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Supplements abuse
and doping
By:
Dr. Razieh Avan Pharm.D, Assistant Professor of Clinical Pharmacy
Faculty of Pharmacy
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• There has been a massive increase in the use of
supplements in the sports community over the past few
decades.
• Companies worldwide make a range of claims about the
ergogenic benefit of many of these supplements.
However, research suggests that only a small number
have demonstrable benefits for athletes.
Supplements in the sports
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• Importantly, throughout the world, quality control for
these substances is generally poor, and regulations
pertaining to their manufacture and marketing are weak,
making it difficult for athletes to determine which
supplements are safe, effective, and legal.
Supplements in the sports
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• As testing for performance-enhancing drugs has expanded to nearly
all levels of competition, athletes have begun to use more over-the-
counter nutritional supplements, assuming they are legal, safe, and
beneficial.
• A survey of athletes participating in the 2004 Athens Olympic Games
found that over 47 percent reported use of nutritional supplements.
Nutritional supplements
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• Many substances are designated or marketed as nutritional
supplements, including vitamins, minerals, herbs, extracts, amino
acids, metabolites, or any combination of these and other substances.
• However, in many countries, the sports supplement industry is poorly
regulated, and supplements are sometimes a source of doping
violations.
Nutritional supplements
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• There is an international movement encouraging larger
supplement manufacturers to submit products for testing.
• Some countries, including Australia, and international
organizations (eg, Informed-Sport) are working with supplement
companies to have them submit their supplements for testing,
with the incentive of being given a "safe in sport" label
acknowledging that their product has been found to be free of
contaminants.
Nutritional supplements
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• Large manufacturers of conventional supplements, such as protein
powders, usually follow reasonable quality-control practices.
• Supplements obtained via the internet from small, unregulated companies
can be contaminated or mislabeled.
• In one case series, a number of healthy individuals were found to be taking
dietary supplements laced with steroids, and they presented for medical
care with complaints including nausea, anorexia, jaundice, severe pruritus,
and kidney failure.
Nutritional supplements
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Supplements promoting increased muscle mass are more likely to contain
anabolic contaminants, such as nandrolone, stanozolol, and oxandrolone.
Prohormones, peptide hormones, and releasing factors have also been
found in supplements.
Stimulants such as methylhexanamine, ephedrine, and sibutramine have
been found in supplements, particularly pre-workout powders, energy
boosters, and fat burners.
Nutritional supplements
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Creatine is likely the most popular nutritional supplement used for
performance enhancement.
Creatine is a naturally occurring substance derived from three amino
acids (methionine, glycine, and arginine).
Approximately 95 percent is stored in skeletal muscle, with the
remainder being located in the brain, testes, and kidneys.
Creatine
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It is not prohibited by WADA and has been shown to be effective at
improving training and performance of short-duration, high-intensity
exercise.
It should be noted that up to 30 percent of individuals do not respond
to creatine supplementation and will not significantly increase muscle
creatine stores.
Creatine
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Reported side effects of acute creatine ingestion include:
× Weight gain (from increased water retention)
× Reduced joint mobility
× Muscle cramping
Although some have claimed that creatine can adversely affect kidney
function, limited published evidence and wide experience with this
supplement suggest that this is not true in patients with normal baseline
renal function.
Creatine
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BCAAs, leucine, valine, and isoleucine, are the most abundant amino acids
in muscle.
They cannot be synthesized in the body, but large amounts are found in red
meat and dairy products.
Vegetarians can obtain sufficient amounts if they eat an adequate amount
and appropriate mix of legumes, nuts, grains, and seeds daily.
BCAAs are oxidized in the muscle during exercise.
Branched-chain amino acids
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Nevertheless, although BCAAs are widely used by athletes, there is
no high-quality evidence of their efficacy, particularly when
compared with eating a diet rich in meat, which is less expensive.
A chicken breast is said to contain the equivalent of seven average
BCAA tablets.
Branched-chain amino acids
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Carnitine is found in skeletal and cardiac muscle and is ingested
mainly through meat, fish, poultry, and some dairy.
Vegetarians have lower muscle carnitine stores.
During intense exercise, carnitine plays a role in the metabolism of
carbohydrates and the oxidation of long-chain fatty acids.
Carnitine
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Despite limited evidence of benefit, L-carnitine is a common
ingredient in fat-loss supplements.
Further research is needed to determine the benefits of carnitine
supplements for athletic performance and body composition.
If the benefits are genuine, long-term supplementation in association
with large amounts of carbohydrate may be necessary, and this would
not suit all athletes.
