesics are mainly from the opiate family such as morphine. Diuretics are used as masking agents in certain sports. Both of these categories are contraindicated for the type of exercise that footballers have to perform on the field over 90 minutes. Three categories that could involve footballers are stimulants, anabolic agents and peptide hormones. Current Doping Control Regulations Cooperation within the Confederations and Associations In 1999, a comparative study of the Doping Control Regulations issued by the confederations showed a high level of agreement as far as the lists of banned substances and methods were concerned. This was because the confederations simply decided to adopt the FIFA Doping Control Regulations that were in force. A detailed survey of the doping control regulations issued by associations, however, revealed some differences in the procedure and concerning the inclusion of certain substances in the categories of prohibited substances (1999). Following this comparative study, the FIFA Sports Medical Committee and F-MARC proposed to the Executive Committee that the doping control regulations of all associations be harmonised and that they adopt the list of prohibited substances and methods. Following the FIFA Executive Committee decision, the FIFA Ordinary Congress ratified this decision in Seoul (May 2002), thereby paving the way for the decision of the FIFA Extraordinary Congress in Doha/Qatar (December 2003), i.e. following the method of individual case management, expulsion sanctions by the disciplinary committees of associations will be extended for all international matches and vice versa. Stringent Rules of Procedure While the in-competition Doping Control Regulations outline a clear procedure, the out-of-competition controls have not been performed routinely in football, mainly because the professional football player is in competition for almost the entire year with the exception of brief seasonal breaks (2-4 weeks) or when rehabilitating after severe injury. For the first time, FIFA and UEFA produced a joint set of regulations for out-of-competition doping controls prior to EURO About one month before the tournament, all competing countries were informed that unannounced doping controls might be carried out at training camps and were instructed on the procedure to be followed. After lots had been drawn to select four national teams, two doping control co-ordinators (one from UEFA and one from FIFA) visited the training camps in question at around 11 a.m. and immediately reported to the national team s head of delegation. The head of delegation was requested to find a suitable location for collecting the required samples. The players to be tested four per team were then drawn by lots and the doping control procedure was carried out by the UEFA and FIFA doctors immediately thereafter. FIFA Doping Control Officers are physicians for confidentiality reasons and educational purposes The experience of these out-of-competition tests showed the need for a much greater level of cooperation between associations, confederations and FIFA to ensure that procedures for standard doping controls and unannounced out-of-competition controls were brought more closely into line. A similar procedure for out-of-competition controls was performed during the training camps prior to the 2002 FIFA World Cup (Korea/Japan) and Euro 2004 (Portugal). The procedure proved to be feasible and the compliance of involved teams and individual players was 100%. Out-of-competition, unannounced controls are also planned prior to the 2006 FIFA World Cup Germany. Using Medical Doctors as Doping Control Officers Although some sporting organisations and anti-doping agencies continue to employ coordinators who are not medical doctors for doping controls, FIFA and its member confederations insist on physicians. This question requires closer analysis. Players from teams selected to undergo a doping test are required to provide details of any treatment with medication from seven weeks to 72 hours before the test or the competition in question. Prohibited Substances Prohibited Methods Substances and Methods Prohibited in Competition Anabolic Agents Enhancement of Oxygen Transfer Stimulants Hormones and related substances Chemical and Physical Manipulation Narcotics BETA-2-Agonists Gene Doping Cannabinoids Agents with Anti-Estrogenic Activity Glucocorticosteroids Diuretics and Other Masking Agents Table 3: Categories of banned substances and methods from FIFA Doping Control Regulations

12 16 FIFA S APPROACH TO DOPING IN FOOTBALL F-MARC DOPING UPDATE 2006 F-MARC DOPING UPDATE 2006 FIFA S APPROACH TO DOPING IN FOOTBALL 17 All medications that a player has received must be listed together with details of the method of administration, dosage and medical indications. The information declared on the forms used for this purpose is covered by patient confidentiality and may not be communicated to non-medical persons (for example, the general secretary of the football association concerned, the player s coach or his club s general manager) unless the A sample tests positive. For confidentiality reasons alone, it is essential that the doping control officer is a physician with appropriate qualifications for this position. Clinical studies show that until recently, most of the doping substances were, as a general rule, drugs developed for therapeutic purposes that are primarily used for medical therapy. Today, however, an increasing number of substances are being developed for the sole purpose of doping and no studies have been conducted into their clinical effectiveness. This is a final reason why specially trained physicians, working in close co-operation with laboratory specialists, should serve as doping control officers. The doctor not only has to carry out the control procedure, but also has an educational function before, during and after the doping control. In case of Therapeutic Use Exemption, strict confidentiality is necessary and guaranteed Prohibited Substances Prescribed for Medical Reasons (TUE Therapeutic Use Exemption) If there is doubt surrounding the appropriate therapeutic treatment of a player who has a medically confirmed pathological condition, drugs containing prohibited, or partially prohibited, substances could be permitted in exceptional cases if: the player s health would be impaired if the prohibited drug were withheld; no performance enhancement could result from the prohibited substance being administered as medically prescribed; no permitted or practical alternative drug is available in place of the prohibited substance. In such a situation, a player or his doctor must request an exemption by submitting a formal application to the FIFA Doping Control Sub-Committee. Strict confidentiality is necessary and guaranteed. FIFA has become part of an international network in this field, initiated by the Australian Sports Drug Medical Advisory Committee (ASDMAG), and will be able to draw upon the accumulated body of knowledge from other team sports, WADA and individual cases. The TUE applications are managed by the FIFA Doping Control Sub-Committee. The copy of approval or rejection is sent automatically to WADA for information and possible appeal. If requested, the complete medical file is submitted to WADA medical staff for further investigation, following the rules of medical confidentiality. Laboratory Analyses of Samples Chain of Custody The laboratories throughout the world that are in charge of doping analyses are all specialised and well equipped institutions, empowered by their national sporting authorities to perform analyses on urine samples received from sporting authorities. WADA has established an accreditation system for such laboratories. A total of 33 are fully accredited for 2005 (table 4). This accreditation is based on quality control checks performed annually on each laboratory. The main objective of accreditation is to guarantee uniform quality of analysis at laboratories all over the world. International federations, including FIFA, use these official laboratories for their major events and competitions. The laboratory is requested by the governing body concerned to analyse the samples and is obliged to comply strictly with the rules laid down in their medical codes. The laboratories treat all samples anonymously with each sample being labelled with a code number known only to the player and the committee in charge of the controls. This is essential to assure the player that the analyses are completely objective and avoid any undue pressure on the laboratory when analysing the samples. The results (negative or positive) are communicated to the committee in charge of the controls. If the A sample is positive, the test is performed a second time before the result is sent to the relevant committee. A copy from the report of any positive case is simultaneously sent to the international federation (if the latter is not in charge of the controls), to FIFA and to WADA. The committee in charge then informs the player, who then has a limited time to request an analysis of the B sample. Analyses The analyses are carried out with the aim of identifying all detectable banned substances. The equipment used is state-of-the-art technology designed to generate a molecular fingerprint. The techniques of choice are gas (or liquid) chromatography controlled with detectors based on mass spectrometry. Chromatography is the first step in the analysis, consisting of a preliminary separation in the mixture of several natural or nonnatural substances contained in each urine extract. After the substances have been sorted, a mass spectrometer provides a picture of the molecular structure that can be compared with others stored in the chemical databases of the computer that controls the entire system. Ankara (Turkey) Warsaw (Poland) Bogota (Colombia) Athens (Greece) Bangkok (Thailand) Barcelona (Spain) Beijing (China) Bloemfontein (South Africa) Cologne (Germany) Gent (Belgium) Helsinki (Finland) Seibersdorf(Austria) Havana (Cuba) Kreischa (Germany) Lausanne (Switzerland) Lisbon (Portugal) London (England) Los Angeles (USA) Madrid (Spain) Montreal (Canada) Moscow (Russia) Oslo (Norway) Paris (France) Penang (Malaysia) Prague (Czech Republic) Rome (Italy) Seoul (Korea) Sydney (Australia) Tokyo (Japan) Stockholm (Sweden) Tunis (Tunisia) Rio De Janeiro (Brazil) Cambridge (England) Table 4: FIFA/WADA accredited laboratories in 2006

