Prohibited performance-enhancing drugs in sport: Testing and exemptions

INTRODUCTION — 

Athletes continue to use a wide range of substances and methods to improve their performance. Substances and methods prohibited from international competition 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.

Evaluation and formal testing procedures for banned substances and methods for obtaining appropriate exemptions are reviewed here. Prohibited and permitted drugs and supplements used in sport are discussed separately:

●(See "Use of androgens and other hormones by athletes".)

●(See "Prohibited nonhormonal performance-enhancing drugs and other substances and methods in sport".)

●(See "Prescription and non-prescription medications permitted for performance enhancement".)

●(See "Nutritional and non-medication supplements permitted for performance enhancement".)

TESTING FOR BANNED NONHORMONAL PERFORMANCE-ENHANCING DRUGS

Recognition and the athlete-clinician relationship — It is important that clinicians are aware of banned substances and their possible use by athletes, both elite and recreational. Many athletes have received competition bans for inadvertent use of prohibited substances, and serious medical problems can occur when the dangers of these substances are not recognized. (See 'Risks from sports and dietary supplements' below and "Use of androgens and other hormones by athletes" and "Prohibited nonhormonal performance-enhancing drugs and other substances and methods in sport".)

Athletes using prohibited performance-enhancing drugs (PEDs) are unlikely to tell their clinicians spontaneously. This makes detection difficult and reinforces the importance of a good therapeutic alliance between clinician and athlete when obtaining a medical history.

When dealing with athletes whom you suspect may be taking PEDs, it is essential to build trust throughout the consultation. This is accomplished by being respectful, communicating clearly, and addressing the athlete's concerns. Emphasize that everything shared during the consultation is confidential and encourage the patient to be open and honest about all supplements they are taking, licit and illicit. This approach allows a more comprehensive history and examination to be performed and enables more accurate diagnosis and better management. It is best not to accuse athletes of illicit drug use. Use of such substances may be inadvertent, possibly from adulterated or contaminated samples.

Typically, athletes using PEDs are attempting to improve speed, endurance, or strength. They may compete at a level just below elite and may use PEDs in the hope of achieving such status. Others may use these substances to improve recovery after injury, surgery, or demanding athletic events. If the athlete does not admit to using PEDs, these historical features combined with suggestive symptoms and signs may raise suspicion. Use can often be confirmed with urine or blood testing. (See 'Urine testing' below and 'Blood testing' below.)

When presenting symptoms and signs are consistent with the use of PEDs, it is important to take a thorough history and perform a standard physical examination (see 'Symptoms and signs' below). Next, the clinician should discuss the possible diagnoses with the athlete and the likely causative or contributing factors, including the possible role of PEDs. It is appropriate at this stage to ask the athlete if they have been using any such substance.

In some circumstances, a third party may raise concerns about a particular athlete or group of athletes that a clinician helps to care for or is otherwise involved with. In such cases, it may be possible to mention to a particular athlete that someone has raised questions about PEDs and to ask if they are aware of or involved in such activity. It is important to be honest and frank but not accusatory.

There may be situations, such as when there is a risk of significant morbidity or death, or where there is evidence of widespread misuse among a group of athletes or teams that may be sanctioned by sporting officials, when it is appropriate for information to be given to drug enforcement agencies on an anonymous basis. Most anti-doping agencies have a process for the public to provide anonymous information regarding anti-doping violations. However, clinicians must be careful not to breach patient-doctor confidentiality principles, professional guidelines, and relevant laws.

Risks from sports and dietary supplements — Clinicians should help to educate athletes about the potential harms of supplements marketed as performance enhancers, which may be sold online, through magazines, or at health fitness stores. Specific supplements and associated health risks are discussed in greater detail separately. (See "Nutritional and non-medication supplements permitted for performance enhancement" and "Overview of herbal medicine and dietary supplements" and "High-risk dietary supplements: Patient evaluation and counseling".)