Carnitine
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The consumption of beverages explicitly for sport began with drinks
developed to replace the electrolytes and carbohydrates lost during
intense physical activity.
The original drinks are known as "sports drinks" and contain a low
percentage carbohydrate solution and a mixture of electrolytes to
allow maximal, rapid absorption in the stomach.
Energy beverages
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The newer generation of beverages, so-called "energy drinks," include
a wide variety of stimulants and other additives, including caffeine,
taurine, glucuronolactone, B vitamins, antioxidants, trace minerals,
guarana, Ginkgo biloba, ginseng, L-carnitine, and sucrose.
Of note, some of these additives may interact with prescription
medicines, so care should be taken investigate potential adverse
interactions before consuming these drinks.
Energy beverages
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The amount of caffeine in an energy drink ranges from approximately
50 to 500 mg per can or bottle.
Energy beverages should not be used for the purposes of athletic
hydration or rehydration.
The higher carbohydrate content results in slower absorption from the
stomach and may cause nausea, bloating, cramping, diarrhea, or
vomiting.
Energy beverages
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Multiple reports found on the website of the US Food and Drug
Administration (FDA) describe cases of acute myocardial infarction,
convulsions, cardiac arrest, anaphylaxis, spontaneous abortion,
arrhythmias, renal and liver impairment, and psychiatric disorders
associated with heavy consumption of energy drinks.
Energy beverages
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Caffeine may act as a diuretic, resulting in increased urine output
during and after exercise. For the same reasons, athletes who are
dehydrated should not consume energy drinks.
Energy beverages
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Potential adverse effects of energy beverages may be due to caffeine
or other stimulants or ingredients, and may include:
× Elevated blood pressure
× Arrhythmias
× Seizures
× Sleeplessness
× Mood changes
Adverse effects of Energy beverages
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The risk of dental caries is often overlooked by those drinking large
quantities of sugar-containing energy drinks.
Some drinks contain up to 8 teaspoons of sugar, which can contribute
to weight gain, hypertension, and diabetes.
Adverse effects of Energy beverages
Agents used to attempt to enhance athletic
performance, and in the case of
weightlifters/bodybuilders, physical
appearance, with a goal of appearing leaner
and more muscular.
Although users take these drugs to improve
their performance, data supporting their
efficacy are limited.
Androgenic steroids :
These (naturally occurring or synthetic)
hormones increase lean body mass and
decrease fat mass and are the most frequently
used class of performance-enhancing drugs.
Patterns of use
Athletes often take these drugs in various patterns, including in escalating
doses ("pyramiding") and/or combining two or more steroids ("stacking").
Often, androgen users "pyramid" their doses in cycles of 6 to 12 weeks. They
start with low doses of each drug, slowly increase until the middle of the cycle,
and then taper back down to zero.
Androgen deficiency may occur during this interval, and users typically take
other medications such as clomiphene citrate or hCG to attempt to help the
hypothalamic-pituitary-gonadal axis recover more quickly, but there is no
evidence that they do so.
Patterns of use
Users may attempt to counter a side effect of one medication with
another medication.
As examples, most stacks will include both androgens and other
drugs such as:
Growth hormone for additional anabolic effect
hCG to counteract the reduction in testicular size resulting from high-dose
androgen use
An aromatase inhibitor to counteract gynecomastia
A 5-alpha reductase inhibitor to prevent balding and acne that occur with
exogenous androgens
Diuretics to promote water loss.
Doping:
is the application of
chemical substances
with the deliberate
intention or effect of
altering performance
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Withdrawn golden medal
Ben Johnson (CAN. runners) — Stanozolol Rick DeMont (US. swimmer) — Ephedrine
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Death
Len Bias (Basketball Maryland university)
Cocaine
Don Rogers (US footballist)
Cocaine
Kurt Enemar Jensen (Danish cyclist)
Amphetamine
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Substances prohibited at all times
(In- and out-of-competition)
• Anabolic agents
• Peptide hormones, growth factors, related substances, and mimetics
• Beta-2 agonists
• Hormone and metabolic modulators
• Diuretics and masking agents
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Anabolic agents
Anabolic Androgenic Steroids
Oxymetholone
Stanozolol
Danazol
Nandrolone
Testosterone
DHEA
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Androgens
• The testosterone esters include the enanthate & cypionate, which are also used for hormone
replacement.