13 18 FIFA S APPROACH TO DOPING IN FOOTBALL F-MARC DOPING UPDATE 2006 F-MARC DOPING UPDATE 2006 FIFA S APPROACH TO DOPING IN FOOTBALL 19 The aim of all these analyses is to prove that no banned substances are present in the urine samples provided by clean players (the vast majority: a true negative), so that the player can then be declared negative. In positive cases, the same technology must also deliver absolute chemical proof that a banned substance or its degradation products (called metabolites) are present in the urine (a true positive). Every possible step is taken to prevent samples from erroneously being declared positive (a false positive); in general, the purpose of B sample analysis is to provide confirmation of the result obtained during the first test in presence of the player or one of the player s representatives. with another steroid called epitestosterone that is similar to testosterone and is very stable in its concentration. The normal Caucasian and African population has a mean ratio (testosterone to epitestosterone = T:E) of 1.5:1 (for males) with some variability, rising to 4:1 in very rare cases. The mean ratio for Asian people is generally lower than 1:1. A player with excessive levels of testosterone will show a much higher ratio, resulting from an increase in testosterone concentration. It was later decided that the maximum permissible T:E ratio would be 6:1, and that any ratio over this limit would be declared positive. Currently, the limit for an adverse finding has been fixed at 4:1. In addition to the T:E ratio, monitoring of the complete steroid profile of the athlete over time can be a demonstration of manipulation. The latter can also be due to the consumption of other steroids like testosterone precursors that are easily purchased over the internet. Moreover, a laboratory s use of new instrumentation, the isotope ratio mass spectrometer (IRMS), allows a differentiation between steroids of endogenous origin from those of exogenous origin in urine. This tool, together with the retrospective values of the player, if they exist, and in some cases, additional endocrinologic investigations, provide the disciplinary committees with the opportunity to make the most accurate decision in a timely manner. A 2004 FIFA-initiated validation study conducted jointly with LAD (WADA-accredited laboratory in Lausanne) is in progress. Switzerland (A and B Leagues) was tested after a game (356 players in total over two weekends) in collaboration with the Swiss anti-doping committee. The results were compared with those obtained by testing amateur footballers and students. Without revealing anything about the origin of these products, the study showed that some players had nandrolone metabolites in their urine after the game. The traces of metabolites in those players urine samples were very small and all were below the limits of a positive reading. On the basis of the study, FIFA was able to organise the anti-doping programme for the World Cup with a degree of assurance to provide reliable information to the competing teams to rule out any occurrence of false positive tests. With FIFA s support, this study into nandrolone and its derivate substances continued. Extraordinary variability in the excretion was demonstrated, making the relationship between dosage, time delay and the urine concentration very critical. The involvement of the world governing body in such a research programme is essential if any worthwhile progress is to be made in this area. The players can also be given the assurance that, scientifically and ethically, they start a match on a level playing field with their opponents as far as doping is concerned. Peptide hormones There are several peptide hormones in the list, of which the two most important are erythropoietin and human growth hormone. Erythropoietin (EPO) The use of erythropoietin (EPO) in sport can be detected in urine by a novel method based on biochemical properties of the substance. EPO and analogues are too large to be filtered by the kidney and easily eliminated in urine. Their concentrations in urine are so low that there was a need for improvement in biochemical technology to allow the detection of this product in urine. Thus, in 2000, the laboratory in Paris implemented a method based on a small structural difference between recombinant and natural EPO to determine whether doping had taken place. This method is now applied in several accredited laboratories in the world. Every possible step is taken to prevent samples from being erroneously declared positive The purpose of B sample analysis is to provide confirmation of the A result Nandrolone Unfortunately, not all banned substances used in sport can be detected using this technology (a false negative). In addition, some of them have exactly the same structure as their natural endogenous forms and are quite difficult to tell apart. The T/E Ratio Just before the FIFA World Cup in France in 1998, a number of well-known players tested positive for small amounts of nandrolone metabolites in their urine. Nandrolone (chemical name: nortestosterone) is an anabolic steroid that often occurs in body-building doping cases. In general, this compound is taken in high doses and its degradation products (metabolites) remain detectable in urine for up to several months. Widespread use of anabolic steroids in doping began in the 1980s and testosterone was one of the preferred androgenic anabolic agents. Until recently, it was difficult to differentiate between synthetic and natural testosterone in the body. The only method available was a quantitative one involving the establishment of a ratio Prior to the 1998 World Cup, FIFA commissioned an independent anti-doping laboratory (University of Lausanne) to carry out a collaborative study to obtain a true picture of the situation in football. With the agreement of national and international bodies, every player from every team in the top national leagues in

14 20 FIFA S APPROACH TO DOPING IN FOOTBALL F-MARC DOPING UPDATE 2006 F-MARC DOPING UPDATE 2006 FIFA S APPROACH TO DOPING IN FOOTBALL 21 Human Growth Hormone (hgh) The chemical structure of bioengineered human growth hormone is almost identical to the natural hormone produced by the body. Consequently, it is particularly difficult to differentiate between injected and natural hormone. Recently developed methods use blood as a biological sample for the determination of a specific ratio diagnostic for the use of recombinant hgh. This new approach clearly demonstrates the necessity to implement blood sampling for anti-doping purposes in future. Blood Sampling Recently, blood has been introduced as an alternative biological matrix to urine for anti-doping purposes. Since 2004, blood has been recognised as absolutely necessary for reliable results for some forbidden substances and methods. The list of these substances and methods is not definitive, but currently, hgh, synthetic haemoglobins and homologous blood transfusions can be reliably detected with several blood matrices. Some other blood tests are also carried out in certain sports, not for the purpose of determining the presence of doping, but rather as general health checks conducted in the context of medical screening of the competitors. This has potential for the future and could easily be introduced by some national or international federations depending on their structural organisation. However, this concept is more difficult to implement in larger federations where there are players on every continent. FIFA Network of Doping Control Officers In cooperation with the confederations and associations, FIFA has established a worldwide network of more than 250 specially trained physicians who act as FIFA Doping Control Officers. With regard to medical confidentiality and the necessity for specific knowledge in the field, FIFA only accepts physicians as doping control officers. Doping Control Officers (DCO) all have attended instructional seminars conducted by F-MARC (Prof. Jiri Dvorak, Chairman) and FIFA Doping Control Sub- Committee (Prof. Toni Graf-Baumann, Chairman) in order to secure unity of doctrine. Such seminars were held in Tunis in November 2000 for CAF, in Penang in January 2001 for AFC, in Zurich in January 2001 for UEFA, in Miami in February 2001 for CONCACAF, in March 2001 for OFC, in Tunis in January 2004 and in Marrakech in November 2004, in Buenos Aires in March 2005, in Oman in May 2005, in Port of Spain in December 2005, in Auckland in February 2006 and in Buenos Aires in April The DCOs, as members of the FIFA network, are currently distributed around the world. In order to make doping control cost-effective, the FIFA Congress followed the recommendation of the Sports Medical Committee that DCOs should be, by profession, physicians who follow the Hippocratic Oath and their professional law. DCOs perform doping controls on their national team in their country when playing a team from other countries. The FIFA doping control procedure is straight forward and transparent, leaving no place for cheating or wrong-doing when all steps are performed in the presence of representatives from both teams. This makes the logistics easier and significantly reduces the costs involved, particularly for qualifying matches for major competitions. Research The current list of banned substances contains a number of drugs for which there is no conclusive scientific evidence to justify inclusion on the list. Research on selected substances has highlighted some performanceenhancing effects while other references are doubtful. In view of the potentially enormous repercussions (as demonstrated at the Sydney Olympic Games) there are several ways of improving the current situation: A database containing all currently listed substances should be set up. This should give details on the pharmacological background, research findings and clinical papers documenting the effects of the particular substance; Borderline substances should be reconsidered on the basis of research studies that provide a scientific analysis of their effect on physical and psychological performance as well as their effect on metabolism; A standard study design (double-blind, randomised trials) should be set up for the substances under scrutiny, proven in pilot projects and implemented multi-centrically; would appear rational, it has not been scientifically proven, leaving the window wide open for discussion. Further double-blind studies are being conducted to obtain the scientific evidence needed to end the ongoing speculation. Nevertheless, this cut-off level is valid and will remain in effect. FIFA has realised and documented its responsibility by supporting research studies that promise to enhance current medical knowledge. A combined effort with other international sports federations, the IOC and antidoping agencies might, however, accelerate the process. Educating the Football Public about Doping and Performance Cooperation with Team Doctors Supplements and Special Nutrition Continuous and close contact with team doctors is necessary in countries where sports medicine is still developing and where team doctors may not have special training on doping issues. In view of the rapid changes in doping with regard to substances and methods of application, a constant exchange of information with all team doctors is essential. Apart from the facts of the problem, effective procedures against doping cannot be put into practice unless a close, trusting relationship has been established between the team doctors and the Doping Control Officers. The results of such studies should form the basis for a future discussion on the list of prohibited substances; Tracing and identification of masking agents. FIFA doping control procedure is straight forward and transparent, leaving no place for cheating or wrong doing Such initial research work might help to reduce the list of banned substances to focus concentration on the major problem areas like anabolic steroids, peptide hormones and related substances, such as hgh and EPO and others. Research into nandrolone metabolism in footballers, conducted with FIFA s support, eloquently documents the complexity of the problem. The study showed that current laboratory methods cannot distinguish between endogenous metabolism and exogenous intake of nandrolone. Although the cut-off level of 2 ng/ml A trusting relationship has been established between the team doctors and the Doping Control Officers

