Performance 1

Performance Enhancing Agents

Learning Objectives - To recognize drugs that can enhance physical

performance and the mental condition - To appreciate their limitations. - To understand the ethics related to their use.

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Introduction “The desire to take medicine is perhaps the greatest feature that distinguishes man from the animals.” William Osler (1849 -1919) Greek for a drug or medicine is “pharmakon” Prefix pharma = related to drugs Diversity of meanings: - Cure (remedy) Illusion that all drugs cure. “To cure sometimes, relieve often, comfort always.” - Poison - Magical charm : magic bullet, wonder drug

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Introduction

Legitimate place and role for medicines in disease Worrying when healthy persons used drugs to

improve performance (sports, cognition, Viagra), improve looks (Botox), or to handle problems that could be solved or accomodated by the individual (shyness).

“Pill for every ill”

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Drugs and Sports - “Doping” - World Anti-doping Association (WADA) - Why is doping wrong ? - What can be done to rid doping from sports ? - Anti-doping measures Prohibited List Testing - State-sponsored Doping - Blood doping - Game Theory and Doping

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Eric Liddell “And where does the power come from, to see the race to the end?” “From within”

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Lance Armstrong : “You can never win the Tour de France wiithout doping”

Marion Jones “ I am against performance-enhancing drugs. I have never taken them and I will never take them.”

“Doping” Doping : Use of artificial substances or methods to

enhance sporting performance. - First used in 1890s in connection with horse racing. - Dutch word “dop” = alcoholic beverage made from

grape skins. Zulu warriors for battle. Earliest performance enhancing agents were more

“food” - tonics (strychnine, coca), egg white, mushrooms (stimulant) - than drugs.

Growth of pharmaceutical industry in 20th century introduced “drugs” : amphetamines, steroids,

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“Doping” International efforts to control and eliminate doping

is spearheaded by the World Anti-Doping Agency (WADA).

Set up in 1999 by the International Olympic Council (IOC).

Rather late in coming - many cases of doping in Olympic Games prior to 1999.

Formed in response to embarrassingly high incidence of doping among competitors of the 1998 Tour de France.

World Anti-doping Code: Core document defining rules, regulations, policies, 8

World Anti-Doping Code

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Square: Green equal * sign Black background

WADA’s definition of a performance enhancing agent

Substance that fulfills at least 2 of the following criteria:

- Enhances performance - Harms the athlete - Against the spirit of sports

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Why doping is wrong

It is cheating “ The most important thing in the

Olympic Games is not to win, but to take part, just as the most important thing in life is not the triumph but the struggle. The essential thing is not to have conquered but to have fought well.” Olympic Creed

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Why doping is wrong It is not safe : Harms the athlete - Many of the substances used are “designer drugs”:

unapproved substances that have not been tested in humans.

- Of those that are known : Used wrongly and at inappropriate doses (eg: growth hormone, steroids)

It is unfair to those athletes who want to compete fairly.

It harms reputation of the sport and defrauds those who support the game.

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How to get rid of doping in sports

Test more and doping will end Raise the cost of cheating Legalize doping

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Test more and doping will end

Testing is under the purview of WADA: - Prohibited List of substances and methods. - In-competition and out-of-competition testing

of athletes (blood or urine samples). But over-testing may lead to false positives. - Highly sensitive and complicated tests. - Carried out in different laboratories.

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Testing works !

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Raise the cost of cheating Athletes cheat because doping is a rational choice - Drugs are effective and payoffs are high. - If you stay clean, you will be uncompetitive. - Risk of detection is low How to raise the cost of cheating ? - Increase substantially the penalty for getting caught - Extend punishment to other team members

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Legalize doping Because sports is inherently unfair - Athletes have inherently different abilities - Exposed to coaches, training methods and facilities

of differing standards. Sports is intrinsically harmful - Boxing, professional football

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Anti-doping measures: Prohibited List Substances prohibited at all times (in- and out- of-

competition) - Examples: Steroids, hormones (growth hormone,

erythropoietin, insulin), masking agents Substances prohibited in-competition - Examples : stimulants (amphetamines, strychnine),

narcotics (heroin, morphine) Substances prohibited in certain sports. In competition

- Alcohol (archery, automobile, karate) - Beta-blockers (shooting, archery, darts, golf) 18

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To increase the oxygen carrying capacity of blood : Increase stamina +endurance

To ensure that processes for collection of urine or blood samples are robust.

To prevent introduction of genes into cells that would lead to ↑ production of performance enhancing proteins.

Prohibited List of substances An open list

AAS = Anabolic androgenic steroids Loophole : Use (or make) something that is not listed. Designer Drugs 20

Prohibited List of substances Based on threshold values

Backhanded way of saying that if a drug is used below threshold limits, it is permissible.

Does not take into account inter-individual variations in breakdown and/or excretion of drug.

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Anti-doping measures: Testing Elaborate and strictly defined procedure. - Provide samples on demand. (“A” and “B” samples) These samples are kept for many years. - Refusal to provide is admission of guilt. - Results cannot be challenged. - Follow “strict liability” guidelines : guilty regardless

of intent or negligence. - “Non-analytical positive evidence” : Evidence of

purchase is sufficient to indicate guilt.