• "Androgenic steroids," also referred to as "anabolic-androgenic steroids," are synthetic
steroidal androgens: oral 17-alpha-alkylated androgens (such as stanozolol) or parenteral 19-
nortestosterone derivatives (such as nandrolone).
• They were originally developed to have a greater anabolic to androgenic effect than
testosterone.
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Androgen precursors
• The androgen precursors include androstenedione & DHEA.
• Androstenedione does not appear to have an anabolic effect like testosterone, and it has little,
if any, effect on increasing the serum concentration of testosterone.
• DHEA is also available as a "nutritional supplement" and is widely touted in body-building
magazines as an agent that increases muscle strength.
• It is not androgenic itself but is converted to testosterone and raises serum concentrations in
women but not men.
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• Another approach to increasing endogenous testosterone concentrations is by taking exogenous
human chorionic gonadotropin (hCG), antiestrogens such as tamoxifen or raloxifene, or
aromatase inhibitors.
• These drugs result in an increase in serum testosterone concentrations, and all are banned by the
World Anti-Doping Agency (WADA).
Other forms of androgen stimulation
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Hormone and metabolic modulators
Aromatase inhibitors: • Anastrozole
• Aminoglutethimide (Orimeten®)
• Exemestane (Aromasin®)
• Letrozole (Femara®)
Selective estrogen receptor modulators (SERMs): • Raloxifene
• Tamoxifen
• Toremifene
Other anti-estrogenic substances: • Clomifene
• Cyclofenil
• Fulvestrant
Metabolic modulators: Insulins and insulin-mimetics
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• Estrogen blockade with drugs that block estrogen action or synthesis is another strategy for
raising serum testosterone levels in men.
• They are most commonly coadministered with androgens to prevent gynecomastia. Drugs in this
category include antiestrogens and aromatase inhibitors.
Estrogen blockade
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• Antiestrogens bind to and block the estrogen receptor. The original antiestrogens included the
nonsteroidal drugs clomiphene and tamoxifen.
• These drugs are also referred to as selective estrogen receptor modulators (SERMs); they have
estrogen agonist properties in some tissues and estrogen antagonist properties in others.
Antiestrogens
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• Tamoxifen is an antiestrogen that is sometimes used off-label (10 to 20 mg/day) to treat
adolescents and adults with painful gynecomastia.
• Similar doses are used by bodybuilders and other athletes taking testosterone in order to prevent
gynecomastia that develops because testosterone is converted to estradiol.
Antiestrogens
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Aromatase inhibitors
• Aromatase inhibitors are steroidal or nonsteroidal agents that block the conversion of
androgens to estrogen.
• Nonsteroidal agents: letrozole & anastrozole
• Although they are not very effective, they are used to reduce the development of
gynecomastia and to attempt to elevate the serum testosterone concentration.
• Modest elevations of serum testosterone are seen with aromatase inhibitor use in men, but an
effect on muscle strength has not been demonstrated.
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Efficacy of Androgens
It seems intuitive that androgens increase muscle mass & muscle strength, given
the obvious differences between men & women.
Administration of supra-physiologic doses of exogenous testosterone to healthy
young men has been shown to increase their muscle strength.
However, there is no evidence that the androgen precursor, androstenedione,
increases muscle strength, and the evidence for an effect of DHEA is conflicting.
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Side effects of anabolic androgenic steroids
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Peptide hormones, growth factors, related
substances, and mimetics
• Erythropoietin (EPO)
• Peptide Hormones and Hormone Modulators such as:
CG and LH
and their releasing factors, e.g. Buserelin, deslorelin, gonadorelin,
goserelin, leuprorelin, nafarelin and triptorelin, in males
• Growth Hormone (GH)
• Insulin-like Growth Factor-1 (IGF-1)
Growth hormone, like androgens, has been linked
to many prominent athletes in sports, including
baseball, swimming, and cycling.
Athletes take recombinant human growth hormone
(rhGH) because of its demonstrated effects on
body composition (more muscle, less fat).
Growth hormone would be expected to cause
acromegaly if given in high doses long enough, but
no such cases have been reported.
Cancer is another potential concern as epidemiologic
data suggest an association between serum
concentrations of insulin-like growth factor 1 (IGF-
1) and cancer risk.
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Adverse effects of GH
• Sodium retention
• Myopathy
• Carpal tunnel syndrome
• Swelling of the hands
• Hypertension
• Insulin resistance/hyperglycemia/diabetes
• Myocardial injury, cardiomegaly
• Premature epiphyseal closure
The rates of insulin-like growth factor (IGF-I) and insulin use for performance
enhancement is lower than growth hormone.
