On top of the game

During the past year, newspapers have been full of stories about the misuse of banned substances in sport. Karen Hebert and Michele Verroken take a look at doping in sport

The British 4×100 metres sprint team was stripped of its World Championship silver medal earlier this year when Dwain Chambers tested positive for banned substances. This year, sports news has been filled with the scandals of élite players who have tested positive for a banned drug or ergogenic aid (a nutritional, physical, mechanical, psychological, or pharmacological procedure or aid to improve physical work capacity or athletic performance¹). But chasing drug cheats has been difficult--increasing scientific expertise and technology have made it easier to keep a step ahead of drug tests. Sports agencies have to battle to implement rules and regulations to keep a fair and level playing field for all.

OLYCOM SPA/REX

Development of doping

The word doping is thought to be derived from the Dutch "dop"--an alcoholic drink made from grape skins--which Zulu warriors drank to increase their prowess in battle. Doping was first used to describe the illegal drugging of racehorses and now describes the illegal use of ergogenic aids to improve sporting performance in people.²

Doping has been going on for centuries. Historians have described the use of diet and potions by the Ancient Greeks, and, in the 19th century, strychnine, caffeine, cocaine, and alcohol were commonly used. At the 1904 Olympic Games in Saint Louis, Thomas Hicks won a gold medal in the marathon with the help of raw egg, strychnine injections, and brandy.

Longstanding evidence exists of doctors' involvement in doping in sport.Philippe Tissie, a French sports doctor, experimented with doping in 1894. He prescribed mint water, rum, and champagne to a 30 year old cyclist and then documented the stimulatory effects.³

The International Amateur Athletic Federation banned doping in 1928, and was the first international sport organisation to do so. Many other sporting organisations quickly followed, but doping remained widespread because testing methods were ineffective. The amphetamine induced death of Knud Enemark, a Danish cyclist, however, during competition at the Rome 1960 Olympic Games was the catalyst for the introduction of testing. In 1966, football and cycling organisations introduced testing and this was followed by the publication of the first list of prohibited substances by the International Olympic Committee. The death of cyclist Tom Simpson during the 1967 Tour de France increased the pressure on sports authorities to implement antidoping measures, and the1968 Mexico Olympic Games was the first summer games to have drug testing.

An important boost in the regulation of drug misuse in sport came with the development of a reliable test for anabolic steroids in 1974--the International Olympic Committee then added them to the prohibited substances list. This resulted in many athletes being banned--particularly in sports which rely on strength. At the same time, suspicion surrounded certain countries that were thought to be involved in state sponsored doping. Many are as yet unsubstantiated but it appears that this held true in the former German Democratic Republic.²

The world became more aware of the extent of the problem when Ben Johnson, the 100 metres champion at the 1988 Seoul olympics, tested positive for an anabolic steroid, stanozolol, and was stripped of his medal. In 1986, blood doping was banned and soon after erythropoietin was added to the list of prohibited substances. However, not until the Sydney games in 2000 was a reliable test for erythropoietin introduced.²

The 1998 Tour de France saw one of cycling's biggest doping scandals. A large number of prohibited drugs were found in a police raid on the cars and luggage of the cycling entourage--including the medical support team. The incident indicated that although many sports and many countries had introduced antidoping legislation, better cooperation was needed at all levels. As a result an independent international agency was set up--the World Anti-Doping Agency--which "sets unified standards for antidoping work and coordinates the efforts of sports organisations and public authorities." When established, in 2000 the World Anti-Doping Agency stated the aim to "develop a harmonised universal antidoping code by the Olympic Games of 2004 in Athens."²

Doping tests are now taken seriously by sporting federations. Rio Ferdinand, England football international and Manchester United player, was recently banned for eight months after failing to attend a drugs test.

International Olympic Committee code

The International Olympic Committee regularly publishes a list of prohibited substances (table).⁴ The code also prohibits certain ergogenic methods:

1. Enhancement of oxygen transfer Blood doping

   The use of products that enhance the uptake, transport or delivery of oxygen for example, erythropoietin (EPO).

2. Pharmacological, chemical, and physical manipulation--the use of substances and methods, including masking agents, which alter, attempt to alter, or may reasonably be expected to alter the integrity and validity of specimens collected in doping control.
3. Gene doping--the non-therapeutic use of genes, genetic elements, or cells that have the capacity to improve athletic performance.

The World Anti-Doping Agency has also published an international standard for exemptions for therapeutic use as part of the code. This entails what constitutes a therapeutic use exemption and how an athlete must go about gaining such an exemption. It is unacceptable to test positive for a banned substance and claim therapeutic use exemption retrospectively. The code has a strict liability clause which states that "athletes are responsible for any prohibited substance found in their system and therefore need to be certain that they are not putting themselves at risk of failing a test."

