Version July 2025
INTRODUCTION —
Athletes continue to use a wide range of substances and methods to improve their performance. Banned substances and methods are included in the World Anti-Doping Agency (WADA) prohibited list. This list is updated every January and is freely available on the WADA website.
Prohibited nonhormonal performance-enhancing drugs and some other prohibited methods for performance enhancement are reviewed here. Hormonal performance-enhancing drugs and other illicit methods of performance enhancement are reviewed separately. (See "Use of androgens and other hormones by athletes".)
WORLD ANTI-DOPING AGENCY AND PROHIBITED SUBSTANCES USED FOR PERFORMANCE ENHANCEMENT
Essential resources — Nonhormonal drugs used illicitly to improve sports performance are included in a comprehensive list maintained by the World Anti-Doping Agency (WADA). This list is updated every January and is freely available on the WADA website. It is important when reading this topic or any source of information about banned substances to ensure that it correlates with the latest version of the WADA prohibited substance list.
In the United States, United Kingdom, Japan, Canada, Switzerland, New Zealand, and Australia, clinicians and participants can check medications on Globaldro.com. This website also provides the email contact details for many national anti-doping organizations. Many countries have their own dedicated anti-doping website where relevant local information can be found.
Helpful resources for information about supplements include the Informed Sport website, Australian Institute of Sport website, and US Anti-Doping Agency website.
Important warnings — In the past decade, the WADA list of banned performance-enhancing substances has grown to over 200 drugs and methods. In addition to androgens and other hormones, the WADA prohibited list includes stimulants, recreational drugs such as narcotics and cannabinoids, beta agonists, diuretics, and other prescription medications. In 2011, section S0 was added to the WADA list to include substances that have yet to be approved for human use, are still in clinical development, or have been discontinued (S0). In 2021, WADA introduced a new category to the prohibited list, "Substances of Abuse." Athletes found using substances in this category may be required to seek appropriate treatment as well as serve a period of sanction.
When prescribing medications or advising about supplements, clinicians should check that none of the contents are banned by WADA or any relevant national anti-doping organizations. In many countries, supplements are not considered medication and do not undergo the rigorous testing typical for drugs. Supplements may be adulterated or contaminated with banned medications or other substances, may not include them in the list of ingredients, or do so using a pseudonym (eg, methylhexaneamine, a stimulant, is often called geranium oil or extract). (See "Nutritional and non-medication supplements permitted for performance enhancement" and "Overview of herbal medicine and dietary supplements".)
In addition to WADA and government agencies, other national sporting organizations (eg, National Collegiate Athletic Association in the United States) and governing bodies for particular sports (eg, Union Cycliste Internationale [UCI]) may ban substances not included on the WADA list. Thus, it is important for clinicians involved in the care or management of athletes to keep current with the restrictions and guidelines maintained by all such organizations relevant to their athletes.
BANNED NONHORMONAL PERFORMANCE-ENHANCING DRUGS
Stimulants
Overview of effects — Stimulants can enhance both physical and cognitive performance among athletes through a range of effects, including the following [1-4]:
●Improving endurance and anaerobic performance
●Diminishing feelings of fatigue
●Accelerating reaction time
●Improving concentration and working memory
●Increasing alertness
●Decreasing appetite and accelerating weight loss
While multiple studies have failed to confirm the purported ergogenic effect of stimulants, a systematic review of studies of prescription medications and athletic performance included six studies of stimulants and reported some benefit to performance from methylphenidate and amphetamine [5].
Examples of stimulants used by athletes include amphetamine, D-methamphetamine, ephedrine, caffeine, methylphenidate, pseudoephedrine, dimethylamylamine (DMAA), cocaine, fenfluramine, pemoline, selegiline, sibutramine, strychnine, and modafinil [2,4,6,7]. The majority act upon the adrenergic, dopaminergic, or serotonergic systems, and some upon multiple systems [4,8-13]. Therapeutic use of particular stimulants may be genuine in some cases (eg, pseudoephedrine), but this can be hard to validate objectively. An increasing number of athletes are prescribed a form of stimulant to treat attention deficit hyperactivity disorder (ADHD), and this requires a therapeutic use exemption. (See 'Banned stimulants' below and "Prohibited performance-enhancing drugs in sport: Testing and exemptions", section on 'Therapeutic use exemptions'.)
The potential adverse short- and long-term effects from stimulant use are numerous and sometimes dangerous. The presentation and management of acute intoxication and chronic dependence on stimulants are reviewed separately, while the use of particular stimulants for performance enhancement is discussed below. (See "Acute amphetamine and synthetic cathinone ("bath salt") intoxication" and "Methamphetamine: Acute intoxication" and "Stimulant use disorder: Psychosocial management" and "Stimulant use disorder: Treatment overview" and "Methamphetamine use disorder: Epidemiology, clinical features, and diagnosis" and "Cocaine: Acute intoxication" and "Cocaine use disorder: Epidemiology, clinical features, and diagnosis" and "Benefits and risks of caffeine and caffeinated beverages".)
Complications from stimulant use range from relatively mild (eg, nausea, insomnia, anxiety, tremor, and panic attacks) to more concerning (eg, agitation, hypertension, and tachycardia) to potentially life-threatening (eg, myocardial infarction and stroke) [1,2,4,7,14]. Higher doses may lead to aggressive behavior and psychosis. Particularly during activity, stimulant use predisposes to extra exertion, which can lead to heatstroke and rhabdomyolysis [2]. Methylphenidate has been shown to increase core temperature even at rest [2]. One case-control study reported an association between stimulant use and sudden unexplained death in children 7 to 19 years of age [15]. Modafinil may cause Stevens-Johnson syndrome [4]. (See "Exertional heat illness in adolescents and adults: Epidemiology, thermoregulation, risk factors, and diagnosis" and "Rhabdomyolysis: Clinical manifestations and diagnosis" and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)
Banned stimulants — Stimulants are banned in sporting events only "in-competition" according to section S6 of the World Anti-Doping Agency (WADA) prohibited list, where "in-competition" is described as the period just before midnight (11:59 PM) on the day before a competition in which the athlete is scheduled to participate until the end of the competition and the sample collection process. “In competition” includes any time during an event, tournament, game, or regatta. However, in rare cases, a given sporting body may define such a period differently.
The organizations that manage major sporting events (eg, Olympic Games Committee, Commonwealth Games Committee) may create their own rules, whereby the in-competition period begins at 11:59 PM on the day before the event commences and concludes after the last sample collection process is complete at the end of competition.
There are exceptions to this proscription for some drugs in some circumstances (described below). Otherwise, all stimulants on the WADA list are banned, and substances with a similar chemical structure or similar biologic effect are also banned. In some cases, urinary cutoffs have been set, in which case a substance may be legal in small therapeutic doses.