15 22 FIFA S APPROACH TO DOPING IN FOOTBALL F-MARC DOPING UPDATE 2006 F-MARC DOPING UPDATE 2006 FIFA S APPROACH TO DOPING IN FOOTBALL 23 Players should use foods that optimise training and match performance In this regard, particular attention must be paid to food supplements and special diets that might be prescribed for an athlete. Supplements or diets may contain banned substances, meaning the athlete may be taking substances (or using food supplements) without realising that it may contain a banned substance. If the athlete tests positive, it is difficult to prove that the substance(s) in question originated in the athlete s food or food supplements. From a legal point of view, players testing positive in such situations must bear the responsibility themselves. Here, too, a constant exchange of information between Doping Control Officers and team doctors will help everyone keep abreast of developments in the market and prevent problems arising for players. The recently published summary of Nutrition for Football: the FIFA/F-MARC Consensus Conference ( Sept 2005) clearly states that there is no evidence to support the current widespread use of dietary supplements in football. Supplements should be used only on the advice of qualified sports nutrition professionals. Football players can stay healthy, avoid injury and achieve their performance goals with good dietary habits. Players should choose foods that support and optimise training and match performance. What a player eats and drinks in the days and hours before a game, as well as during the game, can influence the result by reducing the effects of fatigue and optimise performance. Food and fluid ingested soon after a game and training can accelerate recuperation. All players should have a nutrition plan that takes account of individual needs. FIFA`S Cooperation with WADA On 4 February 1999, a Lausanne declaration on Doping in Sport was presented to the IOC and international sport federations that an independent International Anti-Doping Agency should be established and fully operational by the Olympic Games in Sydney 2000 in order to coordinate the various programmes necessary to realise the objectives. The medical and legal representatives of FIFA have developed a close collaboration since 1999 based upon numerous meetings with the representatives of the World Anti-Doping Agency, particularly following the meeting of FIFA President Mr Joseph Blatter and the Chairman of WADA, Mr Richard Pound in Montreal in December FIFA s medical legal experts contributed significantly to the improvement of the World Anti-Doping Code particularly in versions 1 and 2. They insisted on having independent expert opinion by prominent European judges and lawyers, including the International Sports Lawyers Association, on individual case management regarding positive cases. This individual case management has been confirmed as a strategy by internal studies of the medical legal aspects of the Team Sports Federations based upon 184 positive samples and cases between 1998 and 2003 in different sports. After intensive discussions with Mr Pound, the management of WADA and a historic speech delivered by Mr Pound (54th Ordinary FIFA Congress in Paris on 19 May 2004), a informal agreement on collaboration between FIFA and WADA was signed by the respective presidents and confirmed by the IOC President, Dr Jacques Rooge. Based upon this agreement and adaptation of the FIFA Doping Control Regulations, changes have been incorporated in the FIFA Disciplinary Code. Legal Background In this regard, the legal background should be briefly illustrated. FIFA is a private association in accordance with Article 60 ff. Swiss Civil Code with headquarters in Zurich, Switzerland. Consequently, FIFA is a legal person in accordance with Swiss Private Law and has to comply with it when setting up its statues and regulations. The principles of fault and individual case management are essentials of Swiss Sanction Law and therefore have to be considered when imposing private sanctions. Every sanction contains a distinctive individual component, because every sentence has to take into account the International sports federations are free to establish disciplinary regulations and sanctioning as they deem appropriate fault of the delinquent. FIFA has been following these principles in his Doping Control Regulations from the beginning. In order to base its decisions on expertise, FIFA itself sought a legal opinion by the Court of Arbitration for Sport (CAS) as to the extent to which the World Anti- Doping Agency s code complied with Swiss law in September In its submission, WADA claimed that FIFA s provisions regarding the fight against doping and the sanctioning of doping offences showed significant deviations from the World Anti-Doping Code. In its legal opinion published in April 2006, CAS explicitly confirmed FIFA s practice of individual case management when sanctioning doping offences. In addition, CAS noted that FIFA s principle of

16 24 FIFA S APPROACH TO DOPING IN FOOTBALL F-MARC DOPING UPDATE 2006 F-MARC DOPING UPDATE 2006 FIFA S APPROACH TO DOPING IN FOOTBALL 25 individual case management complies with the World Anti-Doping Code. At the same time, the independent sports arbitration body, with headquarters in Lausanne (Switzerland), has also ruled that FIFA s provisions with regard to the fight against doping and the sanctioning of doping offences are, to the greatest possible extent, in line with the World Anti-Doping Code, and that they are also fully in line with Swiss law. CAS also compared FIFA s provisions with those of the World Anti-Doping Code in 22 main areas. In 16 points, including the definition of doping, the strict liability principle, the list of prohibited substances, therapeutic use exemptions, testing and analysis, hearings, commencement of the ineligibility period, and disqualification provisions regarding teams, CAS stated that there were no material differences between the two sets of regulations. Furthermore, CAS confirmed FIFA`s attitude by stating that neither the IOC President, Dr Jacques Rooge, FIFA President Mr. Joseph Blatter and Chairman of WADA, Mr Richard Pound International Olympic Committee (IOC) nor WADA has the right to dictate to FIFA as regards the latter s disciplinary regulations for the fight against doping and the sanctioning of doping offences. According to CAS, international sports federations are free to establish such provisions as they deem appropriate, especially as CAS also noted that the World Anti-Doping Code is not legally binding per se. CAS reported differences in six areas between FIFA s provisions and the World Anti-Doping Code, although it only highlighted significant deviations in three of these points. CAS came to the general conclusion that with regard to the approach used to determine the level of punishment to be imposed, there are no considerable differences between the two sets of regulations. With regard to the two-year punishment that the World Anti-Doping Code regards as the standard and FIFA as the maximum punishment, and in terms of the minimum punishment of six months (FIFA) and one year (WADA), CAS also noted that there was a difference that cannot be resolved solely by recourse to jurisprudence. With regard to possibly eliminating a sanction in cases in which an athlete proves that he did not act with fault or negligence, CAS recommended that FIFA incorporate an appropriate provision in its regulations and not impose sanctions on athletes who prove that a prohibited substance entered his body through no fault or negligence of his own. FIFA, however, already follows such a practice by applying the principle of guilt when sanctioning doping offences. In addition, FIFA was advised by CAS to adapt its regulations to clarify WADA s right of appeal against procedures followed in final-instance decisions. Conversely, it was noted that with its provision regarding the statute of limitations, the World Anti- Doping Agency s code is not in line with Swiss law. This legal opinion from CAS has laid the foundations for FIFA to make the necessary adjustments to the relevant provisions independently. FIFA will, however, invite the CAS panel to join a working group and assist to make these adjustments. Beyond that, after being operational for two years, it seems reasonable to reflect on the feasibility and applicability of the World Anti-Doping Code based upon the analysis of positive doping cases as related to the incidence and management amongst the different member associations. Such analysis is foreseen within the revision of the World Anti-Doping Code which has been initiated by WADA in April Occupational Medicine in Football a Vision Occupational medicine deals with all work-related health aspects that have an effect on the employee s ability to function effectively; the workplace itself, the type of work, the state of health of the employee. In addition to purely physical aspects, social and psychological influences must also be considered. It is easy to see that a construction worker who is paid according to how much work he completes will be subject to greater stress factors than, say, a gardener or office worker employed on standard terms. Moreover, within any occupation there are those often a considerable percentage who will regularly need medication to function properly, e.g. those suffering from diabetes, high blood pressure, allergies, rheumatic disorders etc. In such cases, any extra stress in the work environment can easily lead to a situation where the ability of the person to function is close to the borderline of what can be physically expected, and these people can often become incapable of continuing in the job or of only doing so under medical supervision and with the prescription of suitable medication. There are definite limits to the level of stress under which such people can function and it is the concern of occupational medicine to recognise and deal with these limits. Occupational medicine aims to point out to both employer and employee that only under certain specified conditions will optimum performance be possible. The conditions that could be recommended in such cases might include changes in the workplace, in working hours, in the pressure of the job, or might specify regular medical treatment for the employee, e.g. prescribed medication to protect the employee from the effects of workday stress, such as beta blockers. If we now turn to sports like football, a number of examples can be identified: The proportion of players who suffer from allergies is similar to that in the general population, and the treatment will be the same, i.e. appropriate therapy often involving the taking of medication, especially during those times of the year when the allergen count is high. But when we are dealing with open-air sports, the treatment prescribed could lead to problems since many of the drugs normally prescribed are on the list of banned substances (such as corticosteroids) even though their prescription is medically justified. A case that makes the situation very clear is that of an American professional international female player. She suffers from a relatively rare disease that makes her blood pressure and fluid balance subject to extreme variations; this in turn makes it impossible for her, without medical help, to pursue her profession at the required level. She needs ongoing treatment with a socalled mineralocorticoid (Fludrocortisone). However, in contrast to those mentioned above, this medication has neither an anabolic nor an anti-phlogistic effect and is thus not technically a doping substance in the true sense of the term.

17 26 FIFA S APPROACH TO DOPING IN FOOTBALL F-MARC DOPING UPDATE 2006 F-MARC DOPING UPDATE 2006 FIFA S APPROACH TO DOPING IN FOOTBALL 27 This raises the question of whether it really constitutes doping if a player can perform at the expected level only after taking such medication. We suggest that this is a problem that would fall within the scope of occupational medicine. If such treatment is prescribed for genuine medical reasons and involves taking a drug that in itself has no doping effect, then we cannot be talking about a case of doping, rather merely of enabling a professional athlete to exercise his or her normal profession. Occasional treatment with banned substances for bona There are limits of stress under which people can function and occupational medicine recognises and deals with these limits. fide medical reasons should be permitted if the facts of the case are presented openly to the doctors in charge of the doping control. A quite different question is whether the ever-increasing demands made on professional footballers, in terms of the number of matches and tournaments in which they are expected to play, can be compensated for by taking medication so that the required level of performance can be achieved over and over again. Playing so frequently, in football as in other sports, under circumstances necessitating more or less continual treatment with painkillers and anti-inflammatory agents can have serious long-term consequences that really cannot be justified on the basis of occupational medicine or medical ethics. In this case, the limits of doping are recognisable. Admittedly, there is no doping in these cases in terms of performance-enhancing drugs being taken. However, in the sense of medical treatment being used to suppress the symptoms of injuries and over-exertion, there is clearly an aspect of doping involved. The workplace pressure being placed on players in the short term leads to the long-term effects being ignored. As long as the players in question and their associations all have the same approach, only a firm stand taken by sports and occupational medicine will have the effect of providing the players with at least partial protection from such long-term damage. This is yet another reason why the campaign against real doping must be actively pursued. Contributing Authors: Prof. Jiri Dvorak Michel D Hooghe, MD Prof. Toni Graf-Baumann Don Kirkendall, PhD Martial Saugy, PhD Heinz Tännler

