Performance and Drugs Exam 1

2002 Ken Caminiti

(1996 MLB MVP) admits to using steroids and cocaine during MVP year - estimates half of player used steroids (dies of heart attack in 2004)]

proof

1.Positive test 2.Admission by athlete 3.Testimony by a third person 4.Documentary evidence ● Must establish that the proof is greater than the balance of probability.

What is considered an anti-doping rule violation? (ADRV)

1.Presence of a prohibited substance or its metabolites or markers in an athlete's sample. 2.Use of or attempted use by an athlete of a prohibited substance or method. 3.Refusing or failing to provide a sample, after notification without compelling justification. 4.Violation of applicable requirements regarding athlete availability for out of competition testing, including failure to file sufficient whereabouts information and missed tests. Tampering or attempted tampering with any part of the doping control process 6.Possession of prohibited substance or methods. 7.Trafficking or attempted trafficking in any prohibited substance or method. 8.Administration, attempted administration or assisting in the administration of any prohibited substance or method. 9.Intentional complicity (eg. Aiding, abetting, conspiring, covering up) to commit an ADRV. 10.Association in a professional or sport-related capacity of an athlete with support personnel who are serving a period of ineligibility or who have been convicted in a criminal proceeding for conduct what would constitute doping.

2003

104 positive of 1438 anonymous tests in MLB. Leads to new rules in 2004: 1st offense = counseling, 2nd offense = 15 day suspension (with pay)

2002 Norbolethone

2002 Norbolethone - first designer anabolic steroid identified

17alpha-alkylated AAS

Alkylation of 17-alpha position: reduced first pass metabolism = oral administration. Higher hepatotoxicity. •More than 20 developed for different uses • •1935 Methyltestosterone = Android, Metandren, Testred •1955 Methandrostenolone or Metandienone = Dianabol •Side effects include: masculinization, gynecomastia, fluid retention •1956 Fluoxymesterone = Halotestin, Ultandren •Side effects masculinization, gynecomastia, hypogonadism, aggressiveness, etc. •1962 Stanozolol = Winstrol, Anabol, Stanol, Stromba •Greater ratio of anabolic to androgenic effect than testosterone, no masculinization effects

agonist example

Beta-agonist - causes bronchodilation Examples: Salbutamol, Formoterol, Salmeterol, Vilanterol Used in asthma inhalers - also banned by WADA except with certain restrictions

antagonist example

Beta-blockers - used to reduce heart rate by blocking epinephrine (adrenaline), causes reduced blood pressure via reduced heart rate and ejection force Examples: Propranolol, Acebutolol, Atenolol WADA prohibits in certain sports in competition, and some out-of-competition as well

textbook definition of a drug

Chemical substances which can alter the biochemical systems of the body

2015

IAAF - International Association of Athletics Federations - whistleblower releases files that reveal 1/3 of medals (including 55 Olympic gold) won in endurance events at Olympics and world championships by athletes who have recorded suspicious tests - described by experts as "highly suggestive of doping".

1991

MLB commissioner sends 7 page memo prohibiting the possession, sale or use of any illegal drug or controlled substances - including steroids. Because of lack of testing, enforcement, or publicity of rule, it is largely ignored.

2002

MLB includes "survey testing" of player in new contract with player's union - tests to "gauge the use of steroids among players". Tests were anonymous and no one would be punished.

2005

MLB institutes new penalties: 1st offense = 50 game suspension, 100 for second, lifetime ban for third - all without pay •NHL and player's union agreement implements new PED program. Teams tested twice a year (training camp and during season). Players get random no-notice testing during season, but not on a game day. Off-season - up to 60 total tests (1 out of 12 players). •Discipline: 1st offense = 20 game suspension, 2nd = 60 games, 3rd = permanent suspension (but can reapply after 2 years). •List of prohibited substances not same as WADA - no agreement with WADA

1998

Mark McGwire admits to using androstenedione (not illegal)

2012

Ryan Braun (MLB) first player to successfully appeal a positive drug test after sample is held for 2 days before testing (against guidelines). MLB issued dissent over ruling, but had to abide by it. In 2013, Braun implicated again, and admitted to 2012 drug use.