Banned stimulants more commonly used for performance enhancement include:
●Amphetamines – Amphetamines are used by athletes to increase alertness and concentration [4]. Although amphetamine, methamphetamine, and cocaine are primarily drugs of abuse, amphetamine salts (eg, dextroamphetamine) are used for legitimate treatment of some conditions (eg, ADHD). Some substances in this class are designated as substances of abuse and may be subject to different sanctions (eg, cocaine). (See "Acute amphetamine and synthetic cathinone ("bath salt") intoxication" and "Cocaine use disorder: Epidemiology, clinical features, and diagnosis" and "Methamphetamine use disorder: Epidemiology, clinical features, and diagnosis" and "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Amphetamines'.)
●Ephedra – Ephedra alkaloids are derived from the herb Ephedra sinica (or Ma huang), and supplements are made using the stem of the plant. Ephedra is commonly used by athletes to promote alertness, endurance, and strength, although no studies have demonstrated a significant athletic benefit [16]. The alkaloids in ephedra have been identified as ephedrine, pseudoephedrine, and phenylpropanolamine. Supplements containing ephedra may be purchased over the counter, and ephedra is included in some cough medicines, decongestants, and diet agents. Adverse effects may be significant, with one sporting fatality in 2003 attributed to the supplement. WADA prohibits urinary concentrations greater than 10 mcg/mL of ephedrine or methylephedrine. Ephedra is reviewed in greater detail separately. (See "Overview of herbal medicine and dietary supplements", section on 'Adverse effects'.)
●Ephedrine – Ephedrine is heavily used among athletes to improve alertness and accelerate weight loss and can be obtained with relative ease on the internet. According to a 2007 review article, ephedrine use among track and field athletes may be over 50 percent [17]. Among respondents to a 2004 survey of United States college hockey players, 38 percent reported using ephedrine, while 46 percent reported using pseudoephedrine [18]. Survey results from nearly 900 male and female college athletes and non-athletes published in 2008 reported that just over 6 percent of male athletes and 4.5 percent of female athletes used ephedrine, but the surveys did not include pseudoephedrine [19]. According to the 2016 WADA prohibited list, ephedrine may be used in small doses. Urinary cutoff levels are listed below. (See 'Urine concentration thresholds for selected stimulants' below.)
The US Food and Drug Administration (FDA) banned ephedrine for use as a diet aid due to the increased risk of heart attack and stroke [2]. It remains a common remedy in Chinese medicine. Pseudoephedrine has been banned in some countries due to its illegal use in the preparation of methamphetamines. (See "Overview of herbal medicine and dietary supplements", section on 'Adverse effects' and "Obesity in adults: Drug therapy" and "Obesity in adults: Drug therapy", section on 'Therapies not recommended'.)
●Dimethylamylamine (methylhexanamine) – DMAA (1,3-dimethylamylamine) is an amphetamine derivative widely used in sports supplements sold in the United States [7]. Because of health concerns, in 2011, the United States military removed supplements containing DMAA from military exchanges [20], and Health Canada classified DMAA as a drug subject to regulation and removed approval of any DMAA-containing products [21]. In 2013, the FDA made the manufacture and sale of methylhexanamine illegal due to toxicity and side effects. However, DMAA continues to be found as an unacknowledged additive in many sports supplements, particularly those purchased over the internet, and hence is the cause of many inadvertent violations of anti-doping rules.
DMAA has numerous other names, such as dimethylpentylamine, pentylamine, geranamine, forthane, and 2-amino-4-methylhexane. Not all these names are included on the WADA prohibited list, creating more confusion. Some supplements label this ingredient as geranium oil or geranium root extract, but analysis has shown that the substance is not a natural ingredient of geranium plants. A health warning on the United States National Center for Biotechnology Information website states that "DMAA, especially when used in combination with caffeine, can be a health risk elevating blood pressure and leading to cardiovascular problems ranging from shortness of breath to heart attack."
Unscrupulous companies continue to create designer analogs of these molecules, requiring continuous monitoring by the relevant anti-doping organizations.
●MDMA (ecstasy) – While not a performance-enhancing drug per se, MDMA may give a perception of enhanced energy that some athletes may believe to be helpful. In addition, some MDMA users may feel a sense of well-being, mental stimulation, and reduced anxiety [22].
MDMA (3,4 methylenedioxymethamphetamine) is an illicit drug with potentially serious side effects, which may include severe hypertension, hyperthermia, delirium, psychomotor agitation, and profound hyponatremia. Acute MDMA intoxication and its management are discussed separately. MDMA is further classified by WADA as a substance of abuse. (See "MDMA (ecstasy) intoxication".)
●Methylphenidate – Methylphenidate (also known as Ritalin, Methylin, Concerta, Focalin, and Metadate) is used to treat ADHD, but illicit use is widespread among athletes and the general population to improve alertness [23,24]. Among United States professional baseball players, the number of therapeutic use exemptions for the use of stimulants to treat ADHD increased almost fourfold, from 28 athletes to 103 in 2007, after these stimulants were banned in 2006 [2,25]. (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Stimulants' and "Attention deficit hyperactivity disorder in adults: Treatment overview".)
Banned stimulants less widely used include the following:
●Fenethylline – Also known as phenethylline and fenetylline (common brand name Captagon), fenethylline is a codrug to amphetamine and theophylline and was developed initially as a treatment for narcolepsy and ADHD. It is used as a drug of abuse and by soldiers in armed conflict but was banned worldwide due to side effects such as hallucinations, visual distortions, psychosis, rare myocardial infarctions, and seizures [26,27]. There is some evidence that fenethylline has been used by athletes to increase endurance.
●Modafinil – Modafinil is a non-amphetamine psychostimulant used to treat narcolepsy and circadian rhythm disorders, but use among military, pilots, and truck drivers to promote wakefulness is widely reported [28-31]. Modafinil may improve cognitive function, including memory, attention, and learning [32]; and subjects report feeling more energized and alert [28,33]. The risk of addiction appears to be low at therapeutic doses, but dependence has been reported [31,34]. At therapeutic doses, side effects are mild and include headache, nausea, tiredness, dizziness, and insomnia; but at high doses, psychosis and mania have been reported [35]. While there are few studies of modafinil and athletic performance, effects such as improved concentration, increased alertness, and speed of decision-making could benefit a range of sports, including multi-event disciplines (eg decathlon), multi-race events (eg rowing regatta), and activities requiring rapid reaction and decision-making (eg, automobile or bicycle race) [36].
●Oxilofrine (methylsynephrine) – Oxilofrine is a sympathomimetic agent used by athletes as a "fat burner," as well as for improved alertness and mental focus. Oxilofrine increases inotropic cardiac activity [13]. Although oxilofrine has never been approved for use by the FDA as either a dietary supplement or pharmaceutical and is not widely used in the United Kingdom, it has been identified as a contaminant in a variety of supplements, and two well-known sprinters tested positive for this substance in 2013 [37].
