British Journal of Pharmacology (2008) 154, 606–622 & 2008 Nature Publishing Group All rights reserved 0007– 1188/08 $30.00 www.brjpharmacol.org REVIEW Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA) JR Docherty Department of Physiology, Royal College of Surgeons in Ireland, Dublin, Ireland This review examines the pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA). Stimulants that increase alertness/reduce fatigue or activate the cardiovascular system can include drugs like ephedrine available in many over- the-counter medicines. Others such as amphetamines, cocaine and hallucinogenic drugs, available on prescription or illegally, can modify mood. A total of 62 stimulants (61 chemical entities) are listed in the WADA List, prohibited in competition. Athletes may have stimulants in their body for one of three main reasons: inadvertent consumption in a propriety medicine; deliberate consumption for misuse as a recreational drug and deliberate consumption to enhance performance. The majority of stimulants on the list act on the monoaminergic systems: adrenergic (sympathetic, transmitter noradrenaline), dopaminergic (transmitter dopamine) and serotonergic (transmitter serotonin, 5-HT). Sympathomimetic describes agents, which mimic sympathetic responses, and dopaminomimetic and serotoninomimetic can be used to describe actions on the dopamine and serotonin systems. However, many agents act to mimic more than one of these monoamines, so that a collective term of monoaminomimetic may be useful. Monoaminomimietic actions of stimulants can include blockade of re-uptake of neurotransmitter, indirect release of neurotransmitter, direct activation of monoaminergic receptors. Many of the stimulants are amphetamines or amphetamine derivatives, including agents with abuse potential as recreational drugs. A number of agents are metabolized to amphetamine or metamphetamine. In addition to the monoaminomimetic agents, a small number of agents with different modes of action are on the list. A number of commonly used stimulants are not considered as Prohibited Substances. British Journal of Pharmacology (2008) 154, 606–622; doi:10.1038/bjp.2008.124 Keywords: stimulants; monoaminergic agonists; re-uptake inhibitors; noradrenaline; dopamine; serotonin; respiratory stimulant Abbreviations: ADHD, attention-deficit hyperactivity disorder; CNS, central nervous system; DA, dopamine; 5-HT, 5-hydroxytryptamine, serotonin; MAO, monoamine oxidase; MDA, methylenedioxyamphetamine; MDEA, methylenedioxyethylamphetamine; MDMA, methylenedioxymethamphetamine; NA, noradrenaline; OTC, over the counter; VMAT-2, vesicular monoamine transporter-2; WADA, World Anti-Doping Agency Introduction This review looks at stimulants prohibited by the World Anti- a stimulant can be seen as any agent that enhances function, Doping Agency (WADA) from the viewpoint of Pharmacology, perhaps an agent which mimics the actions of an excitatory or at least of a pharmacologist. The WADA stimulants list has neurotransmitter or antagonizes the actions of an inhibitory not been compiled primarily with consideration of pharma- neurotransmitter. However, in the context of sport, the word cology, so that a pharmacological classification of the list is stimulant usually refers to agents stimulating the central now attempted and such a classification would allow for a nervous system (CNS), affecting mood, alertness, locomo- rational extension of the list to include compounds of tion and appetite, or targeting the sympathetic nervous similar properties. system causing particularly cardiovascular actions. The well- A stimulant can be seen as a general term in dealing with known fight-or-flight reaction to increase blood flow to the properties of drugs. We can think of cardiac stimulants, skeletal muscle and mobilize energy is a sympathetic respiratory stimulants, central stimulants and so on. Hence, response, which can be mimicked by stimulant drugs. The US Anti-Doping Agency defines a stimulant as ‘An agent, especially a chemical agent such as caffeine, that temporarily Correspondence: Professor JR Docherty, Department of Physiology, Royal arouses or accelerates physiological or organic activity’ College of Surgeons in Ireland, 123 St Stephen’s Greeen, Dublin 2, Ireland. (USADA, 2007). E-mail: [email protected]> Received 12 October 2007; revised 22 February 2008; accepted 13 March Stimulants can include drugs that increase alertness/ 2008 reduce fatigue, such as coffee or the major ingredient Stimulants prohibited by WADA JR Docherty 607 caffeine, or drugs like ephedrine available in many over-the- actions would have cardiac stimulant effects. This would counter (OTC) medicines. Others such as amphetamines, be especially important, perhaps not in