affinity

ability of a drug to bind to a receptor

efficacy

ability to cause effect once bound

antagonists

block stops action of "endogenous biochemical substance"

potency

depends on Affinity and Efficacy

idiosyncrasy

drug produces unusual reaction due to biochemical deficiency or genetic difference

testosterone esters

enhanced lipid solubility = slow release, long activity, decreased hepatotoxicity. •1936 Testosterone propionate: injection = Testoviron •1951 Testosterone cypionate: injection = Depo-testosterone •1954 Testosterone enanthate: injection = Delatestryl •2014 Testosterone undecanoate: oral = Andriol & Jatenzo, injection = Aveed & Nebido. Jatenzo approved by FDA in March 2019

aromatase

enzyme that converts androgens to estrogens: aromatization

drug cumulation

frequency of administration exceeds elimination

distribuution

from bloodstream to local receptor sites on specific cells

Aromatase Inhibitors

inhibit the action of aromatase enzyme •Prevent conversion of exogenous testosterone and other AASs to estrogen •Clinically used to treat breast tumors, depriving them of estrogen •Used to prevent gynecomastia in men that use AAS •Used to increase circulating endogenous testosterone by preventing conversion to estrogen •Decrease in aromatase increases LH and FSH = increased testosterone •Common brand names: Arimidex, Aromasin, Letrozole

1997

new MLB commissioner issues memo prohibiting drug use, asks it to be posted in clubhouses and handed out to players - again, largely ignored.

agonists

stimulate mimics action of "endogenous biochemical substance"

drug allergy

typical allergic reaction

drug resistance

typically acquired through regular use - called tolerance - can lead to physical dependence

testing methods

urine test blood test athlete biological passport (ABP)

2004

• President Bush signs the Anabolic Steroid Control Act - adds hundreds of steroid-based drugs, and precusors like androstenedione to Schedule III controlled substances. •MLB rules align with drugs banned by Congress •WADA takes control of Prohibited list from IOC, removes caffeine

1904-1920

•1904 Olympics (St. Louis, USA) - Most blatant use of stimulants to that point - Thomas Hicks, winner of marathon. Injected with strychnine and given brandy during race. •Coaches/athletes developed mixtures of strychnine, heroin, cocaine, opium and caffeine (mad science!). •Coca-Cola switched from cocaine to caffeine in 1903 •Cocaine became illegal in 1914, Heroin in 1924.

exogenous steroid

•1931: Adolf Butenandt extracts androstenone from urine •1935: Leopold Ruzicka synthesized androstenone •Both given Nobel Prize in Chemistry (1939) •1935: Ernst Laqueur isolated testosterone in the testis of bulls •1935: Butenandt publishes chemical synthesis of testosterone • •Over 200 exogenous steroid forms

19-nor testosterone (Nandrolone)

•1950s, Injection only, strong anabolic, weak androgenic, most commonly used AAS •Nandrolone deconate = Deca-durabolin •Nandrolone phenylproprionate = Durabolin •Trenbolone acetate (another 19-nor, 500:500 anabolic:androgenic ratio in mice!)

1970s

•1971 NFL issues first drug policy - designed to educate - not test or ban any particular drug (Alzado enters league) •1973 NFL policy expanded to include disciplinary measures •First full-scale testing at 1972 Munich Olympics •2079 athletes tested, 7 positive results (book says 9) •All positives were from stimulants • •1975 IOC adds anabolic steroids to list of prohibited substances •1976 Olympics - first tests conducted for steroids •786 tested, 11 positive

1980s

•1983 Pan-Am games - surprise drug testing finds 19 positive tests •12 US athletes and about 12 others withdrew from competition before being tested and did not compete •1985 - Blood doping, beta-blockers, diuretics added as Prohibited; and pharmacological, chemical and physical manipulation added as prohibited methods. •Many countries developed anti-doping organizations - athletes took advantage of drugs/methods listed on IOC list but not on individual country or federation lists. •1984 Court for Arbitration for Sports established •1988 President Reagan signs Anti-Drug Abuse Act of 1988 - outlaws sale of steroids for non-medical purposes •Ben Johnson - 1988 Olympics 100m Final •6 of 8 sprinters eventually implicated on PED use •NFL enacts policy to start testing for drug use •NFL sued by player's union over unfair labor practices because of testing policy without collective bargaining over processes - led to player's strike after 3rd game of 1982 season (only 9 games) •1982 Agreement allowed preseason testing with reasonable cause •Next several years - NFL tried to implement drug testing, always rejected by players union •Alzado retires 1985 •1982 Agreement expired in 1989

1990s

•1990 Congress passes Anabolic Steroids Control Act - places steroids as a Schedule III narcotic - same as codeine, hydrocodone, and ketamine. •1991 Lyle Alzado SI article - admits to steroids and HGH, dies 1992 •Erythropoietin (EPO) added to Prohibited list, without a valid test •Blood testing begins at 1994 Winter Olympics - leads to development of "Athlete Biological Passport" •Ross Ribagliati - men's snowboard goal medal - tested positive for marijuana, stripped of medal - given back since marijuana was not prohibited

2008

•1st suspensions in MLS after 9 years of testing. 2 players receive 10 game suspension and fined 10% of salary. •2008: 6 NFL players suspended for games for testing positive for Bumetanide (steroid masking agent). •2008: NASCAR outlines drug policy for teams and drivers. Drivers can be tested for "anything".