In one study, oxilofrine was identified in 14 different supplements available for over-the-counter purchase in the United States [37]. The drug's potentially harmful cardiac effects are similar to ephedrine, and there are reports of tachycardia, vomiting, and agitation [37]. It is easily available on the internet and can be disguised in medications such as methylsynephrine or "Acacia rigidula," often in dosages that far exceed therapeutic recommendations. Oxilofrine is approved for use in some countries where it is given during anesthesia and for treatment of orthostatic hypotension.
●Sibutramine – Sibutramine is a combined serotonin and norepinephrine reuptake inhibitor that acts by increasing thermogenesis and making the user feel fuller after a meal. It is used as a weight-loss supplement and has been shown to be more effective than placebo in obese populations when combined with diet and exercise interventions [38]. Its use in sport was suspended in 2010 in Europe due to associations with an increased risk of cardiovascular events such as hypertension, myocardial infarction, and stroke. Sibutramine has been detected in weight loss products and in some cases was not included in the list of ingredients. Contamination or adulteration of such weight loss products has resulted in inadvertent doping offenses since 2006.
Monitored stimulants
●A number of stimulants included in the 2016 WADA monitoring program are not prohibited. However, the status of these agents may change, and we suggest that readers check the WADA list each January to determine whether any of these drugs have subsequently been banned. These stimulants include:
•Bupropion – While not technically a stimulant, bupropion is structurally similar to amphetamine and possesses some stimulatory properties. It is used “off-label” for treatment of ADHD. There is limited evidence that bupropion may decrease perceived exertion during activity, allowing athletes to exercise longer [8]. (See "Atypical antidepressants: Pharmacology, administration, and side effects", section on 'Bupropion'.)
•Caffeine – Caffeine was on the prohibited list from 1980 to 2003 but is now on the monitoring list. Athletes may use caffeine in their diet at any desired dose. Caffeine is discussed in detail separately. (See "Benefits and risks of caffeine and caffeinated beverages" and "Cardiovascular effects of caffeine and caffeinated beverages" and "Nutritional and non-medication supplements permitted for performance enhancement", section on 'Caffeine'.)
•Nicotine – Nicotine may act like a stimulant by reducing anxiety, elevating mood, enhancing weight loss and satiety, and improving attention [3,4]. Chronic use through smoking increases the risk of cardiovascular disease, chronic obstructive lung disease, and several types of cancer. Nicotine is not prohibited in most sporting events, obviating the need for testing. (See "Cardiovascular effects of nicotine" and "Cardiovascular risk of smoking and benefits of smoking cessation" and "Cigarette smoking and other possible risk factors for lung cancer".)
•Phenylephrine – Phenylephrine is an alpha-1 adrenergic receptor agonist causing vasoconstriction. It is available in several preparations and used clinically to treat severe hypotension, nasal congestion (it is a common ingredient in many cold and flu medications), and hemorrhoids, and as a pupil dilator [39]. Phenylephrine at recommended dosages is considered safe.
•Phenylpropanolamine
•Pipradrol
•Synephrine
Urine concentration thresholds for selected stimulants
●The stimulants listed below may be used in normal therapeutic doses, provided that urine concentration thresholds do not exceed those listed:
•Cathine – Prohibited when the urine concentration is greater than 5 micrograms per milliliter (mcg/mL).
•Ephedrine and methylephedrine – Prohibited when the urine concentration of either is greater than 10 mcg/mL.
•Epinephrine (adrenaline) – Not prohibited for local administration (eg, nasal, ophthalmologic, or coadministration with local anesthetic). Prohibited when the urine concentration is greater than 10 mcg/mL.
•Pseudoephedrine – Prohibited when the urine concentration is greater than 150 mcg/mL.
Recreational drugs — In addition to the stimulants discussed above, other recreational drugs used for performance enhancement include opioids, alcohol, and cannabinoids. Opioids, MDMA (3,4-methylenedioxymethamphetamine; commonly called "ecstasy"), and cannabinoids (THC) are banned by WADA during competition (ie, "in-competition") only for all sports. Testing for these drugs is reviewed separately. (See "Urine drug testing".)
Some sporting organizations perform independent, out-of-competition testing for recreational drugs. Sanctions vary by sport but may range from mandatory rehabilitation to suspension or bans from competition. Under the new "Substances of Abuse" section of the WADA prohibited list, this process occurs as a part of management for positive tests involving a substance of abuse. For such substances, if the athlete can establish that use occurred out of competition and was unrelated to their sporting performance, a three-month period of ineligibility is enforced. This may be reduced to one month if the athlete completes a treatment program approved by the relevant anti-doping organization.
Nicotine is not currently banned and is discussed briefly with the other monitored stimulants. (See 'Monitored stimulants' above.)
Opioids — Opioids have been used to increase an athlete's pain threshold during competition [40]. In rare circumstances, a retrospective therapeutic use exemption (TUE) may be necessary for appropriate administration of an opioid following an injury or illness. Application for a TUE should be made as soon as possible after the event. (See "Prohibited performance-enhancing drugs in sport: Testing and exemptions", section on 'Therapeutic use exemptions'.)
Adverse effects include dependence, nausea and vomiting, constipation, impaired coordination, decreased concentration, and fatigue. Many opioids are detectable using standard urine drug screens. (See "Opioid use disorder: Epidemiology, clinical features, health consequences, screening, and assessment" and "Acute opioid intoxication in adults" and "Urine drug testing".)
Opioids are considered a substance of abuse in some circumstances. Codeine and hydrocodone remain on the WADA monitoring list. Tramadol was added to the list of prohibited drugs in 2024 due to its widespread misuse by athletes and potential side effects of light-headedness, drowsiness, and physical dependency.
Tramadol was banned previously by the Union Cycliste Internationale (UCI) due to high use among cyclists. In the 2017 WADA drug-monitoring program, 900 samples surpassed the threshold set for tramadol (0.7 percent of the sample total), and cyclists comprised 61 percent (548 samples) [41]. Between 2013 and 2017, the Madrid Doping Control Laboratory tested 9851 anonymous in-competition samples obtained from athletes competing at national (Spain) and international events for tramadol and identified 135 samples (1.4 percent of all samples) above the reporting threshold, of which 65.2 percent were from cyclists, 8.1 percent from triathletes, and 5.9 percent from rowers [42].
Alcohol — Alcohol is occasionally used to reduce performance anxiety during athletic events. Previously, alcohol was banned in some sports, such as archery, air sports (aerobatics, hang-gliding), automobile and motorcycle racing, and power boating, but it has been removed from prohibited substance lists. Alcohol can be quantified by blood testing. (See "Risky drinking and alcohol use disorder: Epidemiology, clinical features, adverse consequences, screening, and assessment" and "Cardiovascular benefits and risks of moderate alcohol consumption".)
