Drugs and Doping in Athletes

Definition

According to the World Anti-Doping Agency (WADA) Code, doping is defined as the occurrence of one or more of the following antidoping rule violations:

• The presence of a prohibited substance or its metabolites or markers in an athlete’s bodily specimen.

• Use or attempted use of a prohibited substance or prohibited method.

• Refusing, or failing without compelling justification, to submit to sample collection after notification as authorized in applicable antidoping rules or otherwise evading sample collection.

• Violation of applicable requirements regarding athlete availability regarding out-of-competition testing, including failure to provide required whereabouts information and missed tests that are declared based on reasonable rules.

• Tampering, or attempting to tamper, with any part of doping control.

• Possession of prohibited substances and methods.

• Trafficking in any prohibited substance or prohibited method.

• Administration or attempted administration of a prohibited substance or prohibited method to any athlete, or assisting, encouraging, aiding, abetting, covering up, or any other type of complicity involving an antidoping rule violation or any attempted violation.

• Association by an athlete with someone currently sanctioned under WADA rules (e.g., working with or receiving coaching by someone who is sanctioned).

• Acts by an athlete or other person to discourage or retaliate against people reporting doping to authorities (whistleblowers), newly adopted in the WADA 2021 Code.

Historical Events in Modern Sports Doping

• 1964: Drug testing begins at the Olympics.

• 1968: Formal drug testing adopted for Summer and Winter Olympic Games. Drug testing has been used at every Olympiad since.

• East German swimmers admit to systematic doping in the 1970s that was sanctioned by their National Olympic Committee.

• Widespread use of blood doping by US cyclists participating in the 1984 Summer Olympic Games discovered.

• In 1985, the National Collegiate Athletic Association (NCAA) began a series of quadrennial surveys that documented substance use and abuse patterns by intercollegiate athletes. The methodology changed significantly in 1997 and increased the number of participating schools and subjects. The ninth iteration in 2017 measured the substance use patterns in 23,028 men and women athletes. Periodic surveys are helpful in assessing usage patterns of recreational and ergogenic substances in order to allocate resources for overall deterrence.

• Following a series of doping scandals, the International Olympic Committee (IOC) convened the World Conference on Doping and Sport in February 1999 that led to the creation of the WADA. WADA was charged with developing standards and a consistent, worldwide doping-control program. WADA develops criteria for inclusion on a prohibited substances list that is provided in Box 26.1 along with a clinical guide to those substances in Table 26.1 .

  BOX 26.1

  Summary of Inclusion Criteria for Wada Prohibited List (From Wada Code 2021)

  Data from World Anti-Doping Code International Standard Prohibited List, 2021 at https://www.wada-ama.org/en/content/what-is-prohibited .

  At least two of the three following criteria must apply:

  • 1.

    The substance has the potential to enhance performance

  • 2.

    Use of the substance poses an actual or potential health risk

  • 3.

    Use of the substance violates the spirit of sport ^a

    a Spirit of Sport is defined in the WADA Code as the celebration of the human spirit, body, and mind. It is the essence of Olympism and is reflected in the values we find in and through sport, including health, ethics, fair play, respect for rules and laws, and many others.

  Substances or methods that mask the effect or detection of prohibited substances are also prohibited. In addition, a substance that has not been approved for human use is likely to be prohibited.

  The Prohibited List is reviewed annually in consultation with scientific, medical, and antidoping experts to ensure it reflects current medical and scientific evidence and doping practices. The Prohibited List comes into effect on January 1 of each year and is published by WADA three months before coming into force; however, in exceptional circumstances, a substance or method may be added to the Prohibited List at any time.

  Table 26.1

  Clinical Guide to the Wada Prohibited List

  Data from World Anti-Doping Code International Standard Prohibited List, 2021. https://www.wada-ama.org/en/content/what-is-prohibited .