2003 BALCO

•2003 - BALCO raided. Bay Area Laboratory Co-operative. Victor Conte started by testing athletes for mineral deficiencies, gained popularity with Bill Romanowski. •Chemist Patrick Arnold created Tetrahydrogestrinone (THG) "The Clear" - undetectable steroid. Balco administered mineral supplements with erythropoietin (EPO), human growth hormone (HGH), modafinil (stimulant), testosterone cream "The Cream", and THG. •Several professional athletes caught in scandal for using BALCO, and drugs administered by personal trainer Greg Anderson, including: Dwain Chambers, Jason Giambi, Barry Bonds, Marion Jones, and Bill Romanowski. Dwain Chambers (sprinter) was first person to test positive for THG - banned from Olympics for life. •

ABP steroidal module

•2014: Steroidal Module - collects info on markers of steroid doping from urine samples •testosterone (T) •epitestosterone (E) •androsterone (A) •etiocholanolone (Etio) •5-alpha-diol •5β-diol •and the following ratios: •testosterone to epitestosterone (T/E) •androsterone to testosterone (A/T) •androsterone to etiocholanolone (A/Etio) •5-alpha-diol/5βdiol 5-alpha-diol/E

2011

•5 north Koreans test positive for steroids during Women's World Cup. Blamed test on traditional Chinese medicine based on deer musk glands used to treat them after being struck by lightning a month earlier. •2011 NFL first major sport to conduct blood testing for HGH •2011: Mike Jacobs (MLB) first US professional athlete to test positive for HGH.

dictionary definition of a drug

•A substance recognized in an official pharmacopoeia or formulary •A substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease •A substance other than food intended to affect the structure or function of the body

AAS side effects

•Acne •Water retention - prevented with aromatase inhibitor, not diuretic •High blood pressure: caused by water retention due to conversion of testosterone to estrogen (called aromatization) •Increased total cholesterol, decreased HDL, increased LDL •Gynecomastia •Hair loss if genetically predisposed •Liver damage - most pronounced with C17-alpha alkylated steroids (most oral steroids) •Prostate enlargement •Testosterone suppression, testicular atrophy, and spermatogenesis cessation •Virilization - masculine traits

Corticotrophins

•Adrenocorticotrophic Hormone (ACTH) - secreted by pituitary gland, stimulates adrenal gland to secrete its hormones - glucocorticoids •Corticosterone that is involved in regulation of energy, stress response, immune reactions •Cortisol - steroid hormone, causes gluconeogenesis (breakdown of protein - particularly in lean tissue), causes inflammation •Corticosteroids - exogenous, slow or stop immune system processes that trigger inflammation (Prednisone, Cortisone, Hydrocortisone). •Prohibited In-Competition by WADA (S9) when administered by oral, intravenous, intramuscular, or rectal

Anabolic-Androgenic Steroids (AAS)

•Anabolic - muscle building •Androgenic - increased male sexual characteristics •Synthetic AAS designed to: •Maximize anabolic and minimize androgenic effects •Limit first-pass metabolism & increase half-life • •32 common types of anabolic androgenic steroids (AAS) •WADA Prohibited list: Class S1 Anabolic Agents •Exogenous AAS: currently 62 specific and "other substances with a similar chemical structure or similar biological effect" •Other anabolic agents: clenbuterol, selective androgen receptor modulators (SARMs), tibolone, zeranol, zilpaterol

776 BC - 393 BC (end of ancient games)

•Ancient Greeks could do anything during competition except what was considered blatant cheating or game-fixing. •Non-typical foods used for performance enhancement •Wine potions •Hallucinogenic mushrooms •Animal hearts & sheep testicles •Meals of excess raw meat •Rear hooves of an Abyssinian ass, ground up, boiled in oil, flavored with rose hips and rose petals

AAS therapeutic uses w/ physiological doses

•Anemia - AAS increase RBC count •Andropause - slow decline in testosterone production •Angioedema - rapid swelling of tissue (anti-inflammatory) •Breast cancer - non-aromatizing AAS are anti-strogenic •Burn victims - increase lean tissue and recovery •Delayed Puberty •Low testosterone •Muscle wasting diseases •Osteoporosis - increases bone mineral content and collagen synthesis •Renal insufficiency - side effect is low RBC count •Strength loss from lean tissue loss (AIDS) •Weight loss from other disease