Manufacturers commonly promote these supplements as "muscle building" or "energy boosting," or as fulfilling a special role, such as pre-workout preparation or post-workout recovery. Many supplements contain banned substances, such as anabolic steroids, stimulants (eg, 1,3 dimethylamylamine [DMAA]), and selective androgen receptor modulators (SARMs), which may not be included in the ingredients list or possibly listed as an "herbal" substance.

Athletes should be aware of the risk of inadvertent doping from adulterated or contaminated substances. In 2016, the Australian Supplements Survey found that of the 67 common supplements tested, 1 in 5 were contaminated by a banned substance [1]. Some supplements produced by larger manufacturers are batch tested, but no supplement should be considered 100 percent safe from contamination. The US Food and Drug Administration (FDA) has warned against the increasing use of SARMs in body-building supplements, which are unapproved and pose serious health threats to users. Deaths and other adverse events have been reported from the use of supplements containing stimulants in recreational athletes and armed forces personnel [2,3].

Symptoms and signs — When PED use is suspected, the clinician should look for presenting symptoms that seem unusual or do not make sense. Initial symptoms and signs may include any of the following:

●Sudden onset of sleep problems without other explanation

●Relatively acute changes in mood, energy, or body weight

●Psychomotor retardation, dysphoria, hypervigilance

●Palpitations, jitteriness

●Recent history of heat-related exertional illness, with or without rhabdomyolysis

●Myocardial infarct or stroke in the context of competitive exercise, particularly in a younger, driven athlete

●Blood pressure and heart rate elevation not attributable to other causes

●Unexplained or unusual medical conditions not attributable to other causes

●Other physical changes (eg, acne, rapid increase in muscle bulk, menstrual dysfunction)

●Hypokalemia in a fit, otherwise healthy athlete

Competitive athletes may be more susceptible to pressure or the temptation to use nonhormonal PEDs at particular times, such as early during the preseason, during the height of the competitive season, or when recovering from an injury. During the pre-season, athletes may take PEDs to increase muscle mass and tolerate higher loads of training, and they may believe they are less likely to be tested at this time. The pressure to return to play after an acute injury can lead players to use PEDs, particularly in team sports.

Athlete biological passport — The athlete biological passport (ABP) is an individual electronic record for elite athletes, in which profiles of biological markers of doping, along with results of doping tests, are collected over a period of months to years [4]. The purpose of the ABP is to monitor selected athlete variables (referred to as biomarkers of doping) over time that indirectly reveal the effects of doping, rather than the substance itself.

A computer algorithm assesses multiple data points, including blood and urine test results over time, allowing variations from normal patterns to be identified. This approach stands in contrast to traditional detection methods based on direct testing for the presence of illicit substances in urine or blood. Each sporting body assesses the physiologic demands of its discipline to determine which modules are most applicable. If markers fall outside the athlete's expected or normal range, this is flagged as abnormal and further investigation is performed by independent experts.

The ABP has three active modules:

●Hematological module ‒ Introduced in 2009, the hematological module is used to help identify illicit interventions to enhance oxygen transport, use of erythropoiesis-stimulating agents (ESAs), and any form of blood transfusion or manipulation. Blood tests are used to follow relevant biomarkers.

●Steroidal module ‒ Introduced in 2014, the steroidal module is used to help identify endogenous anabolic androgenic steroids administered exogenously and other anabolic agents, such as SARMs. Both blood and urine tests are used to monitor relevant biomarkers.

●Endocrine module – Introduced in 2023, this module aims to identify markers of human growth hormone (hGH) doping, including hGH and hGH analogs, fragments, and releasing factors, along with use of insulin-like growth factor-1 (IGF-1).

Following collection of appropriate samples, the athlete must complete the ABP doping control form, which includes questions about the following items:

●Whether the athlete trained at an altitude above 1500 meters during the two weeks prior to the test (information includes location, duration of stay, and altitude)

●Whether the athlete used a hypoxia tent or any other type of altitude simulation during the two weeks prior to the test (information includes the exact device and how it was used)

●Confirmation that the athlete had not participated in training or competition in the two hours prior to sample collection

Over the longer term, the World Anti-Doping Agency (WADA) wishes to develop a large panel of doping biomarkers to improve monitoring. The ABP is not intended to replace traditional testing but serves as an important complement, making anti-doping programs more effective.