Cannabinoids — Cannabinoids include marijuana and hashish (a resin). The active ingredient is tetrahydrocannabinol (THC), which can also be found in synthetic form, delta 9-tetrahydrocannabinol. All natural and synthetic cannabinoids are prohibited. The latter includes mimetics of cannabinoids, such as Spice, JWB-18, JWB073, and HU-210.
Cannabidiol (CBD) is a cannabinoid compound that is not prohibited. If required by an athlete, medicinal cannabis must be prescribed by a doctor and approved through the therapeutic use exemption process. Some para-athletes are prescribed medicinal cannabis for neuropathic pain, spasticity, or seizures. (See "Prohibited performance-enhancing drugs in sport: Testing and exemptions", section on 'Therapeutic use exemptions'.)
CBD products purchased over the counter or on the internet may be adulterated or contaminated despite being marketed as “pure.” They often contain a mix of THC and CBD. It is important that athletes are aware of this risk, as is true with any supplements purchased in this manner. (See "Nutritional and non-medication supplements permitted for performance enhancement".)
A survey of French university students found higher rates of cannabinoid use among participants in windsurfing, skiing, snowboarding, surfing, and sailing [43]. The physical effects of cannabinoids on sports performance are not well studied, but cannabinoids can reduce anxiety.
Adverse effects of cannabinoids include reduced alertness, impaired short-term memory, and psychomotor retardation [43,44]. These substances may cause dysphoria, increased anxiety, paranoia, and psychosis [44]. Given the long excretion profile for cannabinoids and the potential for "passive inhalation," WADA sets the acceptable limit for free and conjugated urinary carboxy-THC at 15 mcg/L [44]. This group of compounds is tested "in-competition" in all sports. (See "Cannabis use disorder: Clinical features, screening, diagnosis, and treatment" and "Cannabis use and disorder: Epidemiology, pharmacology, comorbidities, and adverse effects" and "Cannabis (marijuana): Acute intoxication" and "Synthetic cannabinoids: Acute intoxication".)
THC is highly fat soluble and therefore has a long half-life. For individuals who rarely use THC, the half-life is approximately 1.3 days. For regular users, the half-life is between 5 and 13 days. In chronic users, the compound is stored in tissues and released slowly into the bloodstream, so it may stay in the system for many months. The window of detection varies depending on the sample taken. Blood samples are unlikely to detect THC after 12 hours post-ingestion, whereas urine samples may test positive for up to 30 days, depending on the frequency of use. This is likely to be much less for one-off use. When CBD products are contaminated with THC, excretion times for the latter tend to be much shorter due to its low concentration.
Concerns that secondhand exposure to cannabis smoke may result in a positive doping test are largely unfounded with positive tests likely to be rare. According to a small laboratory study, exposure to high concentrations of cannabis smoke in a poorly ventilated space may produce positive urine tests using common cutoffs [45]. However, positive tests were limited to the hours immediately following exposure and did not occur with lower concentrations or proper ventilation. Thus, test results vary by the conditions of exposure and the individuals.
Athletes prescribed medicinal cannabis in their home country must understand that when entering some other countries, the medication may be illegal and possession subject to criminal liability.
Beta antagonists (blockers) — The effects of beta blockers (ie, beta adrenergic antagonists) include a decrease in heart rate, reduction of hand tremor, and temporary relief of anxiety; thus, they are used by athletes in sports such as archery or billiards where these effects are thought to confer a benefit [6,46].
Clinical study results are mixed. In a blinded cross-over study of 15 archers using both selective and non-selective beta blockers, medication conferred no benefit in shooting scores or body control (eg, fluctuations in aim) despite reductions in heart rate [47]. Two studies of pistol shooting reported improvements in performance when using selective [48] or non-selective [49] beta blockers.
Beta blockers are of little use and may be counterproductive in endurance sports as they reduce maximum heart rate and increase stroke volume (via increased filling time for a given intensity of activity), reduce gluconeogenesis in skeletal muscle, and restrict muscle blood flow [50]. Beta blockers are banned in-competition for specific sports, such as archery, automobile racing, billiards, darts, golf, shooting, and some ski and snowboard disciplines [46]. In addition, they are prohibited out of competition for archery and shooting. Beta blockers can be detected by gas chromatography mass spectrometry.
Beta blockers are used routinely in the treatment of heart disease, including heart failure and coronary artery disease. The athlete who requires therapy with a beta blocker must obtain a therapeutic use exemption, including a clear explanation as to why alternate therapies cannot be used. (See "Acute myocardial infarction: Role of beta blocker therapy" and "Prohibited performance-enhancing drugs in sport: Testing and exemptions", section on 'Therapeutic use exemptions' and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.)
Adverse effects of beta blockers with short-term use include bradycardia, increased airway resistance, and decreased endurance due to reduced maximum workload [46]. (See "Major side effects of beta blockers".)
Beta 2 agonists
Inhaled (partial ban) — Inhaled beta agonists (ie, beta 2 adrenergic agonist) are commonly used to treat asthma. The purported performance-enhancing effects of beta agonists on non-asthmatic athletes are debated, but evidence overall suggests some benefit for anaerobic performance [6,51-54].
Evidence pertaining to performance — Inhaled beta agonists do not appear to improve aerobic performance. A 2011 meta-analysis of 26 randomized trials involving 403 healthy, non-asthmatic athletes reported no significant improvements from inhaled beta 2 agonists on endurance, strength, or sprint performance compared with placebo [52]. A similar meta-analysis of 47 randomized cross-over trials involving 607 healthy, non-asthmatic participants but limited to assessments of aerobic performance found no significant effect on maximum oxygen consumption (VO2 max) and no significant improvement in athletic performance (eg, race time, time to exhaustion) regardless of type of beta agonist, dose, or duration of treatment compared with placebo [53].
However, inhaled beta agonists may slightly improve anaerobic performance. A systematic review and meta-analysis of 34 studies involving 472 healthy, non-asthmatic participants reported an average improvement of 5 percent on measures of anaerobic performance [54]. Strength and sprint performance measures also improved with use of beta 2 agonists. Inhaled medication provided less benefit than oral, particularly with sustained use, and doses above recommended were necessary to achieve benefit. (See "Beta agonists in asthma: Acute administration and prophylactic use".)
Permitted and banned medications; concentration thresholds — All beta agonists are banned in sport, both in and out of competition; however, salbutamol, formoterol, vilanterol, and salmeterol are permitted when used by inhalation at therapeutic doses. Urine concentration thresholds for these substances are used for testing.
Inhaled terbutaline, fenoterol, and tulobuterol are banned and require a TUE and pulmonary function testing as proof that the athlete has asthma. Terbutaline's actions are similar to salbutamol, and a TUE is typically only granted when the athlete can demonstrate that they have been using the medication successfully for many years. Vilanterol and tulobuterol are longer-acting beta agonists. (See "Prohibited performance-enhancing drugs in sport: Testing and exemptions", section on 'Therapeutic use exemptions'.)
