Performance-enhancing drugs: a (brief) historical overview

The use of performance-enhancing drugs (PEDs) is perhaps as old as sport itself. The ingestion of plant and animal extracts to improve sport performance dates back to the origins of competitive sport, when Greek athletes competed in the ancient Olympics. Later, Roman gladiators had special potions prepared using a wide variety of natural products, including mushrooms, roots, and wines, to attempt to supplement performance. The use of PEDs became more systematic, no longer based on sorcery and alchemy but instead biochemistry and pharmacology, during the twentieth century, when the Olympic Games were reinvented after the recovery and promotion of the Olympic spirit heralded by Baron Pierre de Coubertin.

To compare the lifespan of the ancient Olympics with that of the modern Olympic Games, the first ancient Olympic Games took place in 776 bc and the last one was held in 393 ad , when, although the Games already had degenerated, they officially were abolished by the Roman emperor Theodosius, who, as a Christian, was against the heathen spirit of the Games. The modern Olympic Games, the first edition of which took place in Athens in 1896, celebrates their 112th anniversary in Beijing in August 2008. It follows that the history of the ancient Olympics, spanning more than 11 centuries, is approximately 10 times longer than that of the modern Olympic Games.

The history of PED use strictly follows the history of scientific development that took place at the time of the ancient and the modern Olympic Games; although the drugs used by athletes competing in the first ancient Olympic Games approximately were the same of those used 1 millennium later by their colleagues or by Roman gladiators, the illicit pharmacologic support to sport performance proceeded at a much faster pace in the twentieth century, with a further dramatic increase from the early 1960s to the present.

The problem of drug abuse in sport first was tackled by the international sport authorities, in the form of the International Olympic Committee (IOC), during the 1960s. An official definition of doping first was given by the IOC in 1964 and the first programs of antidoping tests were activated by the IOC and its newborn Medical Commission in 1967. It was in the late 1960s when, in parallel to the official sport competitions, another race began and continues to the present: the race between testers and cheaters.

Classification of performance-enhancing drugs: the “prohibited list”

The first official antidoping tests performed on the occasion of a multisport, international event took place at the Olympic Games of Mexico City in 1968. At that time, the only prohibited substances were those capable of producing a significant effect on sport performance only if administered, in sufficient amounts, right before or during the competition. Although short (compared with its current equivalent), that first list continuously was updated to include any new form of doping substance or method of administration. The periodic upgrades of the list were performed by the IOC Medical Commission until the constitution of the World Anti-Doping Agency (WADA) in 1999. Since then, as mandated by the World Anti-Doping Code, the WADA has been responsible for the upgrade and publication of the list. In the framework of the World Anti-Doping Code, the list is an international standard identifying substances and methods, classified by categories, that are prohibited in competition, out of competition, and in particular sports. In the past 40 years, the “prohibited list” has expanded progressively ( Box 1 ): it now reports hundreds of compounds, including so-called “related substances” (ie, substances with similar chemical structure or similar biologic effects to those of a banned prototype) and several prohibited methods, including blood transfusions and gene doping.

The chronologic evolution of the “prohibited list” over the past 4 decades leads to identifying three main steps in the parallel expansion of the abuse of drugs in sport:

• 1.
  

  The first period, ranging from the origin of the modern Olympic Games to the early 1970s, coincides with the use of drugs whose efficacy, as discussed previously, is maximal if the administration takes place right before or even during the competition. This is the case with stimulants, narcotics, and some drugs of abuse (eg, cocaine).

  
  
• 2.
  

  In the second period, the PEDs also included those compounds—mainly AAS—requiring repeated administration over a prolonged period of time to be effective. It is with the use of synthetic AAS that doping substances start to be used off label (ie, with the aim of achieving one or more effects that are different from those for which a specific drug originally had been developed and authorized). This period also marks the transition from pinpoint, in-competition doping, to carefully planned, out-of-competition, systematic doping.

  
  
• 3.
  

  The third period follows the pharmaceutical industry development of routine techniques in protein chemistry, molecular biology, and genetic engineering, and led to the abuse of peptide hormones (including, but not limited to, erythropoietin, growth hormone, and gonadotropins). The use of PEDs belonging to the class of peptide and glycoproteic hormones led to the development of new analytic strategies for their detection, including the use of “indirect” methods based on the measurements of specific markers.

A fourth period (the recourse to gene doping) is feared by many as the next step in the illicit search for the ultimate PEDs and methods. It is expected that gene doping will develop as soon as gene therapy is available practically.

Regardless of its complexity and length, the prohibited list stands as the fundamental reference document classifying all prohibited PEDs, prohibited methods, and masking agents. The fight against doping in sport has been based—and still continues to be based—on the capability of the antidoping laboratories to develop and apply analytic procedures for the most effective detection of all substances and methods included in the prohibited list.