The ABP involves a series of mandatory protocols relating to sample collection, analysis, and legal considerations that ensure scientific quality and legal standing and enable mutual recognition and data sharing among anti-doping organizations. The Athlete Passport Management Unit (APMU) is responsible for the administration of the ABP, and ideally, it works alongside WADA-accredited laboratories. APMUs are established by WADA or a regional anti-doping organization. They liaise with an expert panel, which reviews test results, interprets the longitudinal data, suggests follow-up testing, and provides an opinion on atypical passport findings to the relevant International Sporting Federation.

With the introduction of artificial intelligence (AI) and machine-based learning approaches, significant opportunities exist for assistance and support around expert interpretation [5]. AI strategies will be implemented in the search for new biomarkers.

Urine testing — Athletes undergoing urine testing only must complete a doping notification form with the doping control officer. On the form, they must note any medication or supplement that they have taken in the last seven days and confirm that they accept the testing protocol. Testing protocols may vary at individual sites, but the standard method of testing in athletes is a split-sample urine test and high-performance liquid chromatography analysis [6].

A split sample involves dividing the initial urine collection into two separate containers, labeled "A" and "B" samples. The samples are then sent to the certified testing laboratory, following strict chain of custody protocols. The "A" sample is run first, and, if positive for a banned drug, the athlete is notified of the positive test and informed that the "B" sample will be run to confirm the result. The athlete or a representative is permitted to be present at the running of the "B" sample unless they waive their right to have the "B" sample tested. A brief description of the immunoassays and other methods used to detect the presence of drugs, particularly common drugs of abuse, is provided separately; a table summarizing common urine drug testing assays follows (table 1). (See "Urine drug testing", section on 'Specific drug assays: Methods and capabilities'.)

If a positive test is confirmed by the "B" sample, the results are turned over to a medical review officer or panel for appropriate follow-up. If the initial "A" test is negative, the "B" sample is not tested. If authorities suspect that PEDs may have been used but current tests are inadequate for detection, in some jurisdictions, urine samples may be stored and frozen for up to 10 years and then reassessed using newly developed tests. In the past several years, many athletes have received sanctions for using PEDs when the drugs were detected in stored urine, which was subsequently tested with more accurate methods.

The length of time a banned substance remains in the body and is detectable depends on several clinical variables, including the half-life of the drug, other medications being taken (eg, diuretics and other masking agents), and other specific pharmacodynamic and pharmacokinetic factors. (See "Prohibited nonhormonal performance-enhancing drugs and other substances and methods in sport", section on 'Agents used to prevent detection of banned substances'.)

Blood testing — Blood testing is used to detect prohibited substances and other methods of performance enhancement (eg, enhancement of oxygen transport, including use of ESAs, hemoglobin oxygen carriers [HBOCs], and any form of blood transfusion or manipulation) [6]. It is also used for long-term monitoring of an athlete's biological variables, in accordance with the ABP guidelines.

The equipment used for blood collection and post-collection processing differs depending on the type of analysis required. The blood sample collection kit includes a sterile needle, syringe, and the relevant vacutainers in a sealed bag. Whole blood or plasma is used for tests to detect blood transfusions, HBOCs, and ESAs and is collected in two 3 mL ethylenediaminetetraacetic acid (EDTA) tubes ("A" and "B" samples). For detection of growth hormone, along with ESAs and HBOCs, two 5 mL tubes ("A" and "B" samples) with a polymeric serum separator gel and an activated clotting factor are required. For the ABP, one EDTA tube of whole blood is required.

