The Chemical Drive to Do Better
The fictional scenario is simple: You are world-class athlete and are offered a banned substance with two sure-fire guarantees. First, you will not be caught, and, second, by taking the substance you will definitely win. Knowing that any self-respecting competitive athlete is in it to win it, what would you do? Would you swallow your pride with the pills all the way to victory?
If you are like the Olympic weightlifters that were asked this question, you would. Of the 198 athletes that were anonymously surveyed in 1995, only three said they would not take it. But what if, after winning every competition for five years, taking the undetectable substance would kill you. Would you take it then? More than half of the athletes polled still said yes.
In the real world of doping, the numbers might not be that different. As the amount of personal and Congressional testimony increases, and the burden of proof builds for more and more athletes (I’m talking about you, Floyd Landis and Barry Bonds), the widespread use of so-called performance-enhancing drugs is clear. Although anabolic steroids have historically received the most attention in sports as a way to bulk up, lift more, or hit harder, a number of other substances are also widely used, including human growth hormone (hGH), erythropoietin (EPO), and amphetamines. What’s not as evident is to what degree they really do enhance performance, and at what costs? After all, we play in a world without guarantees. So to better answer that question, let’s take a look at the science behind the supposed performance benefits and the potential adverse effects of the most dubious substances circulating in the bodies of our highest-level athletes.
Biochemically, steroids come in many flavors. A steroid is any of a number of organic compounds having 17 carbon atoms arranged in four rings, including cholesterols, sex hormones, and the precursors of certain vitamins. In the sports world, however, all steroids are anabolic, meaning they work to boost muscle growth. Anabolism is literally the biochemical process responsible for making bigger things out of smaller things and anabolic steroids are steroids that have been modified many times over to maximize these effects.
Specifically, anabolic steroids are chemical derivatives of testosterone, the natural hormone responsible for male sexual characteristics and muscle growth. Testosterone itself isn’t a doping agent because when it is taken by mouth or injected it is rapidly inactivated. However, chemists eventually discovered that by adding or removing carbon and hydrogen molecules to testosterone they could create new steroids that were more potent, longer-acting, and suitable for oral dosing (see Figure 1). Bet jocks were never happier about science than the day they found 17a-methyltestosterone and epiandrosterone!
Now, one steroid on that list that falls just this side of the banned steroid line is the Mark McGuire-endorsed supplement andro-stenedione. Marketed as an over-the-counter aid that raises testosterone levels in the blood, andro is one of the body’s naturally occurring precursors to testosterone. Making andro is one step in the chain of biochemical reactions that produces testosterone. Thus, it’s thought that if you increase the amount of andro in your body by swalling gobs of it in pill-form, you will increase the levels of testosterone, ultimately increasing anabolism.
Whether it’s increased levels of testosterone (via andro) or another anabolic steroid, the action at the cell level is thought to be generally the same. The molecule passes into the cell after binding to its receptor and stimulates protein synthesis and muscle growth. High doses of anabolic steroids are also thought to block the action of circulating molecules that stimulate protein breakdown. The overall effect of this is a bump in the size of individual muscle cells and entire muscle groups, and a cut in total fat – the kind of results that raise everyone’s collective eyebrows.
In one study of anabolic steroids on body composition, 21 weight-training men were randomly assigned to get either anabolic steroids or placebo for 12 weeks. As you might expect, the fellas that got the goods had significantly larger arm girth and thigh circumference than the guys that got the sugar pills. In addition to the increases in muscle size, several studies have shown that extra-high doses of anabolic steroids also increase strength, even without strength training. In one placebo-controlled trial, weekly steroid doses increased strength in bench press and squat for participants that were both training and not training. Now, whether or not greater strength makes someone a better athlete is a philosophical question, but there is no doubt that a stronger person will tackle harder or hit the ball farther if done in the same way.
For a closer look at the balding, ball-shrinking side effects of anabolic steroids, I refer you to the companion piece.