Therapeutic Use Exemption (TUE)

•Athlete needs to treat an illness/injury with banned drug. TUE is granted if: 1)Athlete would experience significant health problems without the banned drug 2)Use of the drug would not produce a significant performance enhancement other than return to normal state of health 3)No reasonable alternative to banned drug 4)Use of banned drug is not consequence of a prior non-therapeutic use of a banned substance

Blood flow restriction exercise & GH

•BFR partially restricts arterial inflow and fully restricting venous outflow in working muscles during exercise. Also called Kaatsu training (1966). •Resistance training 20-40% 1RM = >80% 1RM •Aerobic training <50% VO2max = >75% VO2max •Results in increased lactate accumulation = increased GH secretion •If resistance training = 100% increase in GH, BFR => 170% increase in GH

ABP

•Began in 2009 with Haematological Module - collects info on markers of blood doping •ABPS: Abnormal Blood Profile Score •HCT: Hematocrit •HGB: Hemoglobin •IRF: Immature reticulocyte fraction •MCH: Mean corpuscular haemoglobin •MCHC: Mean corpuscular haemoglobin concentration •MCV: Mean corpuscular volume •OFFS: OFF-hr Score •PLT: Platelets •RBC: Red blood cell (erythrocyte) count •RDW-SD: Red cell distribution width (standard deviation) •RET#: Reticulocyte count •RET%: Reticulocytes percentage •WBC: White Blood Cells •2 main markers: RET% - Reticulocytes percentage, HGB - Hemoglobin •Hemoglobin (HGB) - carries oxygen •Reticulocytes - immature red blood cells (immature for about a day). •"Normal" reticulocyte % between 0.5% and 1.5%. By itself, this absolute level tells nothing about doping. •After withdrawal, %RET goes UP - body responds to loss of RBC by stimulating RBC formation = Increased %RET •Reinfusion = %RET goes down - "old" blood has less immature RBC •Hemoglobin acts in opposite direction - withdrawal = less HGB, infusion = more HGB.

1960s

•Beta-blockers, tranquilizers, antidepressants developed and experimented with in sports •1960: Knut Jensen - Danish cyclist collapses during 100km team time trial race, fractures his skull. Autopsy finds traces of amphetamine Ronicol. 2nd Olympic athlete to die during competition. •1967: Tommy Simpson - British cyclist dies during 13th stage of Tour de France. Took amphetamines and brandy. His motto: "if it takes ten to kill you, take nine and win". •Neither death directly attributed to drug use, but known use causes increase in push to ban drugs. •1966: FIFA - Federation Internationale de Football (soccer), and Union Cycliste Internationale (cycling), introduce drug tests at World Championships

2013

•Biogenesis of America: health clinic in Florida specializing in weight loss and hormone replacement therapy. Provided MLB players with HGH. ("Screwball") •Florida newspaper gets documents from former employee linking MLB players to drug use •MLB buys documents from former employee and investigates •MLB suspends 13 players (most ever at one time) •Ryan Braun - 65 games and postseason •Alex Rodriquez - 162 games (all of 2014 season) Interview •11 others to 50-game suspensions

side effects

•Can occur at normal dose, but most likely at higher doses. Most are predictable and known. All drugs have side effects. •Non-predictable toxicity: •Idiosyncrasy - drug produces unusual reaction due to biochemical deficiency or genetic difference •Drug allergy - typically allergic reaction

Other Anabolic Agents banned by WADA:

•Clenbuterol - used as bronchodilator for asthma, anabolic in animals - but not humans. Bodybuilders use as a fat-burner. Beta-2 agonist. •Tibolone - used in menopausal hormone therapy, not available in US •Zeranol - mycoestrogen, used as livestock growth promoter, nonsteroidal estrogen (acts like a steroid by binding to estrogen receptor), may proliferate cancer •Zilpaterol - livestock growth promoter, beta 2 agonist, nutrient partitioning effect •Selective Androgen Receptor Modulators (SARMs) - anabolic but not as androgenic, maybe fewer side effects, tissue selective

administration to avoid side-effects

•Cycling - on/off cycles, weeks to months •Post-Cycle Therapy Drugs •SERMs •hCG •Aromatase Inhibitors •Pyramiding - increasing dosage over time to a peak, then slowly decreasing •Pharmacokinetic evidence for this strategy is minimal •Stacking - use of two or more steroids at a time with different effects

Athlete Biological Passport (ABP)