  WADA Prohibited List Category	Examples of Medications Subject to Restrictions
  S0. Unapproved Substances	Investigational drugs or drugs in clinical trials. Athletes participating in drug clinical trials may need a therapeutic use exemption.
  S1. Anabolic Agents	Testosterone creams, patches, or injections, Prasterone/DHEA, HRT with androgens, SARMs (Enobosarm) and others
  S2. Peptide Hormones, Growth Factors and Related Substances	Erythropoietin (EPO) and agonists, CG and LH (in males) and their releasing factors, corticotrophins, growth hormone (GH) and growth factors (e.g., platelet-derived growth factors, thymosin beta 2 and TB-500), and others
  S3. Beta 2 -agonists	All inhaled or oral beta 2 -agonists are prohibited except for albuterol, formoterol, salmeterol, and vilanterol, which have routes of administration and dosage restrictions.
  S4. Hormone and Metabolic Modulators	Aromatase inhibitors, SERMs (tamoxifen), clomiphene, insulin, meldonium, and others
  S5. Diuretics and Masking Agents	Hydrochlorothiazide, acetazolamide, canrenone, spironolactone, and others
  M1. Manipulation of Blood M2. Chemical Physical Manipulation M3. Gene and Cell Doping	Introduction of any type of red blood cell products, or any form of intravascular manipulation (including plasmapheresis/plasma donation, IV infusions of any type, use of nucleic acids, gene editing)
  S6. Stimulants	Adrafinil/modafinil, amphetamine and most ADHD medications, cocaine, pseudoephedrine, epinephrine (Epi-Pen), strychnine, and others
  S7. Narcotics	Oxycodone, methadone, heroin, pethidine, morphine
  S8. Cannabinoids	THC, and other natural cannabinoids, synthetic cannabinoids
  S9. Glucocorticoids	Prednisone, methylprednisolone (Medrol-Dose pack), triamcinolone and others
  P1. Beta-Blocker (prohibited in certain sports)	Atenolol, timolol, and others

  The WADA Prohibited List changes every year. Check the website for the most up-to-date information. This is not an exhaustive list. Medications listed here might require a therapeutic use exemption, have restrictions on dosage or on when the substance is used relative to competition, how it is delivered (route of administration), whether it is used in combination with other medications, or it may be restricted in certain sports.

• In 2003 the investigation into the Bay Area Lab Co-Operative (BALCO) revealed a sophisticated conspiracy involving professional athletes as well as US and international Olympic athletes. In addition to developing designer anabolic steroids, the BALCO records were used to discipline athletes based on “nonanalytic” positives (i.e., athletes were suspended based on doping records rather than an adverse analytical finding on a drug test). The use of nonanalytical positives and forensic investigations has increased since 2003 as another antidoping tool.

• 2007: Major League Baseball (MLB) commissions the Mitchell Report that details past and current anabolic steroid use that leads the MLB to implement a comprehensive drug testing program.

• 2012: Lance Armstrong stripped of his seven Tour de France titles and banned for life from competitive cycling. Highlights the extent of doping in cycling. An example of a typical doping regimen from the Tour de France is listed in Box 26.2 .

  BOX 26.2

  Example of Drug Use by a Tour De France Cyclist in 2008

  • Recombinant erythropoietin (r-HuEPO)

  • Continuous erythrocyte receptor activator (CERA)

  • Recombinant human growth hormone (rhGH)

  • Thyroid hormone

  • Blood transfusions

  • Albumin

  • Insulin

  • Testosterone

  • Designer anabolic steroids

  • Injectable cortisone

• Biogenesis investigation in 2013 leads to criminal prosecution and suspensions of multiple professional athletes.

• 2014: Sochi Olympics reveals systematic doping under the aegis of the Russian Sports Federation. Extensive investigation by WADA culminates in the Maclaren Report with hundreds of athletes involved in 30 sports ( Fig. 26.1 ).

  

• 2020: Rodchenkov Anti-Doping Act is signed into law imposing criminal sanctions on international doping fraud conspiracies. Similar legislation has been passed in several European countries.

Scope of the Problem

• The prevalence of doping in sport has always been difficult to ascertain because of limitations on testing data, surveys, and defining who is an “athlete” and which substances are considered “doping.”

• Reliance on testing data to determine the extent of doping underestimates depending on the program and the use of no-notice testing vs. announced testing. The positive test rates for various organizations are listed in Table 26.2 .

  Table 26.2

  Positive Test Rates in Olympic Sport and Major League Baseball in 2018

  Data from test rates for Olympic sport were taken from the 2018 Anti-Doping Testing Figures published by the World Anti-Doping Agency. https://www.wada-ama.org/sites/default/files/resources/files/2018_testing_figures_report.pdf ; Major League Baseball testing stats: https://www.mlb.com/news/mlb-players-union-release-annual-testing-results-summary/c-40478624 .

