Introduction

The World Anti-Doping Agency (WADA), has been in existence for over ten years. It was set-up in 1999 to standardise and coordinate doping control globally within sport. On January 1st 2004, the World Anti-Doping Code was introduced, together with a set of international standards that included a Prohibited List which superseded the List produced by the International Olympic Committee Medical Commission. Whilst no marked changes were made to the Prohibited List in terms of the major drug classes, several commonly available over-the-counter (OTC) stimulants were removed and transferred to a Monitoring Programme. Whilst no longer prohibited, the Monitoring Programme enabled WADA to continue to assess the use of such substances, and determine whether athletes were misusing these substances and whether they should be re-introduced to the Prohibited List.

Every October the List is updated following a consultation period, which is led by WADA’s List Expert Group, (a group of scientists and practitioners who are experts in the anti-doping field), and involves stakeholders from the anti-doping community, including representations from sport and national anti-doping organisations.

During this period, the List Expert Group meet to consider the suggestions put forward by stakeholders. Decisions are made with regard to the composition of the List in terms of specific substances, their status and the terminology used. The introduction of the WADA Prohibited List in 2004 saw the removal of caffeine and pseudoephedrine, amongst others, from the List. Since this time, however, pseudoephedrine has been re-introduced to the List in 2010 (Table 1).

The WADA Monitoring Programme

The Monitoring Programme is effectively a covert operation, used to inform WADA’s List Expert Group of the use, amongst athletes, of substances commonly available in OTC medications. On an annual basis, WADA publish the substances that it intends to monitor and laboratory results are distributed to National Anti-Doping Organisations and International Federations.

From an anti-doping compliance perspective, it is useful to provide some detail as to the motivation behind the inclusion of particular substances on the programme.

There are many examples where athletes have inadvertently tested positive for substances attributed to the use OTC medication. The most notable include Andreea Raducan, the Romanian gymnast, who was stripped of her gold medal at the Sydney Olympics after testing positive for pseudoephedrine, allegedly given to her by her team doctor as a constituent of an OTC cold medication. In 1988, at the Seoul Olympics, Linford Christie tested positive for pseudoephedrine.

He was exonerated, since he was believed to have taken the drug inadvertently, as an ingredient of the Chinese health supplement, ginseng. Whilst urinary threshold levels were in place for common OTC stimulants, in an attempt to differentiate between therapeutic- and mis-use, it was clear from a number of research studies that these were ineffective. Work by Lefebvre et al.²² demonstrated that athletes could typically reach urinary levels above the then IOC threshold of 5 μg.ml-1 for ephedrine, after repeated nasal application in therapeutic doses. Furthermore, Tseng and colleagues,²⁶ demonstrated that a therapeutic dose of ephedrine may result in a urinary concentration above the current threshold (10 μg.ml-1) for up to eight hours after administration. Chester et al.,¹² found that multiple therapeutic dosing of pseudoephedrine would put an individual at high risk of exceeding the IOC urinary threshold (25 μg.ml-1).

Recent work by Strano-Rossi et al.,²⁴ highlighted the high inter-individual variability of urinary drug concentrations following the administration of therapeutic doses of stimulants contained in OTC medications. In an attempt to limit the number of inadvertent doping cases and reduce the adverse publicity that comes with such cases, it was decided that substances available OTC and deemed not to possess significant performance-enhancing effects would be removed from the List. Whilst these substances would continue to be monitored, no sanctions would be imposed if an athlete was to test positive for such a substance. It was not the intentionvof WADA to advocate the use of such substances for reasons other than for therapeutic purposes. The recent re-introduction of pseudoephedrine to the Prohibited List has demonstrated the role of thevMonitoring Programme within the World Anti-Doping Programme. The implications of this change are significant and have important ramifications on athletes’ health care. It is essential that all those with a role in supporting athletes are versant with the change in status of pseudoephedrine, and are therefore able to advise their athletes accordingly.