•Designed to monitor selected biological variables over time that indirectly reveal the effects of doping rather than attempting to detect the doping substance or method itself. •Uses •Intelligence - data used to develop standards and normal value •Sanctioning - evidence can be used to suspend/ban athlete •Health Protection - provides a direct view of the impact of doping on an athlete's physiology •Deterrence - doping leaves a biological fingerprint that can't be erased

Lyle Alzado

•Did steroids cause Alzado's cancer? •Do you think Alzado's message of compromised health due to steroids was an effective strategy in discouraging young athletes from using anabolics? •Did Lyle Alzado do anything wrong?

administration

•Drugs need to get into the bloodstream for greatest effectiveness • •Oral - liquid or pill •Injection (faster) •Subcutaneous •Intramuscular •Intravenous •Topical • •WADA takes into account route of administration for some drugs

Hypoxia-inducible factor (HIF)

•EPO production regulated by oxygen availability •Tricks body into thinking it is hypoxic, thus making it create endogenous EPO, thus more red blood cells •Altitude training and hyperbaric oxygen chambers •Common gases inhaled: xenon & argon •Minerals: cobalt and nickel •Daprodustat, Molidustat, Roxadustat, Vadadustat • • •SIDE NOTE: Pure oxygen use on sidelines

Chorionic gonadotrophin (CG/hCG)

•Endogenous during pregnancy, produced by placenta and aids in fetal development •Exogenous form injected mimics Luteinizing hormone to stimulate testes to produce testosterone and epitestosterone (up to 50% increase in 2 hours) •Natural LH is inhibited when testosterone levels rise (negative feedback loop), but exogenous CG overrides LH drop and continues testosterone production •Stimulates production of nandrolone metabolites (maybe nandrolone itself?) •Side effects are increased Estrogen production

peptide hormones WADA prohibited

•Erythropoietins (EPO) and agents affecting Erythropoiesis •Erythropoietin-receptor agonists •Hypoxia-inducible factor (HIF) activating agents •GATA inhibitors •TGF-Beta inhibitors •Innate repair receptor agonists •Peptide hormones and releasing factors •Chorionic gonadotropin and luteinizing hormone and releasing agents •Corticotrophins and releasing factors •Growth hormone, its fragments and releasing agents Growth factors and growth factor modulators

Other anti-estrogenic substances

•Estrogen blockers or antagonists •Not selective like SERMS •Anti-estrogenic drugs cause increase in gonadotropin-releasing hormone from hypothalamus, and increased pituitary sensitivity to GnRH = increased LH and FSH = more testosterone •Used by athletes to prevent natural drop in testosterone with AAS use •Common: Fulvestrant - chemotherapy drug (prohibited)

EIGR: Exercise-induced growth hormone response

•Exercise causes increase in GH release due to •Stimulation of catecholamines •Increase in lactate and/or nitric oxide •Changes in acid-base balance • Intensity threshold: Exercise intensity > lactate threshold = hGH secretion Endurance exercise = lowest hGH secretion

GROWTH FACTORS AND GROWTH FACTOR MODULATORS

•Fibroblast Growth Factors (FGFs) - collagen •Hepatocyte Growth Factor (HGF) - liver cells •Insulin-like Growth Factor-1 (IGF-1), and its analogues; •Mechano Growth Factors (MGFs) - IGF1 splice variant in muscle •Platelet-Derived Growth Factor (PDGF) - blood vessels •Vascular-Endothelial Growth Factor (VEGF) - blood vessels •Thymosin-β4 , and its derivatives e.g. TB-500 - hair •and other growth factors or growth factor modulators affecting muscle, tendon or ligament protein synthesis/degradation, vascularisation, energy utilization, regenerative capacity or fibre type switching.

1968

•First drug testing at both winter and summer olympic games. •Winter: 86 tests, 0 positive •Summer: 667 tests, 1 positive •Member of Swedish modern pentathlon team tested positive for alcohol - said he had 2 beers before the shooting event to calm his nerves •14 other athletes tested positive for tranquilizers - which were legal then

1928

•First rule against doping in sports •International Association of Athletics Federation (IAAF) - governing body of track and field events, prohibited doping but didn't test for it. •"Doping is the use of any stimulant not normally employed to increase the power of action in athletic competition above the average. Any person knowingly acting or assisting as explained above shall be excluded from any place where these rules are in force or, if he is a competitor, be suspended for a time or otherwise from further participation in amateur athletics under the jurisdiction of this Federation".