As per WADA protocol, athletes choose a sample kit randomly from a number of kits (usually three) made available by the doping control officer to ensure freedom of choice and reduce the possibility of kit manipulation. The athlete ensures that seals are intact and without signs of tampering. No more than three attempts to insert a needle into an athlete's vein may be attempted. Tamperproof collection bottles are filled, labeled, prepared, and then stored or transported using standard protocols. Following blood collection not intended for the ABP, doping control forms are completed, including the following information:

●Any medications or supplements the athlete has taken in the previous seven days

●Whether the athlete has received any blood transfusions in the previous three months, and if so, an explanation of why it was necessary

Blood samples must be carefully stored after collection and maintained at temperatures between 2 and 12°C.

Dried blood spot testing — The Sports Medicine Research and Testing Laboratory in Salt Lake City (Utah, United States) has developed a blot testing technique for many substances previously assessed using traditional blood samples [7]. This test was introduced in 2022 and can be used to detect IGF-1, growth hormone, erythropoietin, stimulants, common anabolic steroids, and other biological passport substances. Dried blood spot testing (DBST) is not a replacement for standard blood testing, and individual anti-doping organizations determine which process to use. DBST is quick and simple and involves collecting a few drops of blood on absorbent material that are secured in a tamperproof container and sent for analysis.

The 2021 WADA regulations for banned substances include increased reporting thresholds for certain drugs that are currently banned in competition but not out of competition. Given that laboratories can now detect minute quantities of many substances, more violations at competitions are occurring from trace amounts of banned substances detected in the urine. At these low concentrations, the drugs have no ergogenic effect and are most likely residual from the substance being taken prior to competition.

THERAPEUTIC USE EXEMPTIONS

Definition and criteria for exemption — On occasion, an athlete will require a "therapeutic use exemption" (TUE) in order to use a prohibited substance for treatment of a medical condition. Exemptions are granted only when there is no unfair advantage to be gained by the athlete from taking the prohibited substance or using the prohibited method. In most cases, exemption involves a specific medical condition that must be treated with a particular medication or group of medications and no viable alternative treatment is available. Examples of possible TUEs include stimulants for treatment of attention deficit hyperactivity disorder (ADHD), insulin for type 1 diabetes mellitus, and testosterone for treatment of hypogonadism following treatment for testicular cancer.

General information and guidelines for TUEs, including explanations of the roles of different organizations (eg, national anti-doping organizations, international federations, international testing agencies, and major event organizers), are available at the World Anti-Doping Agency (WADA) website.

Information for physicians (WADA Physician Guidelines) who are completing TUE applications for specific medical conditions is available through WADA. It is important that the requirements are followed precisely to ensure that the athlete is given timely approval to use an otherwise banned medication.

The criteria for a TUE as defined by WADA are as follows:

●The prohibited substance or method is needed to treat an acute or chronic medical condition, such that the athlete would suffer a significant impairment to their health if the substance or method were withheld.

●The therapeutic use of the prohibited substance or method is highly unlikely to produce any additional enhancement of performance beyond what might be anticipated by a return to the athlete's normal state of health post-treatment.

●There is no reasonable therapeutic alternative to the prohibited substance or method.

Several points should be noted regarding treatment alternatives:

●Only valid and referenced medications are considered as alternatives. This means the medication must be registered in the athlete's country of residence and prescribed by an appropriately qualified clinician, and compelling evidence of medical necessity must be provided to the appropriate authority. It is important to include all necessary documentation from medical specialists.

●The definition of what constitutes a "valid and referenced" medication may vary from one country to another. These differences should be taken into account. As an example, a medication may be registered in one country and not in another or approval by a government authority may be pending.

●There may be instances when it is not appropriate to use alternatives to the medication containing the prohibited substance. This may occur in a medical emergency or in a situation where the medical condition is serious and treatment must be administered quickly. As an example, this may occur when glucocorticoids are needed to treat severe asthma or a malignancy. In such cases, a physician must explain why the medication is needed.

●A TUE will not be issued to an athlete for treatment of a condition that stems directly from use of a prohibited substance. As an example, an athlete would not be permitted to use an androgenic steroid in order to treat an aromatizing or androgenizing side effect from having used such an agent in the past.