The role of the World Anti-Doping Agency–accredited antidoping laboratories

There currently are 33 antidoping laboratories accredited by the WADA in the world ( Box 2 ), performing more than 200,000 antidoping tests per year. A comprehensive report of the results of the analyses performed by the WADA laboratories worldwide is released yearly by WADA and made available for consultation through their website ( www.wada-ama.org ). In spite of the high number of tests, little information can be drawn simply on the basis of results of the antidoping analyses on the real toxic potential and the related mechanism of action of the many PEDs included in the WADA prohibited list. The antidoping analyses are forensic, but not diagnostic, tests. This means that the aim of the analysis is not to verify the “state of health or disease” of athletes but instead “to supply evidence”—based on the principle of strict liability—of the presence in the biologic sample of a substance (drug/metabolite/marker) included in the WADA prohibited list. It follows that the information supplied by the WADA-accredited antidoping laboratories refers to the identification of “markers of exposure,” not of “markers of effect,” of doping agents and methods.

The data supplied by the WADA-accredited antidoping laboratories also are of little epidemiologic value for the following reasons:

• 1.
  

  Despite the outstanding number of antidoping tests performed worldwide, the total number of positive samples is too limited to support any epidemiologic conclusions.

  
  
• 2.
  

  All samples analyzed by the laboratories are anonymous and, therefore, critical information necessary for the correct compilation of a reference database is not available (eg, ethnicity, age, height, weight, body mass index, genetic endowment, training level and regimen, and diet).

  
  
• 3.
  

  Samples are not collected as a part of a controlled study, and, therefore, it is impossible to carry out a real toxicity study correctly because of the potential influence of other confounding factors.

  
  
• 4.
  

  Finally, the WADA rules state clearly that the biologic samples collected in the framework of official antidoping tests cannot be used for purposes other than the antidoping test itself: this means that the activity of the laboratory has to be limited to the identification of specific compounds (drugs/metabolites/markers) whose presence (or whose concentration above a threshold value) is to be considered a proof of doping. No additional tests (including diagnostic tests) are allowed.

The same points hold true for the research activity performed within the network of the WADA-accredited laboratories via the World Association of Anti-Doping Scientists (WAADS), the international scientific society promoting the sharing of knowledge among the accredited laboratories and the basic and applied research in development of new analytic methods. Because the result of a positive test constitutes the basis for the possible sanctioning of an athlete, all efforts are not devoted to diagnosing the health risks consequent to the use of PEDs but instead to guaranteeing the maximum of solidity of the experimental results. The International Standard Organization 17025 accreditation has been imposed since 2000 as a further prerequisite of accredited antidoping laboratories, and criteria for reporting positive samples must be in compliance with the WADA rules.

It is self-evident that there is little or no room, at present, for toxicologic evaluations. The potential toxicologic risks for abuse of performance-enhancing substances and methods cannot be evaluated fully by a single measurement of urinary/blood concentration values of drugs, metabolites, or other representative indicators of administration. Therefore, no toxicokinetic information can be estimated.

A further step forward will be represented by the final implementation of longitudinal studies, also known as the “athlete passport:” the goal is to build a database for all athletes in which the main hematologic and hormonal parameters are recorded and monitored. Although these strategies are being developed with the main purpose of detecting, via the evaluation of indirect parameters, some forms of doping otherwise problematic to identify (eg, autologous blood transfusions), they also will contribute to shedding further light on the chronic effects of the abuse of PEDs. The implementation of novel diagnostic approaches, to be performed independently of the forensic antidoping tests, for the overall assessment of the toxicity of PEDs will remain mandatory to fully accomplish the requirements of an effective antidoping strategy.

The adverse side effects of performance-enhancing drugs: what is known and unknown

The possible health risks of doping substances and methods have been the subject of several review articles, monographs, and conference proceedings. Mostly, these studies have been based on and supported by review of the scientific and medical literature, which have considered the results obtained in controlled, randomized clinical trials and the direct evidence obtained from clinical practice. It is impossible in this context to review, discuss, and outline the biochemical mechanisms of all the adverse effects of the PEDs described so far. To give an approximate idea of the variety of potential side effects of the different classes of substances included in the WADA-prohibited list (with the exception of alcohol, not a drug in the strict sense of the word), Table 1 lists the most common potential direct and indirect effects and the corresponding side effects of PEDs. It is evident that the risks/benefits ratio is always unbalanced toward the risks. Also, it is virtually impossible for a single drug to produce all or none of the effects listed in Table 1 in one subject.