18 Social Drugs: Cannabis

19 30 SOCIAL DRUGS: CANNABIS F-MARC DOPING UPDATE 2006 F-MARC DOPING UPDATE 2006 SOCIAL DRUGS: CANNABIS 31 Social Drugs: Cannabis Introduction Marijuana, or cannabis, refers to the dried leaves and flowers of the Cannabis sativa plant. Hashish is the dried juice (resin) that is extracted from the leaves. The active ingredient in hashish and marijuana is THC (delta9- Tetrahydrocannabinol) and causes subjective effects of relaxation and contentment. Objective tests of psychological or physical performance all show impairment. Driving ability and memorisation declines. Other effects include a rapid heart rate, dilatation of small blood vessels of the eye and reduction of blood pressure. Huestis et al., 1998, reported an average urinary half-life of THC-COOH of about 45 to 60 hours while other groups have reported wider times of 0.9 to 9.8 days. It is clear that heavy users will show the first negative result in urine after stopping THC consumption much later than infrequent users. In one study, the average time to the first negative result in screening for THC metabolite (cut-off level 20 ng/ml) was 8.5 days (range 3 to 18) for infrequent users and 19.1 days (range 3 to 46) for regular users. Urinary concentration of between 20 and 50 ng can then often be attributed to a late excretion of cannabis consumption and hardly related to any recent intake. The active ingredient in hashish and marijuana is THC and causes subjective effects of relaxation and contentment. Absorption and Metabolism Absorption and metabolism of THC vary as a function of route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes with a peak of effect within 15 to 30 minutes and returning to baseline after 2-3 hours. Oral ingestion leads to later and longer effects with a maximum of between 2-3 hours. THC is metabolised mainly by hydroxylation and oxidation. The main metabolite is the 11-nor-9-carboxy- THC (THC-COOH), which may be glucuronated. Urine Excretion After smoking cannabis, urine starts to test positive for THC-COOH after an average of 4 hours (range = 2 to 8 hours). The long-term excretion of cannabis metabolite is due to the high lipophility of THC, which binds to fat tissues. This leads to a great inter-individual variability of the excretion of this product. Several studies have shown that the urine excretion pattern is strongly dependent on the status of the individuals. After taking a single dose of THC, the metabolite can be detectable for 3 to 5 days, but some authors showed detection for up to 12 days. 15 ng/ml Cut-off This limit of 15 ng/ml has been chosen in forensic science to avoid any false positive cases due to passive inhalation. It has been demonstrated that passive inhalation will not lead to a urinary result above this limit. References Kurzthaler I, Hummer M, Miller C, Sperner-Unterweger B, Gunther V, Wechdorn H, Battista HJ, Fleischhacker WW Effect of cannabis use on cognitive functions and driving ability. [Clinical Trial. Journal Article. Randomised Controlled Trial] Journal of Clinical Psychiatry. 60(6):395-9, 1999 Niedbala RS, Kardos KW, Fritch DF, Kardos S, Fries T, Waga J, Robb J, Cone EJ Detection of marijuana use by oral fluid and urine analysis following single-dose administration of smoked and oral marijuana. [Journal Article] Journal of Analytical Toxicology. 25(5): , 2001 Huestis MA, Cone EJ Differentiating new marijuana use from residual drug excretion in occasional marijuana users. [Clinical Trial. Controlled Clinical Trial. Journal Article] Journal of Analytical Toxicology. 22(6):445-54, 1998 Heather Ashton C Pharmacology and effects of cannabis. A brief review. British Journal of Psychiatry 178: , 2001 Contributing Author: Martial Saugy, PhD Leaf of the cannabis plant

20 Stimulants

21 34 STIMULANTS F-MARC DOPING UPDATE 2006 F-MARC DOPING UPDATE 2006 STIMULANTS 35 Stimulants Introduction This class of drugs stimulates the central nervous system (CNS) and may be used to reduce tiredness and increase alertness, competitiveness and aggression. For this reason, they are considered to have a performance enhancing effect in explosive power activities and endurance events, since the capacity to exercise strenuously is increased and sensitivity to pain is reduced. Stimulants are more likely to be used on the day of a competition; however, they may be used in training, to allow the intensity of the training session to be increased. Since stimulants could increase an athlete s aggression towards other competitors or officials, there are potential dangers involved in their misuse in contact sports. Relatively high doses are needed to reduce fatigue and performance can be reduced by side-effects, such as tremors for example. The stimulants class includes psychomotor stimulants, sympathomimetics and miscellaneous central nervous system stimulants. Examples of this class include caffeine, amphetamines, ephedrines and cocaine. Caffeine is the pharmacologically active substance found in tea, coffee and cola. The amount of caffeine present varies according to the type of drink and the way it has been prepared. In addition, caffeine may be a constituent of some common medications such as cold preparations and pain relief treatments, usually in quantities of less than 100 mg per dose. Caffeine produces mild central nervous system stimulation, similar to that of amphetamines, reducing fatigue and increasing concentration and alertness. Physiological effects include increased heart rate and output, increased metabolic rate and urine production. High doses can cause anxiety, insomnia and nervousness. In 2004, caffeine was removed from the list of prohibited substances and is now part of the monitoring programme. Amphetamines are controlled substances under general drugs legislation, although they have been prescribed as appetite suppressants and for the treatment of narcolepsy. Amphetamines are known to produce dependence, often in increasing doses. Athletes are likely to use amphetamines to sharpen reflexes and reduce tiredness. However, athletes have died as a result of amphetamine misuse, since the increase in blood pressure combined with increased physical activity and peripheral vasoconstriction makes it difficult for the body to cool down. If the body overheats, it dehydrates and blood circulation decreases, and the heart and other organs are unable to work normally. The sympathomimetic drug, ephedrine, is used to treat the symptoms of the cold virus, and was originally prescribed as a bronchodilator for asthma, although it is now regarded as less suitable for this use since it has been linked with cardiac arrhythmia. Ephedrine is likely to be misused for its stimulant effect but could also be ingested inadvertently because of its wide availability in over-the-counter medications. Cocaine has been used as a medication for many years. It was an original ingredient in Coca-Cola until it was removed in Its therapeutic indication is as a local anaesthetic, though misuse would be linked to its euphoric effects and a feeling of decreased fatigue. Its potential for use as a recreational drug emphasises the lifestyle pressures faced by some athletes. In some disciplinary sports, like sprint athletes, cocaine is likely to increase heat and lactic formation, which, coupled with vasoconstriction, could contribute to fatal cardiac damage. Amphetamine Amphetamine was synthesised in 1920 and used to reduce fatigue and increase alertness during World War II. Since then, many derivatives have been elaborated, such as f. e. methamphetamine, dimethamphetamine, methylendioxyamphetamine (MDA), methylendioxy methamphetamine (MDMA, ecstasy ) or selegiline, and they are all forbidden in the practice of sport. Amphetamine was prescribed unsuccessfully as a nasal decongestant, anti-depressant and appetite suppressant, but rapidly appeared to be a powerful central nervous system stimulant acting primarily by enhancing the brain activity of norepinephrine and dopamine, intensifying psychological sensations of alertness, concentration and self-confidence. Metabolism of Amphetamines Amphetamine is readily absorbed, mainly from the small intestine, and the peak plasma concentration occurs 1-2 hours following administration. Absorption is usually complete in hours and is accelerated by food intake. The metabolism of amphetamine has been difficult to investigate because of the wide variation between species in its metabolic effects. The principal amphetamine metabolites are p-hydroxy ephedrine and p-hydroxy amphetamine. Amphetamine is lost from the body by renal filtration. For the detection of amphetamine use in sport, the urine is analysed for the parent compound amphetamine. After a single dose of amphetamine, it has been shown that detection can be achieved in urine in the first urine void and can be seen for at least 48 hours after the intake of the drug. The peak concentration in urine is strongly Amphetamine Ephedrine Cocaine Annual statistics for drug testing by IOC accredited laboratories Year Total A-samples analysed Number of positive samples with stimulants % positive samples with stimulants NH 2 H CH 3 N O C CH 3 N CH ** 151, * 131, * 125, * 117, * 118, * 105, H C CH 3 H 3 C C H O 1997 * 106, * 96, CH 2 H C OH C O 1995 * 93, * 93, * 89, * 87, * 84, * 71, Amphetamine Ephedrine Cocaine 1989 * 52, * 47, Figure 1: Chemical structure of amphetamine, ephedrine and cocaine Table 1: Annual statistics for drug testing by IOC-accredited laboratories * Data from IOC, ** Data from WADA