Pseudoephedrine as a therapeutic agent

Pseudoephedrine is a stereoisomer of ephedrine and a member of a group of drugs known as sympathomimetic amines. Sympathomimetics are drugs that stimulate the sympathetic nervous system, acting directly or indirectly on adrenoreceptors. As a constituent of numerous OTC preparations designed to treat the symptoms of upper respiratory tract (URT) conditions, pseudoephedrine’s primary role is as a nasal decongestant. It acts on the α1-adrenoreceptors of the epithelium of the nasal blood vessels, with the resultant effect being vasoconstriction. Upper respiratory tract conditions may include the common cold or flu caused by viral infection or allergic rhinitis, a condition characterised by an allergic hypersensitivity reaction in the nasal mucosa, caused by exposure to allergens such as pollen. Where the trigger is pollen, this condition is known as seasonal allergic rhinitis, commonly referred to as hay fever. The recommended dosing regime for pseudoephedrine in immediate release formulations is 60 mg every 4 to 6 hours, and not exceeding 240 mg per 24 hours. Clearly, this regime is adjusted when using sustained release formulations (e.g. 120 mg sustained release formulation every 12 hours; not exceeding 240 mg per 24 hours).

Contraindications and potential adverse side-effects

Decongestants, although widely available in OTC preparations, are potent vasoconstrictors. In the UK, ephedrine is licensed for the treatment of hypotension caused by spinal or epidural anaesthesia and phenylephrine is licensed for the treatment of acute hypotension. Ephedrine, phenylephrine and pseudoephedrine use is contra-indicated in hypertensive patients.

The use of ephedrine has been linked to cardiomyopathy²⁵ and stroke,⁶ whilst pseudoephedrine use has also been linked with stroke,¹⁰ temporal coronary artery spasm and myocardial infarction.³⁰ It is clear, therefore, from clinical data that, when taken orally, α1–agonist sympathomimetic amines can evoke profound systemic cardiovascular side effects. Moreover, these effects are both drug-specific and dose-dependent.

There have been numerous reports of the effects upon cardiovascular parameters of sympathomimetic amines contained in OTC medicines. Doses equivalent to over three to four times the recommended therapeutic dose of pseudoephedrine raised diastolic blood pressure above 90 mm Hg.¹⁴ These results were in accord with two other studies. Bye et al.,⁸ reported significant increases in heart rate and systolic blood pressure following relatively high doses of pseudoephedrine (120 mg and 180 mg). Empey et al.,¹⁶ found doses of 120 mg and 180 mg produced statistically significant increases in both pulse and systolic blood pressure. However, the increases were deemed to be clinically unimportant, since they were considerably less than might be expected to occur in response to either emotion or mild exercise.

Whilst several studies have reported increased cardiovascular stimulation following ingestion of OTC sympathomimetics, it is evident that doses used were at least twice the recommended therapeutic dose. Reports of the effects following the ingestion of sympathomimetics in therapeutic doses have been conflicting. Bye et al.,⁸ found that a single dose of ephedrine (25 mg), significantly elevated both heart rate and systolic blood pressure, whilst a single therapeutic dose of pseudoephedrine (60 mg) significantly elevated only systolic arterial blood pressure. Bright et al.,⁵ found only a non-significant rise in resting heart rate following a single therapeutic dose. Empey et al.,¹⁶ reported that ingestion of pseudoephedrine in a therapeutic dose of 60 mg provided maximal nasal decongestion, without any cardiovascular or other side effects.

In terms of action on the CNS, most evidence suggests that OTC sympathomimetics have no stimulatory effect in the relatively low doses used.^9,20 Bye et al.,⁸ found that whilst pseudoephedrine lacked any stimulatory effect, even at supratherapeutic doses (180 mg), ephedrine possessed a stimulatory effect at therapeutic doses. Over-the-counter sympathomimetic amines exhibit less central stimulatory effects than amphetamines, because they are less lipid soluble. Differences in central stimulation are related to differences of lipid solubility within the biological membranes and hence penetration of the blood-brain barrier determines the ease with which these compounds gain access to central receptors.²¹