IGF-1 should have similar effects to growth hormone, but this has not been studied.
Athletes have also begun to use insulin, in particular, short-acting insulins, because
of their anabolic effects on muscle.
Insulin and IGF-I may lead to hypoglycemia.
Serum concentrations of IGF-1 may be associated with an increased risk of prostate
cancer.
IGF-1 and insulin
• Athletes have used methods to increase the
oxygen-carrying capacity of the blood and
thereby athletic performance for decades,
initially by training at high altitudes, then by
transfusions, and more recently by hypoxia
and administration of drugs such as
erythropoietin that stimulate erythropoiesis.
• Recombinant human EPO and later
darbepoetin alfa, which has a longer half-
life.
• Erythropoietin increases the blood's maximum
capacity to transport and utilize oxygen,
thereby augmenting aerobic power and
physical exercise tolerance.
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Adverse effects of EPO
Injection site reactions
Nausea
Headache
Dizziness
Arthralgia
Allergic and anaphylactic reactions
Hypertension and thrombosis
Increased risk for myocardial infarction and stroke
Exogenous hCG, which binds to the LH
receptor & stimulates the Leydig cells of the
testes to secrete testosterone, has also been
used by athletes.
hCG leads to production of endogenous
testosterone in the normal ratio to
epitestosterone, making its use more
difficult to distinguish from normal
secretion.
LH has a very short half-life & is not likely
to be abused.
Side effects of hCG include edema &
gynecomastia.
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• 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 .
• Although beta agonists cause bronchodilation, it is unlikely that this improves performance in athletes
without asthma.
• There is anecdotal evidence of benefit in swimmers who use these inhaled medications prior to a race.
• Albuterol (salbutamol) is the beta agonist used most often to enhance athletic performance.
• Salbutamol, formoterol, and salmeterol are permitted in sport when used via inhalation at therapeutic doses.
Beta-2 agonists
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Masking agents
Products that conceal the presence of a prohibited substance in urine or other
samples.
Probenecid
Desmopressin
Plasma expanders, e.g. intravenous administration of albumin, dextran, hydroxyethyl starch
and mannitol
Acetazolamide; amiloride; bumetanide; chlortalidone; etacrynic acid; furosemide;
indapamide; metolazone; spironolactone
Thiazides, e.g. hydrochlorothiazide
Triamterene
Vaptans, e.g. tolvaptan
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Diuretics
• Diuretics were first banned in sport in 1988 because they can be used by athletes for two
primary reasons:
• First, their potent ability to remove water from the body can cause a rapid weight loss that
can be required to meet a weight category in sporting events.
• Second, they can be used to mask the administration of other doping agents by reducing
their concentration in urine primarily because of an increase in urine volume.
Make weight: wrestling, weightlifting, judo & boxing
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Adverse effects of diuretics
• Weakness
• Drowsiness
• Dizziness
• Fatigue
• Increased risk of thrombosis
• Muscle cramps
• Metabolic alkalosis
• Cardiac dysrhythmia
(caused by hypokaliemia)
Potassium sparing diuretics (eg,
amiloride, spironolactone) can
cause hyperkalemia, &
spironolactone can also cause
gynecomastia
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• Stimulants
• Narcotics
• Cannabinoids
• Glucocorticoids
Substances & Methods prohibited In-competition
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• Stimulants: Amphetamine
D-methamphetamine
Cocaine
Ephedrine
Pseudoephedrine
Methylphenidate
Fenfluramine
Pemoline
Selegiline
Modafinil
Sibutramine
Substances & Methods prohibited In-competition
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Stimulants
• Stimulants can enhance both physical and cognitive
performance among athletes through a range of effects,
including the following:
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
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Stimulants
Bupropion, caffeine, nicotine, phenylephrine,
phenylpropanolamine: These substances are included in
the 2020 Monitoring Program, and are not considered
prohibited substances.
• Epinephrine (adrenaline): Not prohibited in local
administration, e.g. nasal, ophthalmologic, or co-
administration with local anaesthetic agents.
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Hypertension
Myocardial infarction
Psychosis
Headache
Tremor
Nausea
Insomnia
Tachycardia
Adverse effects of
Stimulants
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Amphetamine
• Amphetamines are used by athletes to increase alertness and
concentration.
• Methylphenidate—Methylphenidate (Ritalin) is widely used
as a cognition enhancer by patients with ADHD.
• Ephedrine is heavily used among athletes to improve alertness and to
accelerate weight loss, and can be obtained with relative ease on the
Internet.