For elite athletes included in the registered testing pool for their sport or participating on their national team or at a national championship, TUEs must be issued prospectively so the athlete can begin taking the medication after the appropriate authority has given approval. Such an athlete applies to their respective national anti-doping organization, international federation, or major event organizer using the TUE application form available for download at the national anti-doping organization's website. If the athlete commences use of the prohibited substance or method prior to approval from the relevant national anti-doping organization, they do so at their own risk and may be subject to an anti-doping violation in the event the TUE is denied. (See 'Application process' below.)

Retrospective exemption — One exception to the standard TUE criteria and process is the granting of a retrospective TUE. Application for a retrospective TUE is made after treatment is given for a medical emergency or some other urgent situation. Examples might include treatment with opioids for pain relief following severe trauma or treatment with diuretics for pulmonary edema.

The process of applying for a retrospective TUE should begin as soon as possible, and supporting documentation from the hospital or treating authority must be included.

In exceptional circumstances, a retroactive TUE may be granted. Examples of such circumstances include cases when there was not sufficient time or opportunity to submit the necessary documentation or for the TUE committee to consider the application prior to sample collection.

Application process — In summary, the process for an athlete who wishes to obtain a TUE is as follows:

●A national-level athlete applies to their national anti-doping organization.

●An international-level athlete applies to the relevant international federation.

●For any athlete competing at a major event (eg, Olympic Games), the major event organizer may require the athlete to obtain a TUE for their event. Usually, a TUE obtained from the international federation will suffice, as long as it complies with international standards.

The body to which the athlete submits their application depends on whether the athlete is in the international federation registered testing pool, or planning to compete at the international level, or in the national federation registered testing pool, or subject to testing at the national level. The process of applying for a TUE at the national or international level is as follows:

●The athlete obtains a TUE application form (freely available online from national anti-doping organizations or WADA).

●The athlete completes their section of the form.

●The athlete asks the treating physician to complete the medical details requested on the form. This includes the diagnosis and an explanation of why a permitted medication cannot be used. The form requires "a comprehensive medical history and the results of all relevant examinations, laboratory investigations, and imaging studies. Copies of the original reports or letters should be included when possible. Evidence should be as objective as possible in the clinical circumstances. In the case of non-demonstrable conditions, independent supporting medical opinion will assist this application."

Supporting documentation for a TUE must be thorough, reliable, and relevant. In almost all cases, letters from medical specialists must accompany the application, along with pathology reports, imaging reports (and possibly copies of images), and any other relevant tests and documents (eg pulmonary or cardiac function tests). If the application is incomplete, it cannot be approved and must be resubmitted.

The WADA website includes checklists for clinicians that address most common conditions, including asthma, attention deficit disorders, female infertility, polycystic ovary syndrome, diabetes mellitus, and hypogonadism to help ensure that all relevant information is included in the TUE application.

●Note that the TUE Physician Guidelines and checklists can be accessed by entering the search term "Medical Information" on the WADA website. The guidelines address the diagnosis and treatment of a number of medical conditions commonly affecting athletes and requiring treatment with prohibited substances.

●The physician must include the generic name of the medication, the route of administration, the dose, frequency of use, and duration of treatment.

●The physician and athlete must sign a declaration confirming that the information provided is true and that the submitted forms will be handled according to appropriate confidentiality legislation.

●Letters and applications from allied health practitioners, physician assistants, and nurse practitioners will not be accepted. Psychological screening tests performed by a registered psychologist must accompany an initial TUE application for ADHD.

●The athlete submits their TUE application to the TUE committee appointed by the international federation or national anti-doping organization via WADA's Anti-Doping Administration and Management System (ADAMS) or in paper format using the appropriate TUE form. In the latter case, the national anti-doping organization then enters the information into ADAMS.

●If an athlete has a TUE issued by the national anti-doping organization but plans to compete at an international level, the TUE and approval from the national anti-doping organization must be submitted to and recognized by the international federation.

Submission deadlines — Applications for TUEs must be submitted as early as possible.