Danger during endurance exercise has been associated with impaired thermoregulation as a result of the use of sympathomimetic amines. Clearly, the use of stimulants to mask the symptoms of fatigue may enable an individual to continue exercising in a hyperthermic state. Indeed, the deaths of several cyclists during major competition, (most notably that of Tom Simpson on Mont Ventoux in the 1967 Tour de France), have been attributed to hyperthermia related to the use of amphetamine.³¹ More recently, the death of a Major League Baseball player, (Steve Bechler, in 2003), as a result of heatstroke, was attributed to the use of excessive ephedrine, contained in a weight reduction supplement.¹¹ It is likely that hyperthermia is a consequence of increased motor activity and impaired thermoregulation. Although published studies have identified increased thermogenesis¹⁵ and a reduction in the drop in core temperature during exposure to low temperature²⁷ following administration of ephedrine, no studies have assessed body temperature at comfortable ambient temperatures following the administration of ephedrines.

Pseudoephedrine as a potential performance enhancer

As a constituent of orally administered medication, pseudoephedrine has the capacity to act systemically on adrenoreceptors, both peripherally and centrally. Whilst it is generally considered less centrally active than ephedrine, its potential for crossing the bloodbrain barrier, coupled with its widespread availability, makes it a likely target for abuse. Nevertheless, limited research has examined the effects of pseudoephedrine on performance. Those studies that have assessed pseudoephedrine administration and sports performance are inconclusive.

Gillies et al.,¹⁸ found no improvement in 40-km time trial cycling performance following administration of double the therapeutic dose of pseudoephedrine. Similarly, Chester et al.,¹³ found no improvement in 5- km running performance following a multiple, therapeutic dosing regimen of pseudoephedrine, (i.e. six 60 mg doses over a 36 hour period). Whilst data pertaining to endurance exercise suggests that pseudoephedrine has limited ergogenic effect, exercise of shorter duration has shown positive results. In a study by Hodges et al.,¹⁹ it was concluded that pseudoephedrine administration in greater than the therapeutic dose, (i.e. 2.5 mg per kg body weight) significantly improves 1500 m run performance. Using comparable doses of pseudoephedrine (i.e. 180 mg) Gill et al.,¹⁷ found a significant increase in peak power output during a 30 s sprint cycle test and maximum torque produced in an isometric knee extension exercise. From the available data, it would appear that pseudoephedrine administration in high doses, (i.e. greater than the therapeutic dose), has the potential to augment high intensity exercise performance. However, further research in this area is necessary to confirm this.

Recent work has found that, in combination with caffeine, pseudoephedrine²⁹ and ephedrine^2,3 significantly improves exercise performance. There is however a paucity of research that assesses the effect of combining caffeine with pseudoephedrine and therefore this requires further examination.

There has been considerable interest in the use of sympathomimetic drugs to promote weight loss, by increasing energy expenditure and reducing food intake through appetite suppression. In an animal study performed by Ramsey et al.,.²³ it was reported that energy expenditure was increased, and in some animals, food intake was reduced following the administration of ephedrine and caffeine. Consequently, it was concluded that ephedrine and caffeine treatment could promote weight loss through its action as a thermogenic and anorectic. It appears that ephedrine is effective in increasing thermogenesis and has the potential for body weight loss in obese individuals,⁷ especially when combined with caffeine or aspirin.¹ Boozer et al.,⁴ found significant short-term reduction in weight amongst over-weight and obese subjects following supplementation of natural sources of ephedrine and caffeine (Ma Huang and Guarana). However, there have been no studies that have focused on sympathomimetic drug use and non-obese, athletic populations to promote leanness.

WADA legislation regarding pseudoephedrine

The 2010 Prohibited List states that pseudoephedrine is prohibited in-competition where the urinary concentration exceeds 150 μg.ml-1. At concentrations below the threshold it continues to be monitored. An athlete who tests positive for pseudoephedrine and the urinary concentration is above the threshold, may face a ban from competition for up to two years (first violation). However, it is classified as a ‘specified substance’, which means that, as a common therapeutic agent, any sanctions may be reduced or nullified if an individual is able to prove that the presence of pseudoephedrine in the urine at such high levels was through no significant fault of their own. Whilst this may be difficult to prove, it is clear that further research to support the current threshold is required. As a common therapeutic agent it is also possible to apply for therapeutic use exemption (TUE). This may be granted if it can be established that there is no permitted alternative therapeutic agent.