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Not examinable

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Not examinable

Anti-doping measures: Biological Passport • The biological passport looks for changes in the

individual physiology of an elite athlete that may be indicative of doping.

• Baseline is the athlete’s biological markers collected from blood / urine tests in- and out-of-competition over a period of years.

• Passport would eventually have 3 components: - Blood module to detect blood doping. - Steroid module to detect steroid doping - Endocrine module to detect doping with hormones

(eg: growth hormone) 25

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Claudia Pechstein : German speed skater 5-time Olympic Gold Never failed a doping test Irregularities were found in her blood passport.

Blood count and 8 blood variables (including “% retics”) % retics = % of immature red blood cells. During a competition (2007), her % retics were found to be very high. Returned to normal levels after competition. Found guilty of blood doping in 2009.

“Sports Greatest Cover-up” State Sponsored Doping

East Germany : German Democratic Republic - 1968 : 25 medals - 1972 : 66 medals - 1976: 90 medals - 1988 : 102 medals : ranked 2nd in medal tally Doping program was initiated in early 1970s - State Plan 14.25 - Involved scientists, doctors, coaches, government

ministries. Ministry of State Security (Stasi). - 30% of GDP to sports - Recruited promising athletes – supplemented

training with drugs. 27

Anabolic androgenic steroids (AAS)

Substances related to testosterone (male sex hormone).

- Anabolic : muscle building - Androgenic : masculinizing “They were very strong women. They were very fast. We thought they were machines. Here (we) were, four of America’s best athletes ever put together on a team, and every single day, the East German women were winning every event.” Observation of member of US swim team in 1976 Olympics 28

“Drips, injections, pills, It was all normal. Nothing strange about it and I wouldn’t have known what to ask, because I wasn’t sceptical at all. I didn’t start to look like a man overnight, it happened gradually. I wasn’t really aware of it myself but it was obvious to everyone else. And whether I wore a dress or a skirt, make-up or jewellery, it got worse and worse. They called me a transvestite or a gay, and it shocked me.”

Katharina Bullin, East German volleyball player

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Heidi Krieger 1986 Gold Medalist

European Championships in Athletics

Andreas Krieger (1997)

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“Sports Greatest Coverup” You can listen to the Podcast on BBC Discovery, Episodes 1 and 2. There is a summary that accompanies these podcasts. - To take note of how Plan 14.25 came to an end. - The fates of the victims and perpetrators - Who do you think should take responsibility ?

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Blood Doping

Blood doping refers to the expansion of erythrocyte volume by artifical means.

Erythrocytes (red blood cells) transport oxygen. More erythrocytes greater oxygen carrying capacity Translates to greater stamina and endurance. Downside : blood becomes thick and viscous. Danger of clot formation, stroke. Blood doping is popular with endurance athletes :

cyclists, marathoners, triathletes, cross country skiers.

How to increase erythrocyte volume ? 32

Natural Means Training or living in high altitudes. Low oxygen in atmosphere causes body to produce more erythrocytes. Sleeping in a “low oxygen” tent Use of xenon gas Rare gas Used as an anesthetic gas in Russia Increases level of erythropoietin (EPO) – a hormone that induces formation of erythrocytes.

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Unnatural means Transfusion of erythrocytes Athlete receives from someone else (homologous transfusion) Athlete receives his/her own erythrocytes (autologous) Complicated process, cannot be done just be one person. Athlete will receive erythrocytes 1-7 days before competition. Erythropoietin (EPO) Naturally occurring substance (hormone) that increases production of erythrocytes. Given by injection. Gene doping : introduce EPO gene into cells

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EPO EPO is a drug for renal failure Two main types of EPO: recombinant EPO and

biosimilars. (i) Recombinant EPO Earliest to enter the market EPO gene is inserted into non-human cells EPO protein. α-epoietin (Epogen by Amgen), β-epoietin Not identical to human EPO, but performs same function. Patents on these products have expired.

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EPO (ii) Biosimilars (“follow-on biologics”) Equivalent to generics Products of biotechnology Same function as α or β-epoietin but structurally not identical. Significant impact on testing because tests were designed to detect α or β-epoietin.

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Game Theory and Doping Game theory has been used to explain the widespread abuse of drugs in sports. Game theory deals with conflict of interests between

parties who know each other’s preferences but not their actual decisions. Theory deduces the best course of action for the rational player.

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Game Theory and Doping “Prisoner’s Dilemma” You and your partner are arrested for a crime. You are held in separate cells and are unable to communicate with each other. You are offered the following options: If you confess but your partner does not, you go free and he gets a 3 year jail term. If he confesses but you don’t, he goes free and you get a 3 year jail term. If both of you confess, each will get a 2 year jail term If both of you remain silent, each will a 1 year jail term.

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Game Theory and Doping “Athlete’s Dilemma” (Economist July 20th 2013) Involves not only athletes but the testing organization as well as the fans/sponsors. Athletes : Rational choice is to cheat. Testers: Test thoroughly or test ½ heartedly? Rational choice is to test ½ heartedly. Fans /sponsors : What is their rational choice ? Solution according to Game Theory ?