●For substances prohibited in-competition, the athlete should apply for a TUE at least 30 days prior to the next competition unless it is an emergency or exceptional situation.

●For substances prohibited at all times, the TUE application must be submitted as soon as the medical condition requiring the use of the prohibited substance or method is diagnosed or as soon as the athlete becomes subject to the anti-doping rules.

If an application is approved, the TUE committee sets a start and end date for each approved medication. These are specific to each condition. When approval expires, if the athlete needs to continue treatment, they must reapply for a further TUE well in advance of the expiration of the previous TUE to allow time for submission and approval of the new application (ideally, about four to six weeks).

Major event organizers, such as the Olympic Games or the Pan American Games, have their own TUE requirements for prohibited substances or methods, and these are granted only for the duration of the event. Generally, these TUEs must meet the International Standard for Therapeutic Use Exemptions (ISTUE). TUEs already granted by an international federation or national anti-doping organization that meets the ISTUE must be approved by the major event organizer. If the TUE application is deemed not to meet the international standard, the athlete must be notified promptly. The athlete is given the opportunity to appeal to an independent body appointed by the major event organizer.

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 "Prohibited nonhormonal performance-enhancing drugs and other substances and methods in sport", section on 'World Anti-Doping Agency and prohibited substances used for performance enhancement'.)

•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, the Australian Institute of Sport website, and the US Anti-Doping Agency website. (See "Nutritional and non-medication supplements permitted for performance enhancement".)

●Prohibited and permitted drugs and other substances – Details about the many medications and other substances used to improve sports performance are provided separately. (See "Use of androgens and other hormones by athletes" and "Prohibited nonhormonal performance-enhancing drugs and other substances and methods in sport" and "Prescription and non-prescription medications permitted for performance enhancement" and "Nutritional and non-medication supplements permitted for performance enhancement".)

In many countries, the manufacturing of nutritional supplements is not well regulated and supplements may be adulterated or contaminated with banned substances. (See 'Risks from sports and dietary supplements' above.)

●Detecting banned substances – Determining whether banned performance-enhancing drugs (PEDs) or other substances are being used involves a careful history and physical examination and possibly use of urine and blood testing and the athlete biological passport (ABP). Many athletes using prohibited PEDs are reluctant to tell clinicians, reinforcing the importance of establishing a therapeutic alliance. (See 'Recognition and the athlete-clinician relationship' above.)

When PED use is suspected, look for presenting symptoms and signs that seem unusual or do not make sense. Findings may include any of the following:

•Sudden onset of sleep problems without other explanation

•Relatively acute changes in mood, energy, or body weight

•Psychomotor retardation, dysphoria, hypervigilance

•Palpitations, jitteriness

•Recent history of heat-related exertional illness, with or without rhabdomyolysis

•Myocardial infarct or stroke in the context of competitive exercise, particularly in a younger, driven athlete

•Blood pressure and heart rate elevation not attributable to other causes

•Unexplained or unusual medical conditions not attributable to other causes

•Other physical changes (eg, acne, rapid increase in muscle bulk, menstrual dysfunction)

•Hypokalemia in a fit, otherwise healthy athlete

●Testing for banned substances – The ABP is an individual electronic record for elite athletes in which profiles of biological markers of doping, along with results of doping tests, are collected over months to years. The purpose of the ABP is to monitor selected variables (ie, biomarkers of doping) over time that indirectly reveal signs of doping. Methods of urine and blood testing are also used to detect banned substances. (See 'Athlete biological passport' above and 'Urine testing' above and 'Blood testing' above.)

●Therapeutic use exemptions – Athletes may require a "therapeutic use exemption" (TUE) in order to use a prohibited substance for appropriate treatment of a medical condition. Exemptions are granted only when there is no unfair advantage to be gained. In most cases, exemption involves a specific medical condition that must be treated with a particular medication or group of medications and no viable alternative treatment is available. TUE criteria and the application process are described in the text. (See 'Therapeutic use exemptions' above.)