2010

•Floyd Mayweather & Manny Pacquiao cancel boxing match over disagreements on drug testing. Both lost 25million •2010: Mark McGwire admits to steroid use

GATA-2 Inhibitors

•GATA-2 inhibits the promotor region of gene transcription for EPO

2019

•Geir Helgemo - Norwegian bridge player suspended for 6 months after testing positive for synthetic testosterone and clomifene (fertility drug). •2019 - MLB no longer tests specifically for marijuana

growth hormone and growth factors

•Growth Hormone endocrinology -Ninja Nerd Science 25 min •Doesn't have a lot of effect directly, but stimulates release of hormonal polypeptide: IGF-1 •IGF-1: anabolic, stimulates protein synthesis, collagen formation and repair •IGF-1 video - steroid.com 5 min •Steroids and HGH in Sports - Charles Barkley interview 10 min

Metabolism

•How the body ultimately gets rid of drugs - transforms them into harmless molecules for elimination •How the body treats drugs and what it does with them •Determines a drugs activity by altering what it does, its ability to reach its action site, and rate of elimination. 1)Active to inactive - terminates drug activity 2)Turned into another compound with same or different effect 3)Changed into toxic metabolite Changed into active metabolite (pro-drugs)

AAS effects with supraphysiological doses:

•Increased Protein Synthesis: intracellular rate increased •Increased bone-mineral content = stronger bones •Increased collagen synthesis = base protein of connective tissue (ligaments, tendons, cartilage, muscle) •Increased Glycogenolysis = glycogen converted to glucose •Increased insulin-like growth factor 1 (IGF-1) production: anabolic peptide hormone in recovery process •Increased Nitrogen retention: normal 16%, less is catabolic •Increased Nutrient efficiency •Increased RBC count •Decreased Glucocorticoid production = stress hormones (Cortisol) increase fat gain and storage, muscle catabolism Decreased Sex hormone-binding globulin (SHBG) = binds testosterone

1967

•International Olympic Committee (IOC) institutes Medical Commission - charged with protecting health of athletes, respect for medical and sport ethics, and equality for competing athletes. •First list of prohibited substances •Central nervous system stimulants •Psychomotor stimulants •Sympathomimetic amines •Narcotic analgesics

elimination

•Kidneys (urine) •Salivary glands (saliva) •Sweat glands (sweat) •Pulmonary epithelium (exhaled gases) •Mammary glands (mammary milk) •Rectum (feces) A few others

Transforming Growth Factor B Signaling Inhibitors (TGF-B)

•Luspatercept and sotatercept - increase hematocrit levels in anemics •No known performance enhancement evidence

2009

•Michael Phelps (14 Olympic gold medals) suspended for 3 months by USA Swimming for marijuana use. •2009: Alex Rodriquez named for testing positive for steroids - was supposed to be anonymous, but BALCO documents revealed it. 103 other players kept anonymous. •2009 FIFI rejects WADA "whereabouts" rule and out-of-competition testing for players on vacation. WADA threatens to remove soccer from Olympic games. •2009 US Cyclist Tyler Hamilton receives 8-year ban from cycling after testing positive for DHEA (was in an herbal medicine he was taking). He also tested positive at 2000 Olympics (gold medal), but B sample was frozen so could not be confirmed. •2009 Kentucky Derby tests horse for steroids •2009 Manny Ramirez (MLB) suspended for 50 games, cost 7.7 million in lost salary. Claimed his doctor gave him a medication, not a steroid. 2011 tests positive again, gets 100-game suspension, but retires instead. •2009: 20 bodybuilders flee the Belgium National Championships when anti-doping officials do surprise testing. •The list of 104 MLB players that tested positive during anonymous testing in 2003 is released when government seizes results during BALCO investigation. Published by NY Times. Included: Manny Ramirez & David Ortiz (both on Red Sox World Series winning team in 04/07). Also Barry Bonds, Alex Rodriquez, Sammy Sosa.

therapeutic use of drugs

•Most drugs are not prohibited because they do not provide performance enhancement •Any drug taken must be scrutinized for banned substances. Must check all ingredients!! •Minor injuries, aches and pains can be treated with OTC drugs (Ibuprofen, Aspirin, etc), but narcotic analgesics are prohibited (oxycodone).

2006

•NHL player tests positive for anabolic agent 19-norandrosterone during tryout for US Olympic hockey team - banned from international competition for 2 years. No penalty from NHL. •Floyd Landis wins Tour de France - tested positive, fights it, loses in 2007 - first TDF winner to lose title for doping (Armstrong loses his in 2012)

1940-1945 (WWII)

•Nazis test steroids on prisoners before using on soldiers to promote aggressiveness and physical strength •Hitler's physician reported that Hitler himself may have been using steroids because he exhibited characteristics associated with heavy steroid use: mania, acute paranoid psychoses, overly aggressive and violent behavior, depression and suicidal ideologies. •American, British, German, Japanese all distribute amphetamines to soldiers to combat fatigue, elevate mood, heighten endurance.