  Sport	Analyzed Samples	Positive Tests
  Olympic/Paralympic (WADA/Global)	228,560	1519 (0.66%)
  Olympic/Paralympic (USADA/USA)	6,607	66 (0.9%)
  MLB (US)	11,526	11 (0.09%)

• Research using surveys has revealed a relatively low prevalence of doping in athletes. One of the largest is the NCAA quadrennial survey of athletes from the three NCAA divisions. The most recent iteration was conducted in 2017 involving 23,000 student-athletes. For ergogenic drugs, they reported that amphetamines and anabolic steroids were used 1.5% and 0.4%, respectively, in the previous year. Interestingly, there was little difference in usage rates between the three divisions. Among men’s sports, the highest reported use of these substances was 6.7% amphetamine use for lacrosse and 1.9% anabolic steroid use for wrestling. Interestingly, although the reported use of amphetamines and anabolic steroids was quite low, 11% admitted to using various other performance-enhancing drugs (PEDs) in the past year. These included human growth hormone (hGH), clenbuterol, erythropoietin (EPO), and other ergogenic substances. The use of testosterone boosters was reported as 0.7%, higher than the use of anabolic steroids.

• Because of the limitations of test results and surveys, it is difficult to obtain an accurate extent of the use of PEDs in sport. As was demonstrated from both the Maclaren Report on Russia (see Fig. 26.1 ) and the NCAA 2017 survey, doping is not limited to high-profile sports or sports that generate the most revenue or attention.

Deterrence

The overall measure of effectiveness of any antidoping program is in the deterrent effect. This can be achieved by a combination of education, testing, and discipline. As an example, MLB developed a stepwise deterrence program for their player-development academies beginning in 2005 when the positive test rate for anabolic steroids was over 5%. Because of Dominican law at the time, the only available option for players who tested positive was education. This was in place from 2005 to 2008 and saw a mild reduction in positive tests. Beginning in 2008, suspensions were allowed under the law, and the positive rate began to decrease. In 2011 a series of financial disincentives were added, leading to a further reduction to a rate below 1%. This demonstrates that in a population with a high prevalence of PED use, deterrence can be accomplished with a multipronged approach. These interventions are summarized in Fig. 26.2 .

Anabolic-Androgenic Steroids

• Definition: Testosterone or testosterone-like synthetic drugs that result in both anabolic and androgenic effects, for example, increase protein synthesis (anabolism) and enhance the development of male secondary sexual characteristics (androgenic).

• Prevalence:

  • Since 1988 surveys have sought to assess usage rates in athletes and nonathletes, with conflicting results. However, it is clear that the use of anabolic-androgenic steroids (AAS) is no longer confined to athletes participating in organized sports, but is also used in the general population for nonathletic enhancement.

  • 2019: Monitoring the Future Study reported that 1.0% of 12th graders had used AAS in the previous 12 months, with a lifetime prevalence of 1.6%.

  • A 2014 global meta-analysis of 271 studies by Sagoe et al. determined a lifetime prevalence of AAS use of 6.4% for men and 1.6% for women.

  • Androgenization program developed by the former German Democratic Republic (GDR) provided anecdotal information supporting the efficacy of AAS, as well as adverse effects.

  • Current estimates indicate that there are as many as 3 million AAS users in the United States and that 2.7%–2.9% of young American adults have taken AAS at least once in their lives.

  • Recent estimates are that 1.5 million teenagers have tried AAS and that teenage girls may be the fastest-growing demographic for AAS use.

• Mechanism of action:

  • AAS are bound by cytoplasmic proteins and transported to the nucleus. Activation of DNA-dependent RNA polymerase results in production of messenger RNA for protein synthesis.

  • Muscle size increases in AAS users through hypertrophy and formation of new muscle fibers. As reported by Kadi et al., muscle biopsies suggest that use of AAS enhances activation of satellite cells and contributes to muscle fiber growth.

  • AAS also may have an anticatabolic effect by attenuating effects of cortisol. Haupt proposed that AAS displace cortisol from receptors, allowing athletes to train at a high level. He also suggested that AAS increase motivation through heightened aggressiveness.

• In vivo studies of athletes and anabolic steroids:

  • Numerous studies of anabolic steroid use by male athletes have produced conflicting results. Some support improvement in strength, whereas others found no significant improvement in strength. The American College of Sports Medicine’s (ACSM’s) official position statement, as well as many other systematic reviews, support the following position on AAS:

    • Use of steroids by athletes is contrary to the rules and ethical principles of athletic competition.

    • With adequate diet, AAS can contribute to increases in body weight and lean mass.

    • Gains in muscular strength achieved through steroid use at doses beyond those utilized in clinical medicine improve performance and seem to increase aerobic power or capacity for muscular exercise, giving an unfair advantage to those who are willing to risk the potential side effects to achieve gains in athletic performance.

    • AAS have been associated with adverse side effects in therapeutic trials and in limited research on athletes.

  • Well-conducted study by Bhasin et al. in 1996 demonstrated increase in fat-free mass and muscle size and strength in weightlifters using weekly injections of 600 mg testosterone enanthate for 10 weeks. First study to demonstrate that supraphysiologic doses of testosterone in trained weightlifters, combined with resistance training, can increase strength.