SCANPIX/EMPICS

Doping casualties in sport: (previous page) Italian cyclist Marco Pantani, who failed a drug test in 1999 and was 34 years old when he died; and (above) Danish cyclist Knud Enemark

Supplementary measures

Many athletes take supplements to maximise their performance, believing the supplements to be permitted or free from prohibited substances. However, the International Olympic Committee did a large study in Cologne in 2002 which found that 94 out of 634 samples from non-hormonal dietary supplements contained prohibited anabolic-androgenic steroids that were not listed on the label.⁵ UK Sport also documents that a number of findings of nandrolone could have been due to poorly labelled or contaminated supplements.⁶

Due to the strict liability rule, mislabelling is not a sufficient excuse. This is reinforced by the recent poster campaign by UK Sport with the stark words "Athletes take supplements at their own risk."

UK Sport issued an advisory statement on the subject of supplements advising athletes to be extremely cautious about their use. Richard Callicott, former chief executive of UK Sport, told BBC News, "The last thing we want it to have a British athlete test positive by taking a contaminated supplement and facing consequences which could so easily be avoided by heeding this advice... Claims of 'quicker recovery' or an 'instant increase in strength' are commonplace on supplement labels. However if these supplements do as they claim and make important physiological changes to the body then they should be viewed with caution."

Greg Rusedski, British tennis number two, was recently investigated when he tested positive for nandrolone, one of the banned anabolic steroids. He has now been exonerated, however, as he has successfully claimed that the source of the nandrolone was supplements provided to him by the Association of Tennis Professionals. Rudsedski's appeal was based upon the claim that he should not be held liable if supplements were supplied to players by the Association of Tennis Professionals itself, and he took them in good faith that they were acceptable.

Fig 1 Taken from Bhasin S and colleagues. The effects of supra-physiological doses of testosterone on muscle size and strength in normal men. N Engl J Med 1996; 335:17

Here comes the science

Anabolic steroids

Anabolic steroids work in a similar way to testosterone. Testosterone binds to tissue and muscle receptors resulting in changes in male secondary sex characteristics. These include the sex differences in muscle mass and strength post-puberty. Anabolic steroids are steroids with a synthetically manipulated chemical structure that increase muscle growth from anabolic tissue.¹ Researchers have often questioned the effectiveness of anabolic steroids. However research has shown a significant advantage gained with the use of supraphysiological doses of testosterone by normal men (figure).⁷ Evidence also shows reduced training fatigue and reduced recovery time, but contradictory research clouds the issue. The research may be inaccurate because athletes take huge quantities of steroids--up to 40 times the recommended medical dosage.¹ Athletes combine drug taking with cycling so that their steroid consumption coincides with maximum muscle strength and size at competition. The athlete will take a combination of steroids for a number of weeks--week one at maximum dosage and then reducing down--and this is followed by a 6-8 week course of human chorionic gonadotropin and clomifene citrate. These increase testosterone concentration in the body.

The risks of taking anabolic steroids include infertility, azoospermia, gynaecomastia, chronic stimulation of the prostate, reduced cardiovascular function, possible pathological ventricular growth and decreased diastolic relaxation as well as increased platelet aggregation. A serious event is the development of peliosis hepatitis,¹ when blood filled cysts form in the liver.

Tetrahydrogestrinone has recently caused much furore, particularly in the athletics world. This banned modified steroid was undetectable by normal dope tests--it was designed to evade them.⁸ An anonymous athletics coach informed the United States Anti-Doping Agency about tetrahydrogestrinone, and handed them a syringe of it. A test has since been developed, and many high profile medal winning athletes have tested positive for the drug. One such athlete was Dwain Chambers, the 100 metres European gold medallist, who has now been banned from athletics for two years. He faces a lifetime ban from the Olympics and is said to be considering a change to professional American football.

Blood doping and erythropoeitin

Blood doping refers to the process of red blood cell reinfusion. The process involves the withdrawal of up to four units (450 ml) of blood. Only one unit is drawn at time with a three to eight week interval between withdrawals. This interval prevents a large reduction in blood cell concentration. Immediately after the blood is withdrawn, the plasma is reinfused into the athlete. The packed red blood cells are put into frozen storage. The collective red blood cells are then infused into the athlete some time during the week before competition. This results in an increased red blood cell count as well as an 8-20% increase in haemoglobin concentrations. Compare this with normal physiology: a normal male would have a haemoconcentration of 150 g/l but this reinfusion results in a hemoconcentration of 190 g/l and a 40 to 60% increase in hematocrit concentration which lasts for two weeks.

The theory is that the increased blood volume will cause a larger maximal cardiac output. The extra red blood cells should increase the oxygen transport capacity of the blood. An enhanced ability to transport and deliver oxygen to active muscle tissue translates into a significant advantage for endurance athletes. Research has shown that, with correct storage, red blood cell reinfusion significantly increases haematologic parameters in males and females. This can be seen in a 5 to 13% increase in aerobic capacity, reduced heart rate, reduced lactate in the blood whilst exercising, and overall improved endurance at sea level and at altitude.¹ A test is currently being developed by Australian scientists at the Royal Prince Albert Hospital, Sydney, to detect transfused blood.⁹

Synthetic erythropoietin was developed to treat anaemia in patients with severe renal disease. Treatment with erythropoietin stimulates an increase in whole body haemoglobin and packed cell volume as well as an increase in maximal oxygen uptake.¹⁰ Erythropoietin has definite advantages over blood doping in that it does not require blood withdrawal--with the associated dip in training capacity--storage or reinfusion. Erythropoietin use has become widespread as a doping method but was difficult to test for because erythropoietin is a naturally occurring peptide. Nonetheless, a test was developed and introduced into official competition for the first time at the Sydney Olympics of 2000. The 2002 Edmonton World Athletics Championships saw Paula Radcliffe, marathon world record holder, holding up a banner saying "Ban EPO Cheats."