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Drugs and the Mental State - Turbo-charging the brain : cognitive enhancing drugs Do they work ? Ethical issues - Drugs and Emotion Prozac and depression Medicalization of mental conditions : Diagnostic and Statistical Manual of Mental Disorders (DSM)

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Limitless (2011)

Cognitive Enhancers : “Smart” Drugs

Drugs that improve memory, concentration, planning, problem solving and decision making. Also called nootropics (“mind-bending or turning”) or

Neuroenhancers Do they exist ? Do they really work ? By analog to doping in sports, is it ethical to use these drugs?

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Scientific American, Oct 2009, p 46 44

Amphetamines

Amphetamines are stimulants. World War II : given to soldiers to keep them awake and to booster courage. Paradoxically, they are used to treat Attention

Deficit Hyperactivity Disorder (ADHD) Anecdotal evidence that amphetamines are widely

used in campuses to improve grades, increase capacity for learning, achieve greater focus.

Mood elevation and impulsivity mean that users tend to over-rate themselves and their outputs.

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“Recently in a university hall somewhere in Singapore, two students passed out at their desks while in the throes of an exam. The chief invigilator ascertained that they had been popping pills which purportedly boost one’s mental horsepower. The two said they were introduced to this practice by some in the then graduating class, who continue to use these pills at work to this very day.” Straits Times. Andy Ho “Think before you pop brain-boosting drugs.”

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The “Always on” Drug : Modafinil

Tradename : Provigil , 1998. Treatment of excessive daytime sleepiness (narcolepsy) Subsequently approved for “shift work disorder” Rejected by FDA for ADHD Off-label use: For fatigue related conditions among military personnel, air traffic controllers and jet-lag. Mode of action – unknown. Long term effects – unknown May have addictive potential.

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Can too much memory power be a bad thing ?

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Solomon Shereshevki Forgets nothing. Incapable of analytical thought. “Selective forgetting of the useless is as important as selective remembering of the useful.”

Ethical Issues Is it safe ? - Affects the brain - Deemed safe if used within guidelines of permissible use, not unregulated off-label use. - Risk of side effects : Consider trade-off . Is it fair? - Analogy to drug use in sports is incorrect. Would it lead to a situation where everyone is force to take it (coercion) ? - Military : no choice - Grey zones : Should a school compel all students to take it to improve rankings ? 50

Is it ethical? American Academy of Neurology declared that it is not unethical for doctors to prescribe brain boosters to normal persons. - “The mere fact that cognitive enhancers are drugs is no reason to outlaw them” - New practice that will gain acceptance with time - Means of controlling use and preventing abuse.

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Drugs and Emotion

Prozac is possibly the most influential drug used in mental illness. Used to treat depression. Introduced in 1988. Through books and movies, it has helped fuel social acceptance of antidepressant use Shorthand for antidepressants “Prozac moment” 2010: Antidepressant use: 1 in 10 people in Europe. 11% of people over age of 12 Prozac – 3rd most common prescription drug in US

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Drugs and Emotion

In 2012, new studies caused a re-thinking about the clinical effectiveness of antidepressants. No better than a sugar pill (placebo). Wide usage due to smart marketing by Pharma Industry. Mode of action still remains unclear. Does not just increase serotonin levels in brain but may actually cause re-wiring of certain parts of brain linked to emotion. Or even induce growth of new brain cells in those parts.

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Diagnostic and Statistical Manual of Mental Disorders (DSM)

Influential publication that lists psychological disorders and symptoms used to

diagnose it. American Psychiatric Association Influence diagnosis, treatment and who pays for the

treatment. - DSM-1 (1952) Mental illness as a response to experience and environment. - DSM-3 (1980) and DSM-3 (1994): Checklists of symptoms as diagnostic criteria. “Diagnostic silos” Increase in the number of mental conditions with each revision. 106 (DSM 1 + 2) 265 (DSM 3) 297 (DSM-4)

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Diagnostic and Statistical Manual of Mental Disorders (DSM)

DSM-5 was published in May 2013. “By the Book” Economist May 18 2013 Key features: - Reduce “diagnostic silos” because of evidence from genetic studies and brain imaging. - Has not reduced the number of mental conditions

(diagnostic inflation). A psychiatric diagnosis is an important turning point

in anyone’s life. Done well Life improving treatment. Done poorly Inaccurate label, harmful treatment 55

Diagnostic and Statistical Manual of Mental Disorders (DSM)

DSM-5 was published in May 2013. “By the Book” Economist May 18 2013 Key features: - Reduce “diagnostic silos” because of evidence from genetic studies and brain imaging. - Has not reduced the number of mental conditions

(diagnostic inflation). Mourning a death – depression. Binge eating : eating to excess at least once a week

over past 3 months. Asperger’s disorder (high functioning autism) :

classified as a learning disorder.

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A psychiatric diagnosis is an important turning point in anyone’s life. Done well Life improving treatment. Done poorly Harmful treatment, lower self-confidence and reduce self expectations