• AAS: Chemical alternations to existing synthetic AAS in order to avoid detection by drug testing:

  • Norbolethone

    • Originally documented 30 years ago; isolated in two urine samples from a female athlete in 2002 who later received a lifetime ban.

    • Never commercially marketed because of possible toxic effects in animal studies and/or reports of menstrual irregularities.

    • Anabolic activity 20 times higher than its androgenic activity; thus, very attractive to athletes looking to gain a competitive edge.

  • Tetrahydrogestrinone (THG)

    • Unlike norbolethone, THG is a new chemical entity and would have remained undetectable if a syringe containing it had not been anonymously sent to the United States Anti-Doping Agency (USADA) in 2003.

    • Closely related to gestrinone, a progestin, and to trenbolone, a veterinary androgen.

    • Little information about the safety and anabolic effects of THG; has been found to be a potent androgen.

    • Several Olympics labs have reported positive results for THG.

    • Additional designer AAS have appeared as increasing sophistication of drug testing continues.

• Over-the-counter steroids:

  • 1994 Dietary Supplement and Health Act made supplements available over the counter, including testosterone (androstenedione, androstenediol, dehydroepiandrosterone [DHEA]) and nandrolone precursors (19-norandrostenedione, 19-norandrostenediol).

  • Athletes use these short-acting compounds to increase muscle mass, despite lack of definitive studies of benefits and adverse effects.

  • Some have been found to increase testosterone and nandrolone metabolites. Assumed to have similar profile to AAS.

• Governmental regulation:

  • 1990 Anabolic Steroid Control Act: AAS were added to Schedule III of the Controlled Substances Act.

  • 2004 Anabolic Steroid Control Act: added steroid precursors such as androstenedione to the list of controlled substances. DHEA was not included in the act and is still legally available as a dietary supplement despite being banned by many sports organizations. Also increased the penalties for trafficking.

  • Designer Anabolic Steroid Control Act of 2014: further defined designer AAS and increased penalties.

• Potential therapeutic uses:

  • True medical indications for AAS probably account for <3 million prescriptions/year. Indications include refractory anemias, hereditary angioedema, palliation therapy in advanced breast carcinoma, replacement therapy in hypogonadal males, and muscle-wasting states associated with HIV infection. AAS also may be useful in patients with constitutional delay of growth (as an adjunct to growth hormone [GH] therapy) and osteoporosis and has potential use as a male contraceptive.

  • Acquired hypogonadism: A major marketing effort by pharmaceutical companies and “antiaging” clinics has increased the number of prescriptions for testosterone amid the liberalization of the diagnosis of hypogonadism. The Endocrine Society has published guidelines for the legitimate prescribing of testosterone in men with androgen deficiency. These include:

  • The diagnosis of hypogonadism should only be made in men with symptoms and signs consistent with testosterone deficiency.

  • The use of accurate assays for measurement of total and free testosterone that should be confirmed by repeated measurements of fasting, morning specimens.

  • If androgen deficiency is determined, diagnostic evaluation should be done to ascertain the cause.

• Dosage

  • Doses taken by athletes may be 10–40 times higher than therapeutic doses.

  • Athletes frequently use combinations of anabolic steroids (stacking) or cycling in a pyramidal fashion to achieve maximum effect.

• Adverse reactions:

  • Gastrointestinal: hepatocellular dysfunction, peliosis hepatis, and case reports of hepatocellular carcinoma. Hepatic effects are increased with 17-α-alkylated compounds consumed orally. Serum liver function tests should be checked in athletes with suspected history of AAS use.

  • Cardiovascular: increase in total cholesterol and low-density lipoprotein (LDL) cholesterol; decrease in high-density lipoprotein (HDL) cholesterol; hypertension; increased risk of deep vein thrombosis; compartment syndromes; reported cases of myocardial infarction (MI), atrial fibrillation, and cerebrovascular accident. The Food and Drug Administration (FDA) has released a warning to reflect the potential increased risk of MI and stroke with testosterone use. However, although retrospective reports have suggested that testosterone therapy increases cardiovascular risk, randomized controlled trials have been insufficiently powered to evaluate risk for cardiovascular events in men who have undergone testosterone replacement therapy. A 2017 study by Baggish et al. found 71% of current AAS users had a depressed left ventricular ejection fraction.