• 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. It
remains a common remedy in Chinese medicine.
Methylphenidate
Ephedrine
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• Narcotics:
• Opiates have been used for increased pain threshold in athletics
Buprenorphine; Diamorphine (heroin); Fentanyl and its derivatives; Hydromorphone; Methadone; Morphine; Oxycodone; Oxymorphone; Pentazocine; Pethidine
• Cannabinoids:
Cannabis, hashish and marijuana
• Glucocorticoids:
All glucocorticoids are prohibited when administered
by oral, intravenous, intramuscular or rectal routes.
Substances & Methods prohibited In-competition
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• Dependence
• Nausea
• Vomiting
• Constipation
• Loss of coordination
• Decreased concentration
• Fatigue
Adverse effects of narcotics
The active ingredient is tetrahydrocannabinol (THC).
The physical effects of cannabinoids on sports
performance are not well-known, but they can reduce
anxiety.
Cannabinoids
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Adverse effects of Cannabinoids
• Reduced alertness
• Impaired short-term memory
• Psychomotor retardation
It can cause dysphoria, increased
anxiety, paranoia, & psychosis.
Glucocorticoids
• Alter glucose metabolism and have anti-inflammatory and analgesic properties.
• Their use and efficacy are not well-documented for performance enhancement.
• May cause hyperglycemia, fluid retention, and acute mood changes.
• In chronic use they can suppress the hypothalamic-pituitary-adrenal axis and lead to reduced muscle mass and weakness, osteoporosis, diabetes, hypertension, weight gain and abdominal obesity, cataracts, and various psychiatric symptoms (eg, hypomania, depression, psychosis).
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Beta-blockers:
Acebutolol; Labetalol;
Atenolol; Metoprolol;
Bisoprolol; Nadolol; Pindolol;
Carvedilol; Propranolol;
Sotalol; Esmolol; Timolol
Substances prohibited in
particular sports
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• Beta-blockers
• Beta-blockers are prohibited In-Competition only, in the
following sports, and also prohibited Out-of-Competition
where indicated.
Archery (WA)*
Automobile (FIA)
Billiards (all disciplines) (WCBS)
Darts (WDF)
Golf (IGF)
Shooting (ISSF, IPC)*
Skiing/Snowboarding (FIS) in ski jumping, freestyle aerials/halfpipe and snowboard halfpipe/big air
Underwater sports (CMAS)
* Also prohibited Out-of-Competition
Substances prohibited in particular sports
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Beta-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, and thus they are used by athletes
in sports such as archery or billiards where these effects confer a benefit.
• Adverse effects:
Bradycardia
Increased airway resistance
Decreased endurance due to reduced maximum workload
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Methods prohibited at all times
(In- and out-of-competition)
• Manipulation of blood and blood components
• Chemical and physical manipulation
• Gene doping
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Blood transfusions
Blood transfusions can be autologous or
homologous.
Blood transfusions can increase the number of
erythrocytes and oxygen carrying capacity of the
blood to improve performance and speed
recovery.
Blood transfusions prior to athletic competitions
have been used to enhance performance, but are
currently prohibited by the WADA.
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Can lead to:
Sudden fluctuations in blood pressure
Stimulation of atherosclerosis
Oxidative damage to organs
Impaired blood cell function
Blood-borne infections
Iron deposition in organs
Blood transfusions
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The most common way is to discontinue the drug before
testing will occur.
Manipulation by:
Urine substitutes
Urine dilution (athletes may concomitantly take diuretics &
increase fluid intake to dilute urine)
Some substances have protease activity
Refusing to provide samples of urine or blood
Avoiding detection
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• “Gene doping” is the application of gene therapy techniques to enhance athletic
performance.
• The history of doping in sports clearly demonstrates some athletes will do anything,
& risk everything, to gain a competitive advantage.
• Gene doping has been demonstrated to impact endurance, strength, & tissue repair
in animal models. As an example, gene therapy has been used to promote
erythropoietin production to treat anemia, which makes it a potential target for
abuse.
Gene doping
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• Gene doping is defined as the transfer of genetic material to
improve athletic performance.
• Main techniques used for delivering genes include direct injection
of a gene into a muscle; intravenous or intramuscular injection of
a virus containing a gene of interest; or ex vivo gene transfer into
cells that are subsequently transplanted into the recipient.
• Potential targets for gene doping are considered Epo, IGF-I,
myostatin, vascular endothelial growth factor (VEGF), fibroblast
growth factor, …
Gene doping
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• 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.
Gene doping
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