High urine concentrations of a beta agonist, defined as greater than 1000 ng/mL of salbutamol or 40 ng/mL of formoterol, may constitute a positive test ("Adverse Analytical Finding") for a performance-enhancing drug, as such large doses are not deemed to be therapeutic (whilst unproven, high doses are considered to be anabolic). The athlete must then prove that the high urinary concentrations resulted from hospitalization for severe acute asthma or some other therapeutic use [55]. A maximal dosage of 1600 mcg of albuterol or 54 mcg of formoterol over 24 hours is approved for management of acute asthma exacerbations. An athlete may take a maximum of 25 mg of vilanterol over 24 hours.
Experts suggest that any athlete who experiences a severe asthma exacerbation requiring treatment with high doses of a beta agonist obtain a retrospective TUE as soon as is practically possible. If an athlete is found to have a urine concentration of one of these substances above the threshold, they must undergo a controlled pharmacokinetic study to demonstrate that the abnormal result was the consequence of a therapeutic inhaled dose; however, at this stage, there is no standard test that is performed. There are anecdotes of athletes "stacking" a variety of legal beta agonists, purportedly for their anabolic effects, but evidence supporting the ergogenic effect of this strategy is lacking.
Oral — Oral beta agonists are included in the WADA banned substances list, where they are classified as "other anabolic agents." Oral beta agonists can be detected by gas or liquid chromatography mass spectrometry or tandem mass spectrometry.
Clenbuterol is a long-acting, oral beta agonist that has been used for many years in animal farming as a "repartitioning agent" to increase lean muscle mass due to its direct anabolic effects [56]. Clenbuterol and similar drugs increase skeletal muscle, inhibit breakdown of protein, and decrease body fat [46,56]. There has been some concern that clenbuterol-contaminated food could result in positive drug testing [57].
Clenbuterol continues to be used for agriculture, particularly in Mexico and China. Therefore, international and national governing sporting bodies use a threshold concentration for clenbuterol if the athlete can prove they were in one of those countries and ate significant quantities of red meat. Zilpaterol, another oral beta agonist used in some countries to promote livestock growth, appears to have similar pharmacologic properties but is less potent. Little research has been performed on its anabolic properties in humans, but in horses, it has been shown to cause some negative effects, including muscle tremors, renal damage, and tachycardia [58].
In the authors' experience, clenbuterol has been used by athletes in power sports (eg, Olympic weightlifting), sports with weight categories (eg, wrestling), and bodybuilding. It was first identified as a doping agent in the 1992 Summer Olympic Games when two American field athletes tested positive. In 1991, a study of bodybuilding athletes reported that the substance was present in several urine samples [59]. A prominent cyclist has been banned for using clenbuterol. Athletes usually cycle clenbuterol in two-day on-off cycles for three weeks [60], then go off the drug for 10 to 12 weeks [61] as receptors rapidly deregulate. It is often used in combination with anabolic steroids.
Potential adverse effects of oral beta agonists include tachycardia, arrhythmias, hypokalemia, hyperglycemia, and muscle tremor [46,62]. A systematic review of observational studies involving a total of 24 athletes summarized adverse effects from clenbuterol use and reported that ingestion of doses from 20 micrograms to 30 mg were associated primarily with cardiac complications, including supraventricular tachycardia, atrial fibrillation, hypotension, chest pain, myocardial infarction, cardiomyopathy, and death [63].
Hormone and metabolic modulators — In the 2021 WADA list of prohibited substances, this group was reorganized to clarify terminology and reflect the common underlying mechanism, which involves binding to estrogen receptors and blocking estrogen action. The reorganization did not result in the addition or removal of any substances; all remain banned. The nonhormonal drugs are listed here while the hormonal agents are discussed separately. (See "Use of androgens and other hormones by athletes".)
●Aromatase inhibitors – This group includes aromatase inhibitors (eg, anastrozole, Letrozole, testolactone, formestane, exemestane).
●Anti-estrogenic substances (anti-estrogens and selective estrogen receptor modulators [SERMs]) – This group includes anti-estrogenic substances such as clomiphene and SERMs such as tamoxifen, raloxifene, and toremifene.
●Agents preventing activin receptor IIB activation – This group contains myostatin inhibitors, myostatin- or precursor-neutralizing antibodies, and other substances that affect the activin A and IIB receptors.
Myostatin inhibitors — Myostatin, a myokine produced by myocytes, is a powerful negative regulator of muscle growth. Some researchers have proposed that inhibition of the myostatin pathway may improve functional outcomes in patients with muscular disorders. Of these, there are:
●Agents reducing or ablating myostatin expression.
●Myostatin-binding proteins – Follistatin is a powerful inhibitor of myostatin, first isolated from ovarian tissue. It has been shown to increase muscle mass and strength in animal models [64]. Follistatin also suppresses FSH and thus may have negative effects on the hypothalamic-pituitary-gonadal axis.
●Myostatin-neutralizing antibodies – Domagrozumab, landogrozumab, apitegromab, and stamulumab are antibodies that bind myostatin to impair its function.
Activin A-neutralizing antibodies
●Anti-activin receptor IIB antibodies – BYM338, or bimagrumab, a monoclonal antibody that binds activin type II receptors in skeletal muscle, is being studied in clinical trials involving several muscular diseases, particularly involving sarcopenia and muscle weakness. This antibody blocks the myostatin-induced signaling cascade.
●Activin receptor IIB competitors (eg, Decoy activin receptors [eg, ACE-031]).
Metabolic modulators
●Meldonium (mildronate) was developed in the 1970s to increase growth in animals. The drug is a carnitine analogue that inhibits formation of L-carnitine, which ultimately reduces fatty acid transport into mitochondria [65]. With less fatty acid available to serve as the substrate for energy production, more carbohydrate is used. Meldonium is usually prescribed for patients with ischemic heart disease, as it reduces oxygen consumption through enhanced glycolysis during ischemia. The reduction in oxygen consumption may translate into improved performance and recovery for endurance athletes.
Mildronate was added to the WADA list of banned substances in 2016 after monitoring revealed widespread use during athletic competition [66]. Meldonium was detected in 8.7 percent of the urine samples tested at the 2015 Baku European Games [67]. Since the introduction of the ban in January 2016, several high-profile athletes have been sanctioned for using meldonium. As meldonium accumulates in some tissues, it can sometimes be detected as long as five months after use [68].
●Trimetazidine inhibits the beta-oxidation of free fatty acids, thereby increasing the use of carbohydrate as a substrate for energy production, which requires less oxygen. This may improve performance among endurance athletes. The proscription of trimetazidine has been expanded from in-competition to all sports activity.