22 36 STIMULANTS F-MARC DOPING UPDATE 2006 F-MARC DOPING UPDATE 2006 STIMULANTS 37 dependent on the individuals, but occurs between 3 and 12 hours after the intake of the drug. Amphetamine excretion is enhanced by an acidic urine, and treatments that increase the acidity of urine enhance amphetamine loss a reaction that is useful in the treatment of amphetamine overdose. Amphetamine Action The positive effects of amphetamines include an increase in physical energy, mental aptitude, talkativeness, restlessness, excitement and good humour. Subjects taking amphetamine also report that they feel confident, efficient, ambitious and that their food intake is reduced. Some negative effects of amphetamine (that can be dose-dependant) are anxiety, indifference, slowness in reasoning, irresponsible behaviour, irritability, dry mouth, tremors, insomnia and, following withdrawal, depression. Tolerance develops rapidly to many of the effects of the amphetamines. Tolerance is said to be present when, over a period of time, increasing doses of a drug are required to maintain the same response. There is significant evidence to show that amphetamines induce drug dependence and the amphetamine-dependant person may become psychotic, aggressive and anti-social. Withdrawal of amphetamines is associated with mental and physical depression. The major side-effects of amphetamine administration include confusion, delirium, sweating, palpitations, dilation of the pupil and rapid breathing as well as hypertension, tachycardia, tremors, muscle and joint pain. Chronic amphetamine administration is associated with myocardial pathology and with growth retardation in adolescents. In most cases, the personality changes induced by chronic low doses of amphetamine are reversed gradually after the drug is stopped. High chronic doses may lead to a variety of persistent personality changes, paranoid delusions and tactile hallucinations called amphetamine psychosis. Amphetamines in Sport Amphetamines induce drug dependence and the dependant person may become psychotic, aggressive and anti-social The effect of amphetamines on sporting performance was first investigated in It has been concluded that amphetamines enhance anaerobic performance while having little or no effect on aerobic performance. Amphetamines might enhance sports performance from a supplemental mental stimulant effect as well as the effects on physical power derived from all three human energy systems the anaerobic (ATP-CP, lactic acid) and oxygen energy systems. Depending on the type of effect or effort the athlete has to do, the dosage might be important for the user. Aggressiveness seems to be increased by high dosage, when alertness is stimulated by lower quantities. To summarise, amphetamines might improve reaction time when fatigued, increase muscular strength and endurance, increase acceleration, raise lactic acid levels at maximal exercise, increase aerobic endurance capacity and stimulate metabolism by inducing a loss of body fat. All amphetamines are banned by the WADA and IOC codes. Laboratory analysis is qualitative only, verifying the presence of metabolites in urine. It is sufficient to demonstrate the substance is present in the urine to declare the case as an analytical adverse finding. The presence of amphetamine in urine can be described as a severe doping offence because amphetamines are no longer used therapeutically. Many countries prohibit their use because of their adverse effects. Amphetamines are part of the S6 category of the prohibited substances in competition. Amphetamine Side-Effects in Relation to Sport Side-effects of amphetamine beyond headaches, sleeplessness and anxiety are particularly important to athletes. Indeed, amphetamine use may carry significant health risks for the sportsman as evidenced by several amphetamine-linked deaths in sport. Two of the major risks are amphetamine-induced heatstroke and cardiac arrest that have caused several fatalities in cyclists during arduous effort. Amphetamines obscure painful injuries and have enabled athletes in some sports to continue to compete and exacerbate their injuries. The side-effects of amphetamine on behaviour are also important in sport. Amphetamine administered to promote aggression and weaken fatigue has led to misjudgements and major fouls on the pitch, due to its euphoric effects. Cocaine Cocaine is the most potent stimulant of natural origin. As opposed to amphetamines, which are pure synthetic compounds, cocaine is primarily obtained from coca species and its notoriety belies the fact that the drug has been used as a stimulant for thousand of years. Incas used to chew coca leaves to fight against tiredness; cocaine was used in a number of patent medicines and even in soft drinks. In its pure form, cocaine is a white crystalline powder extracted from the leaves of the South American coca plant. Pure cocaine was first used medicinally in the 1880s as a local anaesthetic in eye, nose and throat surgery because of its ability to provide anaesthesia as well as to constrict blood vessels and limit bleeding. Many of its therapeutic applications are obsolete though due to the development of safer drugs. Cocaine can be snorted, smoked or injected. When snorted, cocaine powder is inhaled through the nose and absorbed into the bloodstream through the nasal tissues. When injected, a needle is used to release the drug directly into the bloodstream. Smoking involves inhaling cocaine vapour or smoke into the lungs where absorption into the bloodstream is as rapid as by injection. Each of these methods of administration pose great risks to the user. Crack is cocaine that has been processed from cocaine hydrochloride to a free base for smoking. The most popular route of administration is snorting, which produces peak effect from 5-15 minutes and lasts for up to one hour. Inhalation of free-base cocaine produces peak effects in less than 1 minute and a short-lived physiological effect measured in minutes.

23 38 STIMULANTS F-MARC DOPING UPDATE 2006 F-MARC DOPING UPDATE 2006 STIMULANTS 39 Cocaine Action Cocaine is a strong central nervous system stimulant and is probably the most addictive agent known. Its recreational use is widespread, and it is highly addictive with its effect mediated through dopamine release. For ethical and practical reasons, most of the knowledge of the pharmacology of cocaine comes from animal studies or from addict reports. Physical effects of cocaine use include constricted blood vessels, increased temperature, heart rate and blood pressure. It also increases motor activity, talkativeness and is a strong agent to reach euphoria. The duration of cocaine s immediate euphoric effects (hyper-stimulation, reduced fatigue and mental clarity) depends on the route of administration. The faster the absorption, the more intense the effects and the shorter the duration of action. The effects from snorting may last 15 to 30 minutes while the effects from smoking may last 5 to 10 minutes. Increased use can reduce the period of time a user feels high and increases the risk of addiction. Cocaine users usually feel an initial rush or sense of well-being, of having more energy and being more alert. This effect quickly wears off, often leaving the user feeling more down or depressed than before. This down feeling leads the addict to use more cocaine, sometimes just to feel normal. Over a period of time, the amount of cocaine needed and the frequency of use to achieve a high have to be increased. Classic physical effects of cocaine use include constricted blood vessels, dilated pupils and increased temperature, heart rate and blood pressure. Cocaine is more highly addictive than amphetamine and the increasingly higher doses addicts are using may lead to a state of irritability, restlessness, anxiety and paranoia. Other complications associated with cocaine use include disturbances in hearth rhythm and heart attacks, chest pain and respiratory failure, strokes, seizures and headaches and gastrointestinal complications such as abdominal pain and nausea. Cocaine abuse is strongly associated with cerebrovascular accidents arising either from the rupture or spasm of cerebral blood vessels. Different means of taking cocaine can produce different adverse effects. Regular snorting, for example, can lead to loss of sense of smell, nosebleeds, problems with swallowing, hoarseness, and a chronically runny nose. Ingesting cocaine can cause severe bowel gangrene due to reduced blood flow. People who inject cocaine can experience severe allergic reactions and, as with any injecting drug user, are at increased risk of contracting HIV and other blood borne diseases. The initial rush quickly wears off, often leaving the user feeling more down or depressed than before Cocaine in Sport Contrary to popular belief, cocaine does not really enhance performance, whether in the job, in sport, at school or with a sexual partner. On the contrary, long-term use can lead to loss of concentration, irritability, loss of memory, paranoia, loss of energy, anxiety and a loss of interest in sex. In particular, several studies have demonstrated that cocaine has no beneficial effect on running times and reduces endurance performance. Furthermore, at all doses, cocaine significantly increases glycogen degradation while increasing plasma lactate concentration without producing consistent changes in plasma catecholamine levels. The controlling effect cocaine has on an addict s life can lead to exclusion of all other facets of life. Nevertheless, despite these apparently detrimental effects, cocaine continues to be abused in sport. It may be that cocaine only affects activities of short duration requiring a burst of highintensity energy output. It is possible that the central nervous stimulatory effect may be more important than its action on peripheral metabolism. It has been suggested that the heightened arousal and increased alertness effects, achieved principally at low doses, drew athletes to cocaine. Cocaine was federally regulated in December This act banned non-medical use of cocaine, prohibited its importation and sale. Cocaine can currently be administered by a doctor for legitimate medical use, such as local anaesthetic for some eye, ear and throat surgeries. Cocaine is banned by both WADA and the IOC, including its use as a local anaesthetic. Like amphetamines, it is part of category S6 of the prohibited substances in competition and the presence of cocaine and/or its metabolites (benzoylecgonine and methylecgonine) in urine can be described as a severe doping offence. Cocaine Side-effects in Relation to Sport A number of dramatic fatalities associated with coronary occlusion have occurred in cocaine-abusing athletes, usually those who have been exercising intensely following drug administration. Many sports people who abuse cocaine complain of negative central effects such as perceptual misjudgements and time disorientation that sometimes reduces their athletic performance. Furthermore, cocaine addicts frequently turn to other drugs to relieve the down feeling when more cocaine is not available. When used together, these drugs and cocaine can prove even more deadly than when used alone. Some fatalities have also occurred when cocaine abuse has been mixed with alcohol or anabolic steroids. Joint abuse of alcohol and cocaine is extremely cardiotoxic. These practices increase the risk of sudden death by cardiac arrest or seizures followed by respiratory arrest. Ephedrines Ephedra alkaloids which are popular components of many nutritional supplements are naturally occurring central nervous system stimulants obtained from several ephedra plant species. Purified forms of these substances include ephedrine, pseudoephedrine, norephedrine, methylephedrine, norpseudoephedrine and methylpseudoephedrine. Phenylpropanolamine is a synthetic compound functionally similar to the ephedra alkaloids in effect and use. Ephedrine, which is now also produced by chemical synthesis, is closely related in structure to metamphetamine, although its CNS actions are much less potent and also longer-acting than those of amphetamines. Its peripheral stimulant actions are similar to, but less powerful than, those of epinephrine (also called adrenaline), a hormone produced in the body by the adrenal glands. Ephedrines Action Of the ephedra alkaloids, ephedrine is the most potent thermogenic agent. Ephedrine is a mixed sympathomimetic agent, which acts as a stimulant in the central nervous system by enhancing the release of norepinephrine from sympathetic neurons and stimulating alpha and beta receptors. Ephedrine stimulates heart rate and thereby increases cardiac output, but also causes peripheral constriction, resulting in an increase in peripheral resistance that can lead to a sustained rise in blood pressure. Ephedrine relaxes the bronchial smooth muscle and is used as a decongestant and for temporary relief of shortness of breath caused by asthma. Historically, ephedra alkaloids have been used for both asthma and allergies in China for more than 5,000 years. Ephedrine has moderately potent bronchial muscle relaxant properties and has been used clinically for the treatment of asthma. Currently, ephedrine is found in various pharmaceuticals mainly as decongestants and in numerous nutritional and dietary supplements as energy stimulants and anorexic agents. Pseudoephedrine can be found in many prescription and over-thecounter preparations (mostly for the treatment of congestion) that may be used for treating respiratory infections or allergies. Until its recent voluntary removal