WITTERS/EMPICS

Flo-Jo Joyner, American sprinter who died of a heart seizure, aged 38, having retired from athletics only four months after the introduction of random testing

Gene doping

Gene doping has become a possibility with the advent of gene therapy technology. Experimentally, scientists have shown that gene transfer can cause a 25% increase in muscle mass in laboratory mice within the space of two weeks.¹¹ The threat of gene doping was discussed at the last World Anti-Doping Agency conference in Athens. Geoff Goldspink, a professor from University College London said, "We can put genes into mice and create 'Arnold Schwarzenegger' mice. If it can be done on mice, it can be done on humans." He warned the delegates, "It's inevitable that we will have this kind of doping if we don't already have it. Once the technology exists for medical use disreputable people will be putting the stuff in athletes." Current testing methods are unable to catch gene cheats.

Testing methods

Urine and blood analysis are currently the mainstay of antidoping programmes. According to World Anti- Doping Agency guidelines, athletes may be tested in and out of competition. A certified and accredited doping control officer informs the athlete of their selection for testing. During the process of collecting a sample, the athlete will:

• Be entitled to have a representative present
• Provide a sample in unobstructed view of a doping control officer of the same sex as the athlete.

The sample is divided into two and should always be kept in full view of the doping control officer and athlete before it is sealed. Should one sample test positive for a banned substance, the athlete has the right to ask for the other sample to be tested while they are present.

Research has shown success in testing for amphetamines, cannabis, cocaine, and opiates in saliva and for anabolic steroids, corticosteroids, and ß adrenergic stimulants in hair.¹² These tests are gaining recognition but are currently expensive. However, a saliva sample can be obtained with much less embarrassment for the athlete. Hair sample analysis has the particular advantage of being able to show a more accurate drug use history over a number of weeks. The key difference is that hair and saliva analysis indicate the presence of a substance but analysis of urine and blood is based on the identification and measurement of metabolites.

May the best athlete win

Sports organisations are currently debating whether to prevent the use of drugs via antidoping programmes, or allow all athletes to use doping methods if they choose to, effectively levelling the playing field, although this raises many medical, ethical, moral, and legal questions. There may always be athletes willing to cheat in any sport, but in Athens the best clean athletes win.

Karen Hebert third year medical student, University of Bristol
Email: kh9694@bristol.ac.uk

Michele Verroken Drugs in sport expert, formerly incharge of anti-doping in the UK


studentBMJ 2004;12:265-308 July ISSN 0966-6494

1. McArdle W, Katch F, Katch V. Exercise physiology: energy nutrition and human performance. 5th ed. London: Lippincott, Williams, and Wilkins, 2001:549-95.
2. World Anti-Doping Agency. A brief history of anti-doping. Montreal: WADA. www.wada-ama.org/en/t2.asp?p=41 337 (accessed 3 Jun 2004).
3. Hoberman J. Sports physicians and the doping crisis in elite sport. Clin J Sport Med 2002;12:203-8.
4. World Anti-Doping Agency. The world anti-doping code: the 2004 prohibited list: the international standard. Montreal: WADA, 2004. www.wada-ama.org/docs/web/standards_harmonization/code/list_standard_2004.pdf (accessed 3 Jun 2004).
5. Schänzer W. Analysis of non-hormonal nutritional supplements for anabolic-androgenic steroids: an international study. International Olympic Committee. http://multimedia.olympic.org/pdf/en_report_324.pdf (accessed 3 Jun 2004).
6. Expert Committee on Nandrolone. Nandrolone progress report. London: UK Sports Council, 2003. www.uksport.gov.uk/images/uploaded/Nandrolone_Progress_Report_Feb03.pdf (accessed 3 Jun 2004).
7. Bhasin S, Storer TW, Berman N, Callegari C, Clevenger B, Phillips J, et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med 1996;335:1-7.
8. Fordyce T. The THG scandal explained. London: BBC, 2004 http://news.bbc.co.uk/sport1/hi/athletics/3210876.stm (accessed 3 Jun 2004).
9. McGrath M. Sport's new doping threat. London: BBC, 2003. http://news.bbc.co.uk/sport1/hi/front_page/2965802.stm (accessed 3 Jun 2004).
10. Joyner MJ. VO2MAX, blood doping, and erythropoietin. Br J Sports Med 2003;37:190-1.
11. BBC Sport News. Experts warn of gene threat. London: BBC, 2003. http://news.bbc.co.uk/sport1/hi/athletics/3178852.stm (accessed 3 Jun 2004).
12. Kintz P, Samyn N. Use of alternative specimens: drugs of abuse in saliva and doping agents in hair. Ther Drug Monit 2002;24:239-46.