●Activators of AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor delta (PPAR-delta) – Examples of these substances include:
•5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) is banned by WADA. It is an intermediary in the generation of inosine monophosphate. AICAR is an analog of adenosine monophosphate (AMP) capable of stimulating AMPK activity, which stimulates glucose uptake by skeletal muscle cells. AICAR is said to have performance benefits, such as accelerating weight loss and boosting oxygen availability. It has been used to treat myocardial ischemia and included in studies since the 1980s, but limited testing has been performed in humans. Some cyclists may have used this compound during the 2009 Tour De France.
•GW1516 (Endurobol) has not been approved for human use and is banned by WADA. It is said to modulate the gene PPAR-delta, which when stimulated causes increased production of slow twitch muscle fibers in mice. A number of elite cyclists were banned from sport in 2013 for using this drug. Preclinical trials were abandoned when high doses were linked to increased cancer rates in animals, and WADA has warned athletes of possible serious side effects. The drug continues to be available for purchase on the internet and is an ingredient or contaminant in online supplements. Websites continue to promote its benefits and safety despite evidence to the contrary.
•REV-ERB alpha agonists (eg, Stenabolic [SR9009]) are banned by WADA. They have been marketed to bodybuilders and other athletes as an alternative to anabolic steroids. The drugs work by altering gene expression and manifest a diverse range of effects in rodent and other animal studies, including alterations in circadian rhythm and metabolism. They have not been widely tested for safety and have no accepted clinical use.
●Insulin and insulin mimetics (see "Use of androgens and other hormones by athletes")
Nonhormonal agents affecting erythropoiesis
Hypoxia-inducible factor (HIF)-activating agents — HIFs are a group of substances banned by WADA and described as peptide hormones, growth factors, and related substances (S2 in the WADA prohibited list). HIFs are transcription factors that mediate the cellular response to hypoxia, which develops in muscles during high-intensity exercise. HIFs determine the genetic response to hypoxia, including regulation of erythropoietin production, the metabolic pathways used for energy production, angiogenesis, and iron supply. Autologous HIFs are quickly metabolized in the absence of hypoxia. HIF stabilizers may extend the activity of HIFs, resulting in higher levels of erythropoietin and increased capacity for oxygen transport. HIFs may increase the number of capillaries in skeletal muscles, thereby increasing carbohydrate metabolism and further improving oxygen-carrying capacity.
HIF-activating or -stabilizing agents are orally bioavailable, small molecules developed as anti-anemia therapies. Most are experimental and the subject of clinical trials. They include the following substances:
●HIF-activating agents include cobalt, FG 4592 (roxadustat), IOX2, and daprodustat (GSK1278863). These agents can be detected by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-EIT-MS/MS). Cobalt salt likely stimulates erythropoietin production more than other HIF stabilizers [69]. Cobalt is an essential base element, but in large amounts can cause end-organ damage, including cardiomyopathy and thyroid disease.
●HIF stimulators (eg, argon, xenon) may stimulate hypoxia-inducible transcription factors in animals. However, the results of preclinical trials have been varied and inconsistent. No human data are available. HIF stimulators are expensive and impractical in athletes, as large amounts are needed and the substances must be inhaled via specialized respirators during the activity [70].
Drugs that improve oxygen delivery — A number of drugs are available that increase oxygen delivery. Drugs that mimic the action of 2,3 bisphosphoglycerate (2,3-BPG, previously called 2,3-diphosphoglycerate or 2,3-DPG) shift the oxygen dissociation curve to the right (figure 1), which allows more oxygen delivery to tissues, such as skeletal muscle. (See "Structure and function of normal hemoglobins", section on '2,3-bisphosphoglycerate'.)
Allosteric modulators improve oxygen delivery to hypoxic tissues by decreasing the oxygen affinity of hemoglobin, which would be useful during athletic endeavors, particularly endurance events. RSR-13 (efaproxiral), an allosteric modulator of hemoglobin, has been shown to increase VO2 max in dogs, but it has a half-life of three to six hours and is easily detectable in urine tests within 36 hours of use. The drug has significant side effects when used for cancer treatment, including headache, nausea, mucosal irritation allergic reactions, and renal dysfunction.
Other agents that affect erythropoiesis include GATA inhibitors (eg, K-11706) and transforming growth factor beta (TGF-B)-signaling inhibitors (eg, luspatercept, sotatercept).
Innate repair receptor agonists — While not true hormones, these synthetic substances are created by modifying the erythropoietin (EPO) molecule. Methoxy polyethylene glycol-epoetin beta, marketed as Mircera, is a long-acting EPO receptor activator used for patients with anemia from kidney disease. None of these compounds has proven performance-enhancing effects in humans. Other erythropoietins (eg, carbamylated EPO [CEPO], Asialo-EPO) and agents affecting erythropoiesis are hormonal substances and discussed separately. (See "Use of androgens and other hormones by athletes".)
AGENTS USED TO PREVENT DETECTION OF BANNED SUBSTANCES —
Masking agents are used to conceal the presence of a prohibited substance in urine or other biologic samples. Substances that have been used as masking agents include diuretics, probenecid, desmopressin, and plasma expanders (eg, intravenous albumin, dextran, hydroxyethyl starch, and mannitol). All masking agents are banned by the World Anti-Doping Agency (WADA).
Diuretics — Diuretics are generally used in the treatment of hypertension and heart failure and include thiazides (eg, hydrochlorothiazide), loop diuretics (eg, furosemide), acetazolamide, amiloride, and spironolactone. All classes of diuretics are banned under WADA regulations. Pamabrom, a drug that includes the weak diuretic bromotheophylline, is sold over the counter and used to treat premenstrual symptoms. It is not banned by WADA.
While diuretics do not enhance performance, athletes may use them to increase urine output in order to dilute banned drugs or their metabolites in the urine. This technique is typically used for drugs with urine concentration cutoffs. In addition, diuretics are used to reduce the fluid retention that can accompany use of androgenic anabolic steroids. Diuretics are best detected by gas or liquid chromatography mass spectrometry or tandem mass spectrometry methods.
Therapeutic use exemptions are not required for topical ophthalmic use of carbonic anhydrase inhibitors or for local use of felypressin in dental anesthesia in conjunction with a threshold substance.
Potential adverse effects from diuretics may result from dehydration (eg, lightheadedness, hypotension, muscle cramps) or electrolyte disturbances (eg, hypokalemia or possibly hyperkalemia from potassium-sparing diuretics). The relative hyperthermia and dehydration that sometimes accompany exercise may potentiate these effects. Diuretic use and side effects are discussed in greater detail separately. (See "Mechanism of action of diuretics" and "Loop diuretics: Dosing and major side effects" and "Thiazides versus loop diuretics in the treatment of hypertension" and "Use of diuretics in patients with heart failure" and "Diuretics and calcium balance" and "Diuretic-induced hyponatremia".)