Innate Repair Receptor Agonists

•Non-erythropoietic derivatives of rHuEPO that have been developed for their potential tissue-protective properties •Asialo EPO & Carbamylated EPO (CEPO) •No performance enhancement shown

ABP off-score

•OFF-score or "stimulation index" = ratio of hemoglobin to reticulocytes: HGB x 10 - 60 (square root of reticulocyte %) •OFF-score picks up both withdrawal of blood (rise in %RET and fall in HGB), as well as re-infusion of blood (%RET fall, HGB rise) •Normal un-doped range is 80-110. Above or Below indicates possible doping. Some natural variation possible. •Probability & False Positive • 99% = 1 out of 100 • 99.9% = 1 out of 1000

Luteinizing hormone (LH)

•Produced by pituitary gland •Stimulates testicular secretion of testosterone in males •Females: stimulates ovulation and production of progesterone (female sex hormone) •Luteininzing hormone releasing hormone (LHRH, also GnRH) - easier to produce and has greater effect - acts on pituitary to cause release of LH and follicle stimulating hormone (FSH)

100 AD

•Roman Gladiators - running/throwing/fighting/chariot races •Fed horses substances to make them run faster - Hydromel (made from honey) •Used hallucinogens and stimulants to reduce fatigue and injury, and improve intensity of their fighting •First recorded use of Strychnine - antagonist of glycine (an inhibitory neurotransmitter). Allows easier activation of motor neurons, but causes spastic muscle contractions, and death by asphyxiation. Now used as a pesticide. FYI: Coliseum held 60,000

2016

•Russian Track and Field Athletes banned from competition - WADA Independent Commission report. Some are cleared and compete under neutral Olympic flag.

Erythropoietin (EPO)

•Speeds up maturation of red blood cells •Increases number of red blood cells •Net effect is increased oxygen supply to muscle & time to exhaustion •Injected: Epogen - no pill •Recombinant EPO = same as endogenous EPO (different isomer ratio) •Synthetic EPO = Darbepoetin (dEPO) - half life of 25 hours •Continuous erythropoietin receptor activator (CERA) - half life of 142 hours •Requires increased iron intake - injection or supplements •Side effects: •Hypertension •Swelling Heart failure/stroke from increased viscosity

Late 1800s

•Sporting events increased - European and American mainly cycling and athletics •Most common drugs were plant/animal based - very few manufactured drugs yet •Stimulants - caffeine, strychnine, cocaine (less fatigue and hunger) •Analgesic - opium / morphine (less pain) •Depressant - alcohol (less sense of pain) •Vin Mariani - "wine for athletes" - combination of wine and cocaine •Coca-Cola invented 1886 •Amphetamine invented 1887 - nasal decongestant •First documented case of doping: 1865 Dutch swimmers used stimulants •1886 - Dutch cyclist died from Strychnine use •Olympic games resumed 1896

1950s

•Steroid use in sport first reported •FYI: Steroids "invented" in 1889 - mixture of testicular extracts from dogs and guinea pigs reported to improve physical strength, intellectual abilities and appetite. •Dr. John Zieglar "godfather of steroids" - invents Dianabol after noting the success of Russian weightlifters using testosterone. Receives FDA approval. •1954 World Weightlifting Championships: Russia 4G,3S USA 3G,2S,2B •Soviet Union won every event until 1984 (after collapse)

WADA also bans

•Substances which mask the effect or detection of prohibited substances •Substances not approved for human use - classified as Class S0 Other substances always under review or being "monitored" - example: Caffeine

steroidal module

•T/E ratio - 4:1 = positive test •Testosterone administration (any form) •Dehydroepiandrosterone (DHEA) administration (any form) •Suppression of epitestosterone excretion •Alcohol can cause variation of T/E •A/T ratio •5-alpha-diol/5-beta-diol •Both metabolites of Testosterone •Sensitive to shift in metabolic pathway from 5-beta to 5-alpha reductase •Sensitive to transdermal T administration •A/Etio •Sensitive to shift in metabolic pathway from 5-beta to 5-alpha reductase •Sensitive to transdermal T administration •5alpha-diol/E Sensitive to gel T administration

how drugs work

•Target receptors •Intended - desired effect •Unintended - side effect Receptors exist to allow the body's naturally occurring substances to induce the cells biochemical and physiological functions. Receptors are like jigsaw puzzle pieces - the better the drug fits into the receptor, the better it will work.

