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Supplements abuse

and doping

By:

Dr. Razieh Avan Pharm.D, Assistant Professor of Clinical Pharmacy

Faculty of Pharmacy


• 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


• 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


• 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


• 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.



• 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.



• 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.



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.



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


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


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


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


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


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


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


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


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


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


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


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


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


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


Withdrawn golden medal

Ben Johnson (CAN. runners) — Stanozolol Rick DeMont (US. swimmer) — Ephedrine


Death

Len Bias (Basketball Maryland university)

Cocaine

Don Rogers (US footballist)

Cocaine

Kurt Enemar Jensen (Danish cyclist)

Amphetamine


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


Anabolic agents

Anabolic Androgenic Steroids

Oxymetholone

Stanozolol

Danazol

Nandrolone

Testosterone

DHEA


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.


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.


• 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


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


• 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


• 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


• 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


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.


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.


Side effects of anabolic androgenic steroids


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.


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.


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.


• 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


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


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


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


• Stimulants

• Narcotics

• Cannabinoids

• Glucocorticoids

Substances & Methods prohibited In-competition


• Stimulants: Amphetamine

D-methamphetamine

Cocaine

Ephedrine

Pseudoephedrine

Methylphenidate

Fenfluramine

Pemoline

Selegiline

Modafinil

Sibutramine



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


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.


Hypertension

Myocardial infarction

Psychosis

Headache

Tremor

Nausea

Insomnia

Tachycardia

Adverse effects of

Stimulants


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


• 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.



• 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


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).


Beta-blockers:

Acebutolol; Labetalol;

Atenolol; Metoprolol;

Bisoprolol; Nadolol; Pindolol;

Carvedilol; Propranolol;

Sotalol; Esmolol; Timolol

Substances prohibited in

particular sports


• 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


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


Methods prohibited at all times

(In- and out-of-competition)

• Manipulation of blood and blood components

• Chemical and physical manipulation

• Gene doping


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.


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


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


• “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


• 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


• 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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