Human Growth Hormone (hGH)
If you compared Andre the Giant and General Tom Thumb side-by-side, you’d have some idea of what growth hormone does in our bodies. (If the name didn’t already give it away, that is). Unsurprisingly, human growth hormone is a protein that is made, stored, and released by the pituitary gland, a small hormonal powerhouse at the base of the brain, which promotes growth. People who are deficient in it are short in stature; those who have it in abundance are, literally, giants.
Ironically, human growth hormone (hGH) is the pharmaceutical and colloquial name for the synthetic version of the real growth hormone (GH) found in humans. (In the medical field, we just call it growth hormone, because where else would it really come from?) And as far as proteins go, GH is small but mighty. Chemically, GH is only a single-chain of 188 amino acids, the building blocks of protein synthesis. But physiologically, GH has numerous effects that can be globally defined as anabolic, with a main goal of height growth. At the cellular level, GH induces the accelerated passage of amino acids into cells. Proteins are made, enzymes are activated, and cells grow and divide. Cartilage cells in the ends of growing bones are stimulated to multiply. Over in the liver, GH activates another hormone (insulin-like growth factor 1) that independently stimulates growth. In a normal physiologic system, GH helps build protein, break down fat, and regulate our fluid composition. It is involved in a complex combination of events designed to ensure a steady supply of calories while sparing protein destruction in order to build bone, muscle, and cartilage. However, unless you are deficient in GH or are yet to hit your growth spurt, you’re not likely to care much about bone growth.
But, ready-made for abuse, in supra-physiologic doses the non-bone growing effects of hGH (the bones are mostly closed for business) are accentuated. In sports, mass is often what matters, and GH has been shown to increase tissue bulk. It’s just not what you would think. Studies show that the muscle size of hGH abusers increases because of water retention, not actual protein concentration.
Accordingly, why hGH has popularized as a doping agent is not clear. There is one review study that suggests GH might have a role in maintaining the strength of connective tissue in muscles and tendons. Anecdotal reports from bodybuilders and baseball players support that idea. Among dopers, it is believed that tendons are the “weak link in the chain” in those with fast-growing muscles (such as those caused by anabolic steroids) and GH helps prevent tendon or muscle rupture. Thus, it is theoretically possible that hGH supplementation would allow an athlete to train at a higher intensity or reduce recovery time between exercise. But as of yet there is not one single study that shows improved athletic performance as a result of taking hGH.
On the other hand, the risks of hGH are well documented. From experience with acromegalics (individuals with abundant GH), it is known that high levels of GH over long periods of time can actually lead to muscles that are degenerative. At any dose, GH leads to insulin resistance making you prone to diabetes, and carpal tunnel syndrome and leg swelling are common. Recent studies have also shown GH to make pre-existing cancer more aggressive and deadlier -- and if you are buying your hGH from someone with a cadaver for a supplier, reports of Creutzfeldt-Jakob disease have been reported! Although in that case, calling it Mad Cow disease wouldn’t do it justice.
Erythropoietin (EPO)
For endurance athletes, oxygen is like, well, oxygen. (It’s about as precious as a substance can get.) We all need oxygen to live, but having a higher oxygen-carrying capacity can also provide a tremendous advantage to an exercising muscle. More oxygen means less lactic acid production, less pain, and less fatigue. This aerobic advantage is evidenced by the popular training slogan “live high, train low,” referring not to drugs, but to the altitude, which is the inverse of the oxygen concentration around you. Regularly exposing yourself to lower partial pressures of oxygen stimulates the production of red blood cells, the principal carrier of oxygen from our lungs to our tissues, in order to make up the difference. In humans, the hormone erythropoietin jumpstarts this process.
Thus, the rationale for erythropoietin (EPO) as a doping agent is simple arithmetic. If you want to increase the capacity of delivering something (oxygen) somewhere (your muscles), you can either increase the number of transporters (red blood cells) or the load on each one. Since you can’t very well increase the ability of each individual red blood cell, you have to find a way to create more of them. Once upon a time, athletes used to dope their own blood by “donating,” storing, and transfusing it back to its original location after a period of recovery. Nowadays, EPO seems to do the trick just fine.