Further issues surrounding the use of OTC stimulants by athletes

As part of the Monitoring Programme, since 2004, caffeine remains a unique case. Whilst it is a constituent of numerous OTC medications, it is clearly a socially acceptable drug, consumed in large amounts in the diet via the intake of caffeinated beverages such as coffee. With the recent growth in café culture, caffeine intake throughout the UK population would appear to have increased significantly. Caffeine also has renowned ergogenic properties and since its removal from the Prohibited List has become a common constituent of sport-specific supplements such as sports drinks and gels etc. It would appear that despite the clear performance enhancing properties, caffeine’s relative safety and its widespread availability makes it a difficult substance to control. Indeed, the effects of caffeine have been demonstrated at relatively low doses, making the possibility of differentiating between therapeutic or acceptable social use, from its use for performance enhancement or simply over consumption, via urinalysis impossible. This, coupled with the fact that caffeine is used as an acceptable performance enhancer within many working situations (e.g. as a cognitive enhancer during study), makes it difficult to legislate against in sport.

There are a large number of products available for weight reduction, combating drowsiness, relieving fatigue and enhancing sports performance, all containing a variety of herbal stimulants. Herbal stimulants are those from plants or plant extracts that may be categorised according to the agents that they contain. Typically, herbal stimulants contain caffeine and related methylxanthines, of which the most common are coffee and tea. Herbal stimulants may also contain ephedrine and related sympathomimetics. Herbs may however, contain many active ingredients and the exact quantities and contents are seldom labelled. Whilst herbal products contain active ingredients, they are classified as food supplements rather than drugs and they undergo less stringent quality control procedures prior to their sale. Most herbal supplements have not been subject to extensive scientific scrutiny and rigorous clinical trials. This poses a significant problem in terms of the safety of herbal supplement use. The major risks of taking herbal supplements include the purity of the ingredients and the possibility of contamination, via possible interactions between the ingredients and other supplements consumed simultaneously. Athletes should therefore exercise extreme caution when contemplating the use of natural/herbal supplements.

Summary

Sympathomimetic amines contained in OTC medication have clear therapeutic roles in alleviating the symptoms of URT conditions. In therapeutic doses, these sympathomimetics are typically devoid of adverse side effects and performance enhancing properties. Even in supratherapeutic doses, research has found it difficult to elucidate the performance enhancement properties of these drugs. However, pseudoephedrine and ephedrine, both commonly available OTC stimulants, are prohibited in competition. As a consequence of the principle of strict liability, there is a huge responsibility of ensuring that athletes are aware of these stimulants and the products that they are contained in.

Recommendations

• Where possible, try to practice non-drug therapy for the treatment of URT conditions i.e. increased fluid intake and steam inhalations.
• Increase the awareness of pseudoephedrine amongst athletes in terms of its availability in OTC medication and its status in sport with regards to anti-doping regulations.
• Identify safe, (i.e. non-prohibited), alternative medication for the treatment of URT conditions (refer to table 1).
• Where possible, ensure that all medication is prescribed by a team doctor, and that any doubts regarding the status of particular drugs contained in any medication is checked thoroughly via the national anti-doping organisation (i.e. UK Anti-Doping).
• In cases where OTC medication containing pseudoephedrine is used, ensure that the athlete is not competing (i.e. likely to be selected for an in-competition drug test) within at least 48 hours of the final dose.
• Do not be tempted to take greater than the recommended therapeutic dose (refer to details on the packaging).
• Be extremely wary of supplements termed ‘natural’ or ‘herbal’ remedies. Neither of these terms guarantees safety, nor exemption from anti-doping regulations.

References

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