Desmopressin — Desmopressin is a synthetic analog of vasopressin (antidiuretic hormone) that causes increased water reabsorption in the renal collecting ducts. Desmopressin was added to the WADA list of prohibited substances in 2011 when a study demonstrated substantial hemodilution in athletes and reductions in plasma concentrations of hemoglobin and other blood parameters [71]. Desmopressin has been used to mask use of rhuEPO and to modify the hematologic factors used in the WADA Athlete Biological Passport (ABP) program. (See "Arginine vasopressin deficiency (central diabetes insipidus): Treatment", section on 'Desmopressin'.)
Probenecid — Probenecid is an inhibitor of particular transport mechanisms in the renal tubules and thus blocks excretion of a number of drugs, including anabolic steroids and their metabolites. This results in more dilute urine with a lower concentration of the prohibited drugs. Athletes may use probenecid to prevent exceeding thresholds for drugs with a urine concentration cutoff. However, in some cases, athletes are prescribed probenecid in combination with antibiotics for legitimate therapeutic reasons but may still be subject to sanctions for using a banned substance.
Plasma expanders — Plasma expanders are high-molecular-weight, biologically inert substances typically used in transfusions or as a blood substitute. Examples include mannitol, dextran, albumin, and hydroxyethyl starch (HES). These agents have also been used to improve hydration and to mask the use of banned drugs by athletes. When administered, plasma expanders do not readily leave the circulation and hence exert an osmotic effect, pulling fluid into the blood vessels and increasing blood volume. In this way, they may dilute hematologic measurements, such as the hematocrit, important in the ABP, and mask the administration of erythropoietin or erythropoietin-like substances. Many are included in the WADA prohibited substance list. (See "Use of androgens and other hormones by athletes", section on 'Erythropoietin'.)
HES, a synthetic polymer derived from amylopectin, persists in the plasma for 17 to 24 weeks and causes plasma volume expansion for up to 24 hours. Side effects include an increased tendency for blood coagulation. Rapid screening tests for HES and dextran are available. Urinary cutoff thresholds for mannitol are used to distinguish doping from normal dietary intake. Albumin, an endogenous protein, can be administered intravenously after extraction from whole blood. Some drugs bind to albumin, reducing their excretion rate. (See "Complications of mannitol therapy" and "Plasma derivatives and recombinant DNA-produced coagulation factors", section on 'Albumin'.)
Glycerol — Glycerol was removed from the WADA banned substances list in 2019 after research found its ergogenic effects to be minimal. Its use as a volume expander is discussed separately. (See "Nutritional and non-medication supplements permitted for performance enhancement", section on 'Glycerol'.)
Other agents — Although previously designated a masking agent, epitestosterone is now classified as an anabolic agent. When coadministered with testosterone, it can normalize the urine testosterone/epitestosterone ratio, which is used to help detect abuse of exogenous testosterone and like hormones. (See "Use of androgens and other hormones by athletes", section on 'Androgens'.)
Alpha reductase inhibitors were removed from the masking agent category and the banned list in 2009.
BANNED METHODS OF NON-PHARMACOLOGIC PERFORMANCE ENHANCEMENT —
There are a number of prohibited methods used for performance enhancement during sport that do not involve taking drugs. Blood transfusion is among the most common. The World Anti-Doping Agency (WADA) regulations (section M1) specifically ban the manipulation of blood and blood components, including the following actions:
●Administration or reintroduction of any quantity of autologous, allogeneic (homologous), or heterologous blood or red blood cell products of any origin into the circulatory system. Donation by athletes of plasma or plasma components via plasmapheresis is no longer prohibited when performed at a registered donation center.
●Artificial means for enhancing the uptake, transport, or delivery of oxygen including but not limited to perfluorochemicals, efaproxiral (RSR13), and modified hemoglobin products (eg, hemoglobin-based blood substitutes and microencapsulated hemoglobin products). Supplemental oxygen is not proscribed.
●Any form of intravascular manipulation of the blood or blood components by physical or chemical means.
Blood transfusions — Blood transfusions can be autologous (using one's own blood) or allogenic (ie, homologous, using blood from a different person) [72]. In sports requiring endurance, blood transfusions can be used to increase the number of erythrocytes and oxygen-carrying capacity of the blood to improve performance and speed recovery. Blood transfusions prior to athletic competitions to enhance performance are prohibited by the WADA [6,72]. Platelet-rich plasma and other platelet-derived preparations contain growth factors and are used to treat injury, but they are not prohibited by WADA, as no specific performance-enhancing effect has been demonstrated. (See "Tendinopathy: Overview of management", section on 'Autologous blood and platelet-rich plasma injection' and "Investigational approaches to the management of osteoarthritis", section on 'Platelet-rich plasma'.)
Potential adverse effects from blood transfusions include sudden fluctuations in blood pressure, stimulation of atherosclerosis, oxidative damage to organs, impaired blood cell function, blood-borne infections, and iron deposition in organs [73]. (See "Indications and hemoglobin thresholds for RBC transfusion in adults".)
Autologous blood transfusions cannot be detected by direct testing. Homologous transfusions can be detected through surface antigen patterns using flow cytometry, which is highly sensitive and able to detect rare antigenically distinct cells in an athlete's sample. As the life of a red blood cell is three to four months, detection can be made up to several weeks after a transfusion [72,73].
As the ability to test for exogenous erythropoietin has improved, the use of blood transfusions has increased in sport. The athlete biological passport (ABP) is designed to detect sudden or unusual increases in an athlete's hemoglobin, hematocrit, and other indices of red blood cells. (See "Use of androgens and other hormones by athletes", section on 'Erythropoietin' and "Prohibited performance-enhancing drugs in sport: Testing and exemptions", section on 'Athlete biological passport'.)
Artificial oxygen carriers — Artificial oxygen carriers, such as hemoglobin-based oxygen carriers (HBOCs) and perfluorocarbons, bind and deliver oxygen to tissues such as skeletal muscle. They have been used in select situations involving acute blood loss such as trauma and cardiac surgery. These compounds have a short half-life, so they need to be given intravenously at the time of need. All such compounds are banned under WADA regulations because of the possibility of performance enhancement. HBOCs and synthetic hemoglobin impart a red color to the urine, making detection straightforward in most cases.
Free hemoglobin is toxic, particularly to the kidneys; thus, several techniques have been developed to prevent such injury. These techniques, including polymerization, cross-linking, conjugation, and encapsulation, have led to the development of compounds referred to as HBOCs. First-generation HBOCs were reported to cause vasoconstriction, which impairs oxygen release to tissues [73,74]. Third-generation HBOCs involve enclosing the contents of erythrocytes (hemoglobin and particular enzymes) within artificial erythrocytes (liposomes or biodegradable nanocapsules) or modifying them using complex conjugations. These newer HBOCs appear to be highly effective oxygen donors and may cause less vasoconstriction [74,75].