Selective Estrogen Receptor Modulators (SERMs)

•Target specific tissues: act like estrogen receptor agonists in some tissues and antagonists in others •Tamoxifen: estrogen receptor agonist for bone, antagonist on breast •Clomiphene: SERM that also promotes ovulation in females, estrogen receptor antagonist in hypothalamus • Block receptors in some tissues - actually sits in the receptor •Mainly used by postmenopausal women for management of breast cancer and osteoporosis •Blocks the negative feedback loop for testosterone, thus causing increased release of GnRH, LH and FSH, which increase testes output of testosterone •Most commonly used drug to prevent gynecomastia in AAS users

NFL now

•Testing: •Pre-employment: free agent or rookie •Preseason - training camp •Annually - at least once a year •Regular season / playoffs - 10 random players from each team weekly •Off-season - up to six times •Reasonable cause - anytime during employment Penalty: 1st offense = 4-game suspension, 2nd offense = 8 games, 3rd = 1 year All without pay !!

common synthetic testosterone

•Testosterone suspension - oldest and bioidentical to endogenous testosterone •Androgel or Testim = topical gel administration •Androderm or Testoderm = dermal patch administration

drugs on monitored list

•The following substances are on the 2020 Monitoring Program: •Anabolics: Ecdysterone •Stimulants: In-Competition only: - Bupropion (Wellbutrin) - caffeine - nicotine - phenylephrine (Sudafed) - phenylpropanolamine (decongestant - cough and cold) - pipradrol - ADHD, dementia - synephrine - fat burner? Narcotics: In-Competition only: Codeine, hydrocodone and tramadol - pain killers Glucocorticoids: In-Competition (by routes of administration other than oral, intravenous, intramuscular or rectal) and Out-of-Competition (all routes of administration). Mostly used as anti-inflammatory 2-ethylsulfanyl-1H- benzimidazole (bemitil): In- and Out-of-Competition. - antihypoxant, antioxidant, antimutagenic Beta-2-agonists: In- and Out-of-Competition: any combination of beta-2-agonists.

2000

•USADA - independent agency for Olympic sports in US (including Pan-Am and Paralympic)

2007

•WWE wrestler Chris Benoit kills his wife and 7-year old son, commits suicide. Has 10x normal level of testosterone, as well as Xanax and Hydrocodone in his body. •2007 Operation Raw Deal: •Joint operation of DEA, IRS, ICE, FBI, NDIC, USPS •148 federal search warrants = 124 arrests, seizure of 56 steroid labs across US, 11.4m doses of steroids, 242 kilos of Chinese steroid powder, 6.5 million $, 25 vehicles, 3 boats, 27 pill presses, 71 weapons. •2007: Marion Jones (won 3 gold, 2 bronze at 2000 Olympics) - admitted to using PEDs prior to 2000, IOC strips her of medals. In 2008 she serves 6 months in prison for perjury during BALCO investigation. •2007 Martina Hingis (5-time tennis Grand Slam champion, #1 in world) retires and does not fight positive tests at Wimbledon. Tested positive for cocaine (so low she would have passed military drug test). Banned for 2 years. •2007 Barry Bonds indicted on perjury and obstruction during BALCO investigation. Says he never took PEDS (was never tested positive). Found guilty in 2011, Verdict overturned in 2015.

Mark McGwire

•What do you think about Mark McGwire's assertion that he only took steroids for recovery and to avoid injuries, or that he repeatedly claimed to have only used low doses? • •What do you think of McGwire's statement regarding taking steroids, "there is no reason to even go down that road - it's an illusion?" Is it an illusion or do performance enhancing drugs have a very real impact? • •Do you believe Mark McGwire's comment that he would have been just as good a hitter had he not used steroids?

WADA drug definition

•World Anti-doping Agency (WADA): (must meet at least 2) 1) Has potential to enhance, or enhances performance 2) Represents an actual or potential health risk 3) Violates the spirit of the sport - "The essence of Olympism, the pursuit of human excellence, through the dedicated perfection of each person's natural talents; characterized by the following values: - Ethics, fair play and honesty - Health - Excellence in performance - Character and education - Fun and joy - Teamwork - Dedication and commitment - Respect for rules and laws - Respect for self and other participants - Courage - Community and solidarity

AAS action

•acts directly with androgen receptor •Converted by 5-alpha-reductase to Dihydrotestosterone (more potent agonist with androgen receptor) •Attachment to androgen receptor causes DNA transcription which causes contractile protein synthesis and muscle hypertrophy •Reduces release of catabolic cortisol (exactly how is not understood) •May increase # of myonuclei in skeletal muscle - allows growth beyond "genetic limits" •Converted to Estradiol (estrogen) via Aromatase enzyme

endogenous steroid

•testosterone known to exist since 1880s