Table 1

Most common undesired side effects of the main classes of prohibited substances considered in the World Anti-Doping Agency list

Class of the World Anti-Doping Agency Prohibited List	Potential Direct/Indirect Effects Enhancing Sport Performance	Side Effects Reported Most Commonly
S1. Anabolic agents AAS (endogenous and exogenous)	Generic anabolic effect, produced with the aim of enhancing muscle growth and weight and increasing strength, power, speed, endurance, and aggressiveness. Recovery times also should be improved.	A broad variety of effects (exhaustively reviewed in Ref. ), including, but not limited, to the following: Cardiovascular: hypertension, elevated risk of brain hemorrhages, myocardiac damage Hepatic: abnormal liver functions, cholestasis, development of androgen-dependent adenomas, depletion of high-density lipoprotein production Skeletal: water retention Dermal: seborrhea (steroid acne), oily skin, folliculitis, furunculosis Behavioral: increase of aggressiveness (aggressive psychoses), change in the libido, mood swings (euphoria followed by depression), mental disorders, headaches, dependence, or addiction Specific effects for men: testicular atrophy, altered spermatogenesis, prostate hypertrophy, gynecomastia Specific effects for women: virilization, atrophy of the uterus, effects on the ovary (polycystic ovary syndrome, ovary inflammations), reduction of the breast gland, hirsutism, hypothyroidism, lowering of the voice, alteration of the menstrual cycle, alopecia, effects on the connective tissue (striae distensae)
Other anabolic agents	Same as previously.	For the side effects of clenbuterol, see “S3. β 2 -Agonists” Side effects of selective androgen receptor modulators still are under evaluation (these drugs are not yet marketed)
S2. Hormones and related substances		Risk common to all peptide hormones: immunogenicity
Human growth hormone, insulin-like growth factors	Anabolic effect	Data on the effects of prolonged recombinant human growth hormone treatment in adults are limited Acute overdosing could lead to hyperglycemia. Long-term overdosing could result in signs and symptoms of gigantism or acromegaly consistent with the known effects of excess growth hormone Other reported effects are hypertension, cardiomyopathy, respiratory disease, diabetes, abnormal lipid metabolism, and osteoarthritis Increase risk for breast and colorectal cancer
Recombinant erythropoietins	Increased production of red blood cells and hemoglobin, resulting in an augmented efficacy of the transport of oxygen to the muscle	Hypertension, thromboses (thrombophlebitis, microvascular thrombosis, and thrombosis of the retinal artery, and temporal and renal veins), pulmonary embolism, cerebral embolism, seizures Other effects include pyrexia, headache, arthralgias, nausea, edema, fatigue, diarrhea, vomiting, chest pain, skin reaction (on the site of injection), asthenia, dizziness
Gonadotropins (human chorionic gonadotropin, luteinizing hormone, and follicle-stimulating hormone)	To stimulate the endogenous production of androgens, and to contrast the negative effects of testosterone doping	Prostate carcinoma or other androgen-dependent neoplasm Sudden ovarian enlargement resulting from ovarian hyperstimulation, ascites with or without pain, or pleural effusion, rupture of ovarian cysts with resultant hemoperitoneum Arterial thromboembolism, headache, irritability, restlessness, depression, fatigue, edema, precocious puberty, gynecomastia, pain at the site of injection
Insulin	To improve glucose transport to muscle	All adverse effects of hypoglycemia (including loss of consciousness, coma, and death) Respiratory adverse effects Chest pain, dry mouth, otitis media
S3. β 2 -Agonists	To achieve stimulants and anabolic effects after systemic administration of high doses, significantly higher than those prescribed—by inhalation—for the treatment of asthma	Cardiac arrest and even death may be associated with the abuse of any sympathomimetic medications. Other cardiovascular effect include, but are not limited to, increased pulse rate and blood pressure, ECG changes, seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/minute, arrhythmias. Hypokalemia also may occur Nervousness, headache, insomnia, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and sleeplessness
S4. Hormone antagonists and modulators Aromatase inhibitors (eg, anastrozole, letrozole, aminoglutethimide, exemestane, formestane, and testolactone)	To increase the production or decrease the biotransformation of endogenous AAS	At therapeutic doses: nonspecific toxic side effects, including (but not limited to) asthenia, headache, nausea, peripheral edema, fatigue, vomiting, and dyspepsia Long-term endocrinologic side effects can be severe if administered in sequence or in combination with tamoxifen or selective estrogen receptor modulators
Selective estrogen receptor modulators (eg, raloxifene, tamoxifen, and toremifene)	Same as previously	Hot flashes, flu-like syndrome, joint pain, rhinitis Blood clots, including deep vein thrombosis, and pulmonary embolus (rare)
Other antiestrogenic substances (eg, clomiphene, cyclofenil, and fulvestrant)	Same as previously	At high doses, nonspecific toxic side effects, including (but not limited to) nausea, vomiting, vasomotor flushes, visual blurring, spots or flashes, scotomata, ovarian enlargement with pelvic or abdominal pain