24 40 STIMULANTS F-MARC DOPING UPDATE 2006 F-MARC DOPING UPDATE 2006 STIMULANTS 41 from the market because of reports of increased risk of strokes in women, phenylpropanolamine was also used similarly to pseudoephedrine and in overthe-counter diet pills. Ephedrine is excreted in a largely unchanged form in urine and the usual elimination halflife is 3 to 6 hours, which can be prolonged with increased urine ph. Common side-effects of ephedrine are qualitatively similar to those produced by amphetamines, but are generally milder: headache, dizziness, irritability, anxiety, tremor and psychosis. Higher doses (overdose) can cause restlessness and anxiety, dizziness, insomnia, tremor, rapid pulse, sweating, respiratory difficulties, confusion, hallucinations, delirium and convulsions. The most dangerous symptoms of overdose are abnormally high blood pressure and rapid, irregular heartbeat. A dose of ephedrine only two or three times the therapeutic maximum can cause a significant increase in blood pressure. Finally, a number of instances of psychosis, clinically similar to amphetamine psychosis, have resulted from chronic high-dose abuse. Regarding food supplements containing ephedra alkaloids, there are serious doubts concerning their safety. Because supplements are not considered therapeutic, they are not held to the same level of rigor in claiming efficacy and safety as that required of prescribed and over-thecounter medications. Since the 1994 deregulation, an increased number of reports of adverse events, including hypertension, arrhythmia, myocardial infarction, seizure, cerebrovascular accidents and death, has prompted the FDA to recommend a limit on the use of ephedra alkaloids. Furthermore, the joint use of ephedrine and caffeine can augment adverse cardiovascular and CNS effects. Ephedrine in Sport With their stimulant properties and sympathomimetic actions, ephedra alkaloids have been perceived as products that can potentially be used to enhance athletic performance and lending unfair advantages to athletes, even if used in supplement forms. Research has shown that the isolated use of ephedrine, pseudoephedrine and phenylpropanolamine alone at usual dosages has an inconsistent, and probably insignificant, ergogenic benefit for power, endurance, strength or speed. Other studies looking at the use of ephedrine combined with vitamins, minerals or caffeine have supported potential ergogenic effects. Indeed, many athletes use food supplements containing ephedra alkaloids because of perceived benefits of increased energy, increased time to exhaustion and potential thermogenic properties with increased metabolism, increased fat loss and improved muscle strength. In particular, a series of studies evaluated the effects of ephedrine in combination with caffeine, showing an increased time to exhaustion and decreased rating of perceived exhaustion on cycle ergometry compared with either the drug alone or a placebo. The medical use of ephedrine is tolerated by WADA and the IOC at therapeutic levels. Nevertheless, urine concentrations of greater than 10 µg/ml are considered positive. Ephedrine is a category S6 prohibited substance. Ephedrine Side-Effects in Relation to Sport Because of recent highly publicised tragedies, various athletic associations have focused on further evaluations of the use of these substances and on trying to educate athletes about potential health risks associated with their use. Continued evaluation of the use of these substances is necessary, as is continued education of athletes, parents, coaches and trainers regarding the health risks associated with ephedrine alkaloids and corresponding supplements. References Bohn AM, Khodaee M, Schwenk TL Ephedrine and other stimulants as ergogenic aids. Current Sports Medicine Reports, 2(4): pp , George AJ Central nervous system stimulants. Best Practice & Research Clinical Endocrinology & Metabolism, 14(1): pp 79-88, Verroken M Drug use and abuse in sport. Best Practice & Research Clinical Endocrinology & Metabolism, 14(1): pp 1-23, Contributing Authors: Lidia Mateus-Avois, PhD Neil Robinson, PhD Christophe Saudan, PhD Norbert Baume, PhD and Martial Saugy, PhD Regarding food supplements containing ephedra alkaloids, there are serious doubts concerning their safety

25 Testosterone and Synthetic Anabolic Steroids

26 44 TESTOSTERONE AND SYNTHETIC ANABOLIC STEROIDS F-MARC DOPING UPDATE 2006 F-MARC DOPING UPDATE 2006 TESTOSTERONE AND SYNTHETIC ANABOLIC STEROIDS 45 Testosterone and Synthetic Anabolic Steroids Introduction Anabolic steroids are chemical, synthetic derivatives of testosterone modified to enhance the anabolic and minimise androgenic actions of the hormone. Testosterone is a steroid hormone synthesised in the human body from cholesterol and serves distinct functions at different stages of life. During embryonic development, androgen action is central to the development of the male phenotype. At puberty, the hormone is responsible for the secondary sexual characteristics that transform boys into men. Testosterone regulates many physiological processes in the adult male including muscle protein metabolism, sexual and cognitive functions, erythropoiesis, plasma lipids and bone metabolism. The purpose of this article is to give an overview of the use of anabolic-androgenic steroids (AAS) in sport together with the methods used in anti-doping laboratories for their detection in urine. In the following article in this issue, special emphasis is laid on the use of nandrolone, which is known to be one of the most widely used AAS by athletes who need power and muscle strength. Anabolic steroids are effective in enhancing athletic performance, but the side-effects can jeopardise health Pharmaceutical Action of Anabolic Steroids Soon after testosterone was isolated in 1935, it was discovered that it is virtually inactive when taken orally. After oral ingestion, testosterone is absorbed from the small intestines and passes via the portal vein to the liver where it is rapidly metabolised, mostly to inactive compounds. The discovery of testosterone has given rise to the synthesis of anabolic steroids. Chemical modifications of testosterone have been useful pharmacologically to alter the relative anabolicandrogenic potency, slow the rate of inactivation and change the pattern of metabolism. Most oral anabolicandrogenic steroids preparations are 17-alpha alkylated derivatives of testosterone that are relatively resistant to hepatic degradation. Esterification of the 17-beta hydroxyl group makes the molecule more soluble in lipid vesicles used for injection and hence slows the release of the injected steroid into the circulation. Commonly used 17-α alkyl and 17-β ester derivatives are: 17-α alkyl derivatives: stanozolol, danazol, fluoxymesterone, methyltestosterone, methandrostenolone, oxandrolone and oxymetholone 17-β ester derivatives: Nandrolone decanoate, boldenone, trenbolone, methenolone and testosterone enanthate Evidence suggests that at the normal male physiological range of plasma testosterone concentrations, the androgen receptors to which testosterone and dihydrotesterone (DHT) bind are fully saturated. Invitro studies have demonstrated that the dose-response relationship of testosterone on growth of skeletal muscle reaches a plateau once the physiological concentration is exceeded. It has been suggested that when anabolic steroids are abused by athletes, the drugs are producing their effects by another receptor mechanism, unsaturated or unaffected by normal plasma testosterone and DHT concentrations. Indeed, it is supposed that the effect of a supraphysiological dose of testosterone on muscle is mediated through an antiglucocorticoid action independent of androgen receptors. Glucocorticoids such as cortisol and corticosterone are hormones that influence glucose synthesis and protein catabolism. Stimulation of glucocorticoid receptors will lead to an enhancement of protein breakdown in muscle. According to one theory, the high doses of anabolic steroids used by many athletes displace glucocorticoids from glucocorticoid receptors and inhibit muscle protein catabolism, leading overall to an anabolic or muscle-building effect. Therapeutic Uses of Anabolic-Androgenic Steroids A number of clinical studies using a variety of experimental designs have shown that the potent anabolic effects of AAS have positive benefits to various patient populations. Physiological replacement doses of testosterone have been used therapeutically to stimulate sexual development in cases of delayed puberty and in cases where the testicles have been surgically removed, because of either physical injury or testicular tumour. Anabolic steroids are occasionally used to treat gynaecological conditions in women, although longterm usage produces severe side-effects such as erratic menstruation and the appearance of male secondary characteristics. They are occasionally used to combat breast tumours in pre-menopausal women. The first major clinical use of anabolic steroids was to inhibit the loss of protein and aid muscle regeneration after major surgery. Anabolic steroids may be used to increase growth in prepubescent boys who have failed to reach the expected height for their age. Adverse Effects of Anabolic-Androgenic Steroids Anabolic steroids are effective in enhancing athletic performance. The trade off, however, is the occurrence of adverse side-effects that can jeopardise health. Since AAS have effects on several organ systems, a myriad of side-effects can be found. In general, orally administered AAS have more adverse effects than parenterally administered AAS. In addition, the type of AAS is not only important for the advantageous effects, but also for the adverse effects with the AAS containing a 17- alkyl group having potentially more adverse affects, particularly to the liver. One of the problems with athletes, in particular strength athletes and bodybuilders, is the use of oral and parenteral AAS at the same time ( stacking ), and in dosages that may be several (up to 40 times) the recommended therapeutical dosage. The frequency and severity of side-effects is quite variable. This depends on several factors such as the type of drug, dosage, duration of use and the individual sensitivity and response. The potential adverse effects of AAS can be divided into several main categories, including cardiovascular, hepatic, endocrine/reproductive, psychological and tendon injury: Cardiovascular. Chronic administration of anabolic steroids causes a reversible reduction in serum highdensity lipoprotein (HDL) levels. Since HDL binds cholesterol and renders it inert, reduced HDL levels are associated with arteriosclerosis, although no long-term study on athletes has been completed. Hepatic. AAS may exert a profound adverse effect on the liver. This is particularly true for orally administered AAS. Parenterally administered AAS seem to have less serious effects on the liver. Testosterone cypionate, testosterone enanthate and other injectable anabolic steroids seem to have few adverse effects on the liver. However, lesions of the liver have been reported after parenteral nortestosterone administration, and also occasionally after injection of testosterone esters. The influence of AAS on liver function has been studied extensively. The majority of the studies involve hospitalised patients being treated for prolonged periods for diseases such as anaemia, renal insufficiency, impotence and pituitary dysfunction. In clinical trials, treatment with anabolic steroids resulted in a decreased hepatic excretory function.