Reported effects of third-generation HBOCs include increased concentrations of erythropoietin, serum iron, and serum ferritin [75,76] and improved exercise capacity compared with autologous transfusion in untrained, healthy males [77]. Complications from HBOCs may include gastrointestinal dysfunction, renal toxicity, hypertension, and platelet dysfunction. Reactive oxygen radicals, a byproduct of the increased amounts of oxygen formed from HBOCs, may cause the tissue damage noted in clinical trials [76]. Significant safety concerns were raised in phase II and III clinical trials of some HBOCs, and this has slowed development [78]. However, there remain a number of compounds being studied in clinical trials [74]. Several reports describe possession and administration of HBOCs among professional cyclists [75].
Emulsions of perfluorocarbon (PFC) dissolve high concentrations of oxygen and thus can serve as effective oxygen providers to oxygen-deprived tissues. These are synthetic organic, highly fluorinated compounds, and the amount of oxygen dissolved in the emulsions correlates directly with the partial pressure of oxygen. Thus, perfluorocarbons require an environment with a high oxygen concentration to be effective, which is not easily achievable during athletic competition. Perfluorocarbons may cause back pain, fatigue, transient fevers, and clotting dysfunction [73]. There are no published reports of athletes using PFCs, and no studies have been performed on the possible ergogenic effect of PFCs during exercise.
Whether PFCs and HBOCs improve athletic performance remains a subject of debate. Neither responds to endogenous 2,3 DPG (2,3 BPG), and therefore, both are probably less effective at improving oxygenation than transfusions of red blood cells. In addition, HBOCs may cause vasoconstriction, which would limit oxygen delivery to tissues and may even impair performance [73]. Serum testing using an electrophoretic method is fast, effective, and sensitive and is used as a screening test for anti-doping samples [79].
Intravenous fluid — The WADA list of prohibited methods (section M2) includes intravenous infusions, which may be used to offset dehydration during endurance events. Intravenous infusions or injections of more than 100 mL of fluid per 12-hour period, except for those legitimately received in the course of medical treatment, a surgical procedure, or diagnostic investigation, are not permitted. This rule was changed in 2019 due to the number of inadvertent violations occurring as a result of iron and other supplement infusions.
Gene doping and cell doping — "Gene doping" is the application of gene therapy techniques to enhance athletic performance [80,81]. In 2001, WADA declared that the "non-therapeutic use of cells, genes, genetic elements, or the modulation of genetic expression, having the capacity to enhance athletic performance, is prohibited."
Thus, neither of the following actions is permitted:
●Use of nucleic acids or nucleic acid analogs that may alter genomic sequences and/or alter gene expression by any mechanism (including gene editing, gene silencing, and gene transfer technologies) with the potential to enhance sport performance
●Use of normal or genetically modified cells with the potential to enhance sport performance
Candidate genes have been identified that increase the oxygen-carrying capacity of the blood through increased production of erythropoietin, vascular endothelial factor, and other angiogenic factors and that increase strength through stimulation of type I and type II muscle fibers, insulin-like growth factor (IGF) I, and myostatin [80,82-86]. Using laboratory methods, gene doping has been demonstrated to improve endurance, strength, and tissue repair in animal models [80,82,83]. Gene transfer in mouse muscle has been shown to counteract age-related muscle atrophy [87] and enhance the effects of training on muscle hypertrophy [88]. Inactivation of the myostatin gene resulted in marked muscle hypertrophy in mice [89].
To date, there is no evidence of gene doping by human athletes. However, WADA is sufficiently concerned to include gene doping in its official list of banned methods [80,82,90]. The potential for performance enhancement and extension of an athlete's career through improved healing capacity, along with the inherent difficulty in detection [91,92], increases the risk for this form of abuse. The potentially serious risks to the health of the athlete, and possibly others (eg, exposure to viral gene vectors), and the unfair advantage gained by cheaters justify the need for close monitoring and an aggressive education campaign. Examples of possible health risks include inadequately regulated increases in erythropoietin expression that may cause significant polycythemia and increases in IGF-1 or growth hormone that could stimulate production of malignant cells [93].
Although the prospects for gene doping are theoretical at present, improvements in genetic technology should be monitored closely, and further research aimed at detecting genetic manipulation is warranted [81]. Monitoring may involve identifying specific substances (consistent with current methods for detection) but also patterns of changes that may occur as a response to genetic modification.
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Androgens and other banned substances in athletes".)
SUMMARY AND RECOMMENDATIONS
●World Anti-Doping Agency (WADA) banned substance list and other important resources – Clinicians involved in the care of competitive athletes should be aware of doping regulations, particularly as some banned drugs may be taken for medical purposes (eg, diuretics, 5-alpha-reductase inhibitors). WADA maintains a list of prohibited substances, which includes stimulants, recreational drugs (eg, opioids, cannabinoids), beta agonists, diuretics, and other prescription medications. Additional restrictions may be enforced by other organizations for governing bodies relevant to the athletes under their care.
Important resources include the following:
•The WADA banned substance list is updated annually and can be found on the WADA website. (See 'World Anti-Doping Agency and prohibited substances used for performance enhancement' above.)
•In the United States, United Kingdom, Japan, Canada, Switzerland, and Australia, clinicians and participants can check medications on Globaldro.com. This website provides email contact details for many national anti-doping organizations.
•Resources for information about supplements include the Informed Sport website, Australian Institute of Sport website, and US Anti-Doping Agency website. (See "Nutritional and non-medication supplements permitted for performance enhancement".)
●Use of androgens and other hormones in sport – Androgens and growth hormones are among the most commonly used performance-enhancing substances. These are discussed separately. (See "Use of androgens and other hormones by athletes".)
●Use of nonhormonal drugs in sport – Multiple nonhormonal drugs are used for performance enhancement, including:
•Stimulants (see 'Stimulants' above)
•Recreational drugs (eg, opioids, cannabinoids) (see 'Recreational drugs' above)
•Beta agonists (see 'Beta 2 agonists' above)
•Beta antagonists (blockers) (see 'Beta antagonists (blockers)' above)
•Other prescription and non-prescription medications (see 'Hormone and metabolic modulators' above and 'Nonhormonal agents affecting erythropoiesis' above)
Each category is discussed in the text, including mechanisms and restrictions. (See 'Banned nonhormonal performance-enhancing drugs' above.)
●Agents used to prevent detection – Multiple agents and techniques are used to prevent detection of banned performance-enhancing substances. These include diuretics, desmopressin, probenecid, and plasma expanders. (See 'Agents used to prevent detection of banned substances' above.)
●Non-pharmacologic performance enhancement – These methods include blood transfusion, hypoxia induction techniques, and gene doping. (See 'Banned methods of non-pharmacologic performance enhancement' above.)
●Detection methods and therapeutic exemptions – Methods for detecting banned performance-enhancing drugs include the history and physical examination, the athlete biological passport (ABP), and urine and drug testing. Waivers called "Therapeutic Use Exemptions" may be granted to some athletes who need to use a particular banned medication for a legitimate medical purpose. These issues are discussed separately. (See "Prohibited performance-enhancing drugs in sport: Testing and exemptions".)