Agents modifying myostatin functions	To improve muscle growth by interfering with the action of myostatin.	Unknown: myostatin inhibitors never have been tested in human trials
S5. Diuretics and other masking agents Diuretics	1. To obtain a rapid and reversible reduction of the total body mass, an evident potential advantage in sports where weight categories are involved 2. To alter the normal urinary excretion of other PEDs or their metabolites (eg, by increasing the volume of urine and diluting them), making their detection by the antidoping laboratories more problematic	Hypotension Kidney dysfunction, dehydration (risk for central volume depletion), salt and water imbalance, electrolyte dispairement (eg, hyperosmolality, hyponatremia, hypokalemia, hypomagnesemia, hypocalcemia), muscle cramps Dizziness or lightheadedness, gastric effects, rash, impotence, secondary gout
Probenecid	To interfere with the normal excretion of other PEDs, especially AAS	Metabolic effects: precipitation of acute gouty arthritis Central nervous system: headache, dizziness Gastrointestinal: hepatic necrosis, nausea, anorexia, sore gums, vomiting Genitourinary: nephritic syndrome, uric acid stones with or without hematuria, renal colic, costovertebral pain, urinary frequency Hematologic: aplastic anemia, leucopenia, hemolytic anemia Integumental: dermatitis, alopecia, flushing (Rarely) severe allergic reactions and anaphylaxis
Epitestosterone	To adjust the value of the ratio of testosterone to epitestosterone	Unknown (epitestosterone is not a registered drug), even if likely overlapping to many of the side effects of the AAS
α-Reductase inhibitors (eg, finasteride and dutasteride)	Alteration of the endogenous steroid profile, interfering with the quantitation of some AAS and with the correct evaluation of longitudinal data	Alteration of the sexual function (impotence, decreased libido, decreased volume of ejaculate and other ejaculation disorders, breast enlargement, breast tenderness)
Plasma volume expanders (eg, dextran, hydroxyethylstarch and other modified polysaccharides)	To mask the effects of blood doping by blood dilution	Febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, hypervolemia
S6. Stimulants	Increased alertness	Increased alertness
Including, but not limited to	Improvement in coordination	Insomnia, anxiety
Central nervous system stimulants	Increased strength and endurance, as a consequence of a decreased perception of pain and fatigue	Inhibited judgment
Respiratory stimulants Cardiovascular stimulants Appetite suppressants	Glycogen sparing effect in muscle	Increased competitiveness, aggressiveness, and hostility Reduced fatigue (risks for muscle and cardiac overload) Tremor Effect on the cardiovascular systems (increased heart rate and blood pressure) Increased risk for stroke, heart attack, or sudden death Effects on the skeletal muscle (rhabdomyolysis).
S7. Narcotics	Increased tolerance to pain and fatigue Transient reduction of tremor in precision events	Addiction (also as gateway to other drugs), tolerance, physical and psychologic dependence Increased pain threshold Euphoria Excitement, psychologic stimulation Incorrect perception of danger Loss of coordination/equilibrium Reduced capacity of concentration Nausea, vomiting, constipation Depression Reduced breath capacity Reduced cardiac frequency/output Overdosing can lead to respiratory depression and death Effects on the skeletal muscle (rhabdomyolysis)
S8. Cannabinoids	To relieve precompetition tension Social drugs: motivation for their use or abuse may be different from the illicit enhancement of sport performance	Drug dependence Psychomotor changes Antimotivational syndrome (loss of ambition)
S9. Glucocorticosteroids	Effect on glucose metabolism (stimulation of de novo synthesis of glucose, conversion of amino acids into glucose, release of glucose from glycogen storage, and activation of the lipolysis in fat cells) Anti-inflammatory and analgesic properties, accompanied by euphoria Effects on the immune system	Acute: Hyperglycemia Fluid retention Mood alteration Chronic: Immunosuppression Suppression of the hypothalamic-pituitary-adrenal axis Musculoskeletal problems, also due to alteration of calcium metabolism and bone homeostasis Nonspecific effects (cataracts, diabetes mellitus, hypertension, peptic ulcer disease, weight gain, skin thinning, ecchymoses, striae, acne, hirsutism, fat redistribution, and various psychiatric disorders)
P2. β-Blockers	To reduce tremor, which gives a competitive advantage in specific sports/disciplines (eg, shooting, archery, curling, gymnastics)	Cardiovascular effects: bradycardia, cold extremities, postural hypotension, leg pain Central nervous system/neuromuscular effects: reversible mental depression progressing to catatonia, emotional lability, dizziness, vertigo, tiredness, fatigue, lethargy, drowsiness, depression, insomnia Hematologic effects: agranulocytosis Allergic: fever, sore throat, laryngospasm, respiratory distress Gastrointestinal: mesenteric arterial thrombosis, ischemic colitis, diarrhea, nausea Respiratory effects: wheeziness, dyspnea Other effects: impotency, hypoglycemia

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