increasing maximum cocaine and hallucinogenic drugs can affect mood and level of cardiac output in exercise, but in increasing modify mental alertness. Stimulants can have precise clinical the rate of attaining a maximum level. However, the indications such as narcolepsy, attention deficit or appetite superiority of drug induced ‘warm-up’ over an exercise suppression, or even nasal decongestion. However, many warm-up is unclear. Further information on the possible stimulants have potential for abuse, and are thus carefully performance enhancing effects of some stimulants in controlled in many jurisdictions. In terms of sport, stimu- relation to adrenoceptors is included in Davis et al. (2008). lants can provide an unfair advantage: increased alertness Do stimulants confer an advantage on a doped athlete? and diminished fatigue and cardiovascular activation can be Clearly some athletes do think so: cardiac stimulant actions, advantageous in many events. increased alertness, decreased fatigue. However, the risks, in terms both of wellbeing and detection, far outweigh the perceived benefits. Why do athletes take stimulants? Regulations concerning stimulants Athletes may have stimulants in their body for one of three main reasons: Stimulants are banned only in competition, as any advan- Inadvertent (or alleged inadvertent) consumption in a tage they give is transient in nature, and as a total ban would propriety medicine; be difficult given that many OTC medicines contain Deliberate consumption for misuse as a recreational drug; stimulants in addition to the stimulants obtainable as Deliberate consumption to enhance performance. prescription medicines. It is not the intention of this review Stimulants may be taken to increase alertness or convey to discuss the criteria for deciding whether a drug detected in some psychological motivational or attitude advantage from sport is a legitimate prescription or OTC medicine or a central actions. Peripheral actions may increase performance deliberate stimulant. Some general points can be noted as to at least in the early stage of exercise by increasing cardiac how samples are interpreted. Prescription metanephrine is output, increasing blood flow to muscles and by mobilizing available usually as the d-isomer, so that the presence of both energy. A warm-up prior to strenuous exercise results in isomers would be inconsistent with prescription medicine increased blood flow to the exercising muscle and to cardiac (Cody, 2002). Besides a potentially legal prescription of muscle, warming of the body by transferring heat from the amphetamines, many substances metabolize to methamphe- exercising muscles into the bloodstream, a warming that will tamine or amphetamine in the body, including amphetami- also aid oxygen uptake by the tissues (oxygen dissociation nil, benzphetamine, clobenzorex, deprenyl, dimethylam- curve for haemoglobin shifts to the right), and sweating for phetamine, ethylamphetamine, famprofazone, fencamine, temperature regulation. Some or all of these effects can be fenethylline, fenproporex, furfenorex, mefenorex, mesocarb mirrored by agents, which stimulate the cardiovascular and prenylamine and selegiline (Kraemer and Maurer, 2002). system and particularly the heart. Sympathomimetic agents Hence, relative concentrations of metabolites in the urine will mimic, to varying degrees, the fight-or-flight reaction. are relevant while deciding the source of the drug (Cody, In particular, agents with b1-adrenoceptor stimulant 2002). Table 1 Stimulants prohibited in competition Name Specified substancea Metabolized Mode of actionc to A/Mb Adrafinil adrenalined Monoamine Amfepramone Monoamine Amiphenazole Resp. stim. Amphetamine Monoamine Amphetaminil Yes A Monoamine Benzphetamine Yes M Monoamine Benzylpiperazine Monoamine Bromantan Monoamine Cathined Yes Monoamine Clobenzorex Yes A Monoamine Cocaine Monoamine Cropropamide Yes Resp. stim. Crotetamide Yes Resp. stim. Cyclazodone Monoamine Dimethylamphetamine Yes M Monoamine Ephedrined Yes Monoamine Etamivan Yes Resp. stim. Etilamphetamine Yes A Monoamine Etilefrine Monoamine British Journal of Pharmacology (2008) 154 606–622 Stimulants prohibited by WADA 608 JR Docherty Table 1 Continued Name Specified substancea Metabolized Mode of actionc to A/Mb Famprofazone Yes Yes M Analgesic Fenbutrazate Monoamine Fencamfamin Monoamine Fencamine Yes M Monoamine Fenetylline Yes A Monoamine Fenfluramine Monoamine Fenproporex Yes A Monoamine Furfenorex Yes M Monoamine Heptaminol Yes Monoamine Isometheptene Yes Monoamine Levmethamfetamine Yes Monoamine Meclofenoxate Yes Nootropic Mefenorex Yes A Monoamine Mephentermine Monoamine Mesocarb Yes A Monoamine e Methamphetamine (D-) Yes A Monoamine Methylenedioxyamphetamine