  • Psychological effects: changes in libido, mood swings, aggressive behavior, exacerbation of underlying mental illness, delirium, addiction to the appearance on AAS, and suicide attempts. Dependence pattern with opioid medications, as well as conduct disorder, has been reported. Pope and Katz interviewed 41 bodybuilders and football players who had used AAS and found that, according to DSM III-R criteria, 9 (22%) displayed full affective syndrome and 5 (12%) had psychotic symptoms in association with AAS use. However, a well-designed study by Bahrke et al. of current AAS users, previous users, and nonusers demonstrated that although perceived or actual psychological changes may occur, they were not demonstrated on several standardized inventories.

  • Male reproductive effects: oligospermia, azoospermia, decreased testicular size, and gynecomastia. Case of adenocarcinoma of prostate also has been reported. In addition, a case with a young male using high doses of oral turinabol suggests a potential causal relationship to intratesticular leiomyosarcoma.

  • Female effects: reduced luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrogens, and progesterone; menstrual irregularities; male pattern alopecia; hirsutism; clitoromegaly; and deepening of voice. Last three are probably irreversible.

  • Youths: irreversible, premature closure of the epiphyses. Several highly publicized cases of suicide in high school athletes related to steroid use (e.g., Taylor Hooton).

  • Additional drug use: AAS users are likely to use other drugs. A 2007 study by Elliot of high school female students revealed that AAS users were more likely to use alcohol, cigarettes, marijuana, and cocaine. In 2009, Ip conducted the Anabolic 500 survey that demonstrated AAS-dependent users were significantly more likely to report heroin use within the past 12 months and endorse a history of physical and sexual abuse.

• Miscellaneous:

  • Spontaneous tendon rupture.

  • Increase in sebaceous glands and acne.

  • Infectious complications, including HIV (due to sharing of contaminated needles), hepatitis B and C, and intramuscular abscess.

  • A case report described bilateral deltoid myositis ossificans in a patient who repeatedly injected anabolic steroids in his bilateral deltoids in the past.

  • Worsening of tic symptoms in patients with Tourette syndrome.

  • Suppression of humoral immunity and immunoglobulin levels.

  • Anecdotal reports of an association with compartment syndromes after trauma and/or surgical procedures.

  • Reduction in glomerular filtration rate with supraphysiologic usage of AAS.

  • Polycythemia requiring phlebotomy.

• Side effects: Documented in secret AAS program for elite athletes sponsored by GDR: liver damage, gynecomastia, polycystic ovarian syndrome, arrested body growth, and three deaths.

• Prevention: Programs designed to reduce AAS use have been developed (e.g., by Goldberg and the ATLAS program) for use at the high school level.

• Detection: Clinical suspicion should be aroused by the presence of the aforementioned adverse effects. Drug testing (discussed later) can detect AAS with high degree of accuracy.

Selective Androgen Receptor Modulators (SARMs)

• Definition: Nonsteroidal ligands for the androgen receptor. Some of the common ones are Ostarine, Andarine, LGD-4033 (Ligandrol), and RAD140 (Testolone).

• Prevalence: According to WADA 2018 testing figures, SARMs accounted for 4% of positive tests involving anabolic substances globally Actual usage rates are unknown; a 2017 Internet search by Van Wagoner et al. yielded 210 products from 51 supplier sites advertising SARMs.

• Mechanism of action: Ligands bind to the androgen receptor and exert tissue-selective effects such as muscle growth. They have been shown to have anabolic properties in rodents, and early clinical trials demonstrated anabolic activity in older individuals.

• Therapeutic use: They have not received FDA approval, and clinical trials have investigated its use in the treatment of cachexia, cancer, osteoporosis, male contraception, prostate enlargement and cancer, and muscular dystrophy.

• Adverse reactions: Trials using therapeutic doses have demonstrated testosterone suppression, decreases in HDL cholesterol, increases in LDL cholesterol, and liver function abnormalities. Users of Andarine have reported visual disturbance (yellowing of vision) in various blogs. It remains to be seen if the higher doses typically consumed by athletes would result in more significant adverse reactions as seen with traditional AAS.

• Detection: These substances are readily detectable in urine through gas chromatography–mass spectrometry (GC/MS).

• Related compounds: Peroxisome proliferator-activator δ are part of a family of hormone and lipid-activated nuclear receptors that are involved in the metabolism of long-chain fatty acids, cholesterol, and sphingolipids and can act as transcription factors. They have been involved in research studies in the treatment of metabolic syndrome, dyslipidemia, carcinogenesis, and diabetes. They are frequently found in dietary supplements labeled as SARMs, with GW501516 (Cardarine) being one of the more common ones. Because these substances theoretically may trigger transcriptional remodeling of muscle, they have become attractive to the sports community. These are not approved for human use, and safety has not been determined.

Growth Factors