27 46 TESTOSTERONE AND SYNTHETIC ANABOLIC STEROIDS F-MARC DOPING UPDATE 2006 F-MARC DOPING UPDATE 2006 TESTOSTERONE AND SYNTHETIC ANABOLIC STEROIDS 47 Endocrine/reproductive. Endogenous AAS lead to reduced serum testosterone levels that can influence spermatogenesis and lead to a severe decrease of fertility in males. In one study, the sperm count fell by 73%, and in three individuals, azoospermia (complete absence of sperm cells) was present when high doses of anabolic steroids were taken chronically. In-depth interviews with 110 AAS users revealed that 56% of the males reported testicular atrophy and 62% of the females had menstrual irregularities. It should be also mentioned that long-term administration of steroids might lead to the development of mammary tissue because AAS can be converted to oestradiol by hepatic aromatase enzymes, which then induces development of mammary tissue. Psychological. Administration of AAS may affect behaviour. Increased testosterone levels in the blood are associated with masculine behaviour, aggressiveness and increased sexual desire. Increased aggressiveness may be beneficial for athletic training, but may also lead to overt violence outside the training environment. There are reports of violent, criminal behaviour in individuals taking AAS. Other side-effects of AAS are euphoria, confusion, sleeping disorders, pathological anxiety, paranoia and hallucinations. Tendon injuries. Tendon rupture has been linked with AAS based on a small number of published case reports. It has been suggested that these drugs predispose tendon rupture by altering collagen structure. It is possible that the rapid strength adaptations produced by AAS in skeletal muscle are not simultaneously matched by the more slowly-adapting, less vascular tendon structures, making tendons the weak link in the chain. Testosterone Figure 1. Molecular structure of testosterone Athletic Use of Anabolic-Androgenic Steroids For many years, the medical community combated AAS use by denying its effectiveness for promoting lean body mass. Early studies were flawed and did not reflect the way AAS are used. Athletes actually cycle on and off compounds, switching from one to another to avoid developing tolerance. They stack AAS, taking several different steroids at the same time to lower the dose of each and activate different steroid receptors. The scientific basis for stacking is highly questionable and has not been proven. AAS are generally accepted as having the desired anabolic effects, provided athletes also consume adequate protein and exercise intensely. In a randomised controlled trial, those taking 600mg testosterone intra-muscular injections weekly for 10 weeks had significantly increased muscle mass, muscle strength and fat-free mass compared to the placebo. However, not all studies have found such strength gains. Testing for Anabolic-Androgenic Steroids International organisations have established a list of substance classes and methods that athletes are forbidden to use during competition and training. The latest list established by the World Anti-Doping Agency (WADA) for 2005 includes two types of steroids: 1. Typically exogenous steroids, whose main examples have been given previously. 2. Typically endogenous steroids, e.g. androstenediol, androstendione, dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT), testosterone and related substances. Testing for anabolic agents in the urine of athletes was implemented on a large scale during the 1976 Montreal Olympic Games and was mainly based on radioimmunoassay (RIA) techniques. The techniques for the identification and characterisation of steroids and their metabolites in the urine have improved considerably during the last two decades. This improvement is largely due to the use of gas chromatography-mass spectrometry (GC-MS) techniques. Today, most antidoping laboratories use techniques that are based on the solid phase extraction of the urine sample followed by chemical modifications prior to GC-MS analysis. The confirmation procedure in an anti-doping analysis consists of demonstrating unequivocally that there is a correspondence between the GC and MS properties of the anabolic agent or its metabolite with those of an authentic pure standard or of a reference excretion study. The detection of exogenous substances means identifying the parent compound or at least one metabolite. Nevertheless, with substances that are produced endogenously such as testosterone, the presence of the substance alone cannot be considered to be an offence by itself. Moreover, a cut-off value for testosterone concentration cannot be used because of large interindividual and intra-individual urinary concentrations of the steroid. The intake of testosterone, however, causes characteristic changes in the pattern of steroids excreted in the urine. Based on studies of athletic populations, in 1983 the International Olympic Committee (IOC) adopted a ratio of testosterone to epitestosterone (T/ E) with an authorised upper limit of 6.0 as a criterion for the administration of testosterone. Epitestosterone is a minor product of testosterone metabolism and does not increase after testosterone administration; the resulting effect is an increase in the T/E ratio. In the athletic population, the ratio is generally less than 2.0. The IOC rules clearly indicate that a T/E ratio greater than 6.0 constitutes an offence unless there is evidence that this ratio is due to a physiological or pathological condition, e.g. low epitestosterone excretion, androgenproducing tumour and enzyme deficiencies. Before the sample is declared positive, further investigations are conducted as a longitudinal study. As a first step, a comparison with previous values should be done. If no previous values are available, several additional urine samples are analysed over a short period of time. This longitudinal study may represent a useful tool for discriminating the false-positive (naturally elevated T/ E ratios) results from those due to manipulation of the urine. According to guidance given by the World Anti- Doping Agency (WADA) in 2004, urine samples should be now submitted to isotopic ratio mass spectrometry (IRMS) if the T/E is greater than or equal to 4.0 and testosterone, testosterone metabolites, epitestosterone and DHEA concentrations are greater than the fixed cut-off concentrations. Even if a longitudinal study gives good quality information on the potential steroid profile manipulation, there is a lack of definitive proof for the exogenous application of natural steroids. One possible solution is the ratio of the two stable carbon isotopes 13C/12C, which can allow the differentiation of natural and synthetic steroids. As exogenous testosterone or precursors contain less 13C than their endogenous homologues, it is expected that urinary steroids with a low 13C/12C ratio originate from pharmaceutical source. The method for determining the isotopic composition of the relevant analyte includes gas chromatography, a subsequent combustion to CO2 and finally, mass spectrometric analysis of this gas in a special multi-collector mass spectrometer (gas chromatography/ combustion/isotope-ratio-mass-spectrometry, GC/C/ IRMS). The 13C/12C value of testosterone or that of its metabolites will be measured and compared to that of urinary reference steroids within the sample. It should be emphasised that the 13C/12C value of these endogenous reference compounds should not be affected by steroid administration. The result will be reported as consistent with the administration of a steroid if a significant difference is observed between the 13C/12C values of testosterone metabolites and the endogenous reference compound. According to population studies, a different cut-off for positivity was set in 2004 by the WADA Laboratory Committee. If the IRMS study does not readily indicate exogenous administration, the result should be reported as inconclusive and necessitate further longitudinal studies. References Evans NA Current concept in anabolic-androgenic steroids. Am J Sports Med. 2004;32: Saugy M, Cardis C, Robinson N, Schweizer C. Test methods: anabolics. Baillieres Best Pract Res Clin Endocrinol Metab. 2000;14: WADA Technical Document reporting and evaluation guidance for testosterone, epitestosterone, T/E ratio and other endogenous steroids, Contributing Authors: Christophe Saudan, PhD Norbert Baume, PhD Lidia Mateus-Avois, PhD Neil Robinson, PhD and Martial Saugy, PhD

28 Nandrolone

29 50 NANDROLONE F-MARC DOPING UPDATE 2006 F-MARC DOPING UPDATE 2006 NANDROLONE 51 Nandrolone Introduction Nandrolone, or 19-Nortestosterone (Figure 1), is a synthetic anabolic-androgenic steroid (AAS), part of the norsteroids family and derived from the testosterone molecule the main sex steroid hormone produced in man. The small chemical modification (at carbon atom number 19) makes nandrolone more anabolic than androgenic. This is a crucial point for medical use and is at the origin of the widespread misuse of nandrolone in sport. It is important to minimise the main negative, androgenic effects of the AAS. For example, testosterone has an anabolic:androgenic ratio of 1 whereas the same ratio for nandrolone is 10, indicating that nandrolone has powerful anabolic properties. There have been numerous positive doping cases involving nandrolone over the last decade. These positive cases have led numerous anti-doping laboratories to investigate various hypotheses concerning the origin of the nandrolone metabolites found in urine. In this brief review, the medical use and misuse by athletes will be discussed. The Fédération Internationale de Football Association (FIFA) participates actively in the research performed in collaboration with anti-doping laboratories. Nandrolone as a Xenobiotic The first synthesis of nandrolone was reported in Since then, the pharmaceutical industry has produced norsteroids for humans and animals for substitutive (hypogonadism), complementary (osteoporosis and haematological diseases), contraceptive and growth stimulating treatment. Nandrolone is commonly administered as an injectable agent. Deca-Durabolin is the most widely recognised pharmaceutical formulation. Because of its potent anabolic properties, nandrolone is used by athletes as a doping agent to accelerate muscle growth in order to increase lean body mass, strength and aggressiveness. Even if scientific data are not conclusive, nandrolone is also used for faster recovery. Exogenous application can be either by intra-muscular injection or oral ingestion of nandrolone itself or precursors such as 19-norandrostenedione or 19-norandrostenediol. These latter two components are currently popular with nutritional supplement manufacturers to produce prohormone supplements. Nandrolone Excretion in Urine Once introduced in the organism, exogenous substances go through a multitude of metabolic steps that transform the original molecules into its active forms, into metabolites that are excreted in urine, or both. The study of the elimination process relative to time is called pharmacokinetics. Depending on the method of administration, urinary nandrolone metabolites can be detected for several days after oral ingestion or for months after intra-muscular injection. Elimination and detection is strongly dose-dependent and individual. A recent study by the Swiss Anti-Doping Laboratory, in collaboration with F-MARC (FIFA Medical Assessment and Research Centre), showed that urinary nandrolone elimination is a difficult biological process. A total of 22 volunteers ingested two oral doses of labelled nandrolone. Urine was collected over five days after intake and was analysed for 19-NA (19- Norandrosterone) and 19-NE (19-noretiocholanolone). A rapid elimination of metabolites in urine, with wide inter-individual variability, was observed (Figure 2). This variability could be related to the use of oral ingestion. Indeed, the rate of absorption through the intestinal pathway, in particular the first stage through the liver, is likely to be more variable than through an intramuscular injection. Nevertheless, this study demonstrated that, in the case of a positive test for nandrolone, it is very difficult to know the moment and the method of administration of the substance. Nandrolone Figure 1: Molecular structure of nandrolone or 19-nortestosterone. Detection of Nandrolone Nandrolone is transformed in the organism into few degradation products. The two major metabolites are 19-norandrosterone (19-NA) and 19-noretiocholanolone (19-NE). The finding of a potential doping offence with nandrolone is based on the urinary detection of 19-NA and 19-NE. Nandrolone has been on the banned list of the International Olympic Committee (IOC) since the Olympic Games in Montreal in In 1996, the IOC set the threshold for 19-NA at 2 ng/ml urine for males and at 5 ng/ml urine for females. In 2004, a technical document edited by the World Anti-Doping Agency (WADA) set the threshold at 2 ng/ml for both males and females. As with other steroids, nandrolone metabolites are quantified after being extracted from urine samples by gas chromatography coupled with mass spectrometry. Modern analytical instruments used by anti-doping laboratories are extremely sensitive and can detect a very low level of urinary 19-NA and 19-NE. Traces of about 0.2 ng/ml can be detected in urine. NA concentration [ng/ml] Time [h] Figure 2: Inter-individual variability in pharmacokinetics of 13C 19-NA following ingestion of two oral doses of 13C nandrolone. Origin of Nandrolone Metabolites in Urine Some positive cases of nandrolone in football and judo were reported just before the 1998 World Cup in France. This initiated a debate about whether the human body could produce traces of nandrolone metabolites without any intake of forbidden substances. FIFA decided then to support research projects on nandrolone in order to test the three following hypotheses that were presented by specialists: 1. The natural production, by the body, of nandrolone due to enzymatic transformation of endogenous testosterone to endogenous 19-nortestosterone (nandrolone). 2. The intake of nutritional supplements which have been previously voluntary or accidentally contaminated by nandrolone precursors. 3. The intake of smaller doses (oral) of nandrolone precursors. Endogenous Nandrolone Recent studies have shown that the urine of stallions, the follicular fluid of mares and the urine of cows and pregnant boars contain traces of endogenous nandrolone. Similarly, nandrolone has been identified in human ovarian follicular fluid as a possible intermediate in an enzymatic conversion of androgens to oestrogens. Moreover, a pregnant woman might be able to produce nandrolone or 19-NA that has been detected in the urine of women in their 6th and 14th weeks of pregnancy. Regarding men, no clear answer to the question of endogenous production of nandrolone metabolites has been offered. The discussion on the natural origin, in very few sportsmen, of sub-nanograms of nandrolone metabolites in urine has still not been completely resolved. Analyses performed on a worldwide basis by all of the WADA-accredited laboratories in recent years seem to confirm that the urinary concentration of possible endogenous production, if any, should lie below the cut-off value of 2 ng/ml in normally concentrated urine or in over-concentrated urine after correction for specific gravity. Nutritional Supplements and Nandrolone In the last few years, dietary supplements have been widely used by elite athletes and football players who believe that products like creatine, prohormones, amino acids and mental enhancers will boost their physical and psychological abilities. The beneficial effects of most of these products are not clearly established despite the numerous studies performed. The widespread accessibility of supplements is at the root of the use of these unproven products.

30 52 NANDROLONE F-MARC DOPING UPDATE 2006 F-MARC DOPING UPDATE 2006 NANDROLONE 53 Positive cases with very small urinary concentrations of forbidden substances like 19-NA have appeared recently. Anti-doping laboratories investigated the actual composition of over-the-counter supplements available on the internet, in shops or in fitness clubs. Many of these investigations have shown that both hormonal and non-hormonal dietary supplements are mislabelled and may contain anabolic-androgenic steroids or prohormones which could be transformed to compounds that are produced by the metabolism of banned anabolic steroids like nandrolone. There is a clear risk, therefore, of unintentional doping through the use of nutritional supplements. This danger is not very well understood by the athletes and a regular education of athletes, coaches and medical staff is necessary to decrease the abuse of dietary supplements and their related risks. In 2000, the Swiss Anti-Doping Laboratory and the Swiss Federal Office of Sports conducted an initial study on dietary supplements and informed athletes about the findings, warning them about products bought from uncontrolled sources. In 2004, a second investigation was conducted to learn if the situation had improved (or worsened) in the supplement marketplace. About 100 nutritional supplements were ordered from different internet sites and screened for contamination with anabolic steroid parent compounds, stimulants, traces of testosterone, nandrolone and their precursors. The results showed that one creatine product and three so-called mental enhancers contained traces of hormones not identified on the labels. In addition, 14 prohormones (DHEA, Androstenedione, etc.) products contained substances other than those indicated by the manufacturer on the label. These prohormones are in fact all listed as products forbidden by FIFA. But the information about ingredients in these products is generally suppressed in order to deceive sportsmen and individuals. More serious is the contamination of creatine products. It is clear that intake of the recommended daily creatine dose for three days of a product contaminated with norandrostenedione, a nandrolone precursor, led to the presence of nandrolone metabolites in urine with concentrations near or over the WADA limit of 2 ng/ml. As creatine phosphate, or any form of creatine, still seems to be widely used in sport, the obvious contamination of uncontrolled preparations is a real problem for athletes, sport federations and anti-doping laboratories. There are special considerations for female players, as some contraceptive pills or preparations taken to delay the onset of menstruation can contain norethisterone and this product can lead to positive results for nandrolone metabolites because norandrosterone (19- NA) is also a minor metabolite of norethisterone. Nandrolone Intake and Physical Effort Whatever the origin of nandrolone, another question worth addressing is the possible increase in norsteroid excretion and their metabolites during or after strenuous physical exercise. A possible mechanism could be a release of these compounds from fat tissues during effort. A multi-site trial was conducted by the anti-doping laboratories of Lausanne and Montreal and financed by F-MARC on a large population of 621 male subjects. Results from 137 amateur football players did not show any 19-norsteroid production at rest. After exercise, 128 subjects still had no evidence of 19-NA or 19-NE, while 9 of the 137 players showed traces of 19-NA and 19-NE after competition. Eight of these 9 players showed 19- NA and 19-NE values between ng/ml and one a value between ng/ml. In the same study, 358 elite football players were tested after competition. The majority (355 players) had an undetectable or a value less than 2.0 ng/ml for urinary metabolites of nandrolone. The other three players showed values between 2 and 3 ng/ml. After correction for the specific density, however, all but one of these results was under the 2 ng/ml limit. This single result over 2 ng/ml urine is not proof of a possible endogenous production of norsteroids through exercise. It could have been due to previous intake of a contaminated supplement. To further investigate after the results obtained in the first project, F-MARC funded a second study on the effect of exercise on the urinary excretion of nandrolone metabolites. Thirty-four amateur sportsmen took part in the test, 22 ingested two caps of nandrolone and collected urine before and after 8 normalised physical efforts. The measurements of the 19-NA and 19-NE urinary concentrations were quite variable and did not appear to be significantly influenced by exercise. There are several possible reasons for the absence of a relationship between the 19-NA and 19-NE urinary concentrations and physical effort. The most likely explanation may be related to individual differences in how the metabolism was affected by the stress of exercise. Indeed, if the exercise volume, intensity and caloric expenditure did ensure uniform stress levels, resistance to such stress could still have varied among and between different participants. In addition, diet and energy expenditure were not monitored during the study. Furthermore, nandrolone elimination could have been affected by food intake and the type and level of physical activity outside the exercise sessions. that physical exercise cannot be considered as a reliable parameter that systematically affects nandrolone metabolite concentrations in urine. Conclusion Nandrolone is known to be one of the most widely used AAS in sports that need power and muscle strength. Some other beneficial effects (e.g. improvement of recovery even if they are not scientifically proven) are argued as a reason for misuse of nandrolone by athletes. In spite of the numerous investigations conducted, results demonstrate that individual case management has to be considered by the disciplinary panels when making any decision about a sanction to be applied or a follow-up of the concerned athlete. Nevertheless, in view of their side-effects, nandrolone and AAS in general are dangerous substances and athletes remain responsible for forbidden compounds in their body. References Bricout V, Wright F Update on nandrolone and norsteroids: how endogenous or xenobiotic are these substances? Eur J Appl Physiol 2004;92:1-12. Baume N, Avois L, Schweizer C, Cardis C, Dvorak J, Cauderay M, Mangin P, Saugy M [13C]Nandrolone excretion in trained athletes: interindividual variability in metabolism. Clin Chem 2004;50: Green GA, Catlin DH, Starcevic B Analysis of over-the-counter dietary supplements. Clin J Sport Med 2001;11: Pipe A, Ayotte C Nutritional supplements and doping. Clin J Sport Med 2002;12: Contributing Authors: Thus, physical effort can have different effects on the excretion of nandrolone metabolites depending on an individual s metabolism. These results indicate that no model can be elaborated and no extrapolation is possible concerning pre- and post-effort 19-NA and 19-NE urinary levels. The results of this study suggest Norbert Baume, PhD Lidia Mateus-Avois, PhD Christophe Saudan, PhD Neil Robinson, PhD and Martial Saugy, PhD