Erythropoietin is a hormone naturally produced in the kidney in response to low oxygen levels in the blood. Once released, EPO binds to receptors on cells in the bone marrow to stimulate an increase in red blood cell differentiation. Increasing the number of red blood cells increases the measured values of hemoglobin (the oxygen-transporting protein in red blood cells) and hematocrit (the proportion of red blood cells in total blood volume). A rise in the hemoglobin of 1gram/deciliter, or about 7-8%, increases maximum oxygen-carrying capacity (VO2max) by 335mL, also about 8%. Once aerobic exercise starts, oxygen is required in order to continue; otherwise, acidic by-products build up and produce painful exhaustion. Obviously, for most of us, this is difficult to maintain. Depending our level of fitness, we may “feel the burn” and tire out after, say, 20 minutes of light jogging. Olympic-level cyclists on the other hand need to be able to last longer and, in multiple studies, the enhanced oxygen availability created by EPO doping results in a more efficient use of energy and a longer time to exhaustion.
But there’s always a but. High hematocrit levels, called polycythemia, increase the risk of stroke, heart attack, and blood clots, which can be fatal if they travel to the lungs. In 1987, the first year of EPO use in Europe, five cyclists died of unexplained reasons; between 1997 and 2000, 18 cyclists died. More blood is not always a good thing.
Amphetamines
Amphetamines, otherwise known as speed, uppers, pep pills, or “greenies,” were recently thought to be the most commonly abused drug in professional baseball. Before Major League Baseball started testing for them in 2006, some people estimated that as many as 75% of players regularly used amphetamines, not to mention other stimulants like ephedrine. (Insert joke about how boring baseball is here).
Simply put, amphetamines are stimulants. Through indirect activation of the sympathetic nervous system, responsible for the infamous “fight or flight” response, amphetamines increase alertness, physical activity, and overall energy. And as seen in Figure 2, they exert their effect in several ways. In blood vessels, certain types of muscle, the brain, and the heart, the drug binds directly to receptors (alpha 1; beta 1 and 2; D; and Ado). Yet in other places, as dictated by the parent organ’s main action, the drug affects neurotransmitter (NT) release or reuptake back into the original cell. Since the main neurotransmitter involved, norepinephrine, increases concentration and decreases tiredness, amphetamines have been used for the treatment of narcolepsy and attention-deficit hyperactivity disorder.
Figure 2. Amphetamines act on nerve cells. These stimulants work by either binding directly to cell surface receptors or by increasing the release and/or inhibiting the reuptake of neurotransmitters, which are then available to bind to and activate receptors. From: Bouchard: Clin J Sport Med. 12(4): 209-224.
But unless there’s a biologically implausible connection between narcolepsy and athletic ability, it’s safe to say that the abundance of amphetamine use in sports is not therapeutic, but ergogenic. A few poorly designed studies suggest that various amphetamines do improve certain aspects of athletic performance. In a study of middle-distance runners (less than one mile), where they timed themselves in variable weather conditions, taking amphetamines a few hours before the race increased times by about two percent. In a different study, cyclists who took methamphetamine had longer times to exhaustion, but no significant difference in VO2max. Although even harder to quantify, amphetamines have been associated with increased aggression, enhanced concentration, and decreased pain among athletes. Referred to as “the Sunday syndrome,” professional football players hopped up on speed report being more likely to feel revved up as well as play hurt – although it should be noted that the doses taken by wide receivers to improve concentration (5-15mg) were much less than the doses taken by linemen to increase aggression (30-150mg). While it’s not clear if athletes are more interested in amphetamine effects on brain or brawn, there is evidence to suggest that it’s a combination of both. Although largely based on theoretical effects, amphetamines are probably best at improving performance in complex motor activities that involve intense concentration and attentiveness. Like, say, catching a football spiraling down the sideline or hitting a 95 mile-per-hour curveball.
However, it’s important to note that even these effects will decrease with time. In addition to norepinephrine, amphetamines also act via another neurotransmitter, dopamine, which plays a major role in its addictive potential. Regardless of why they’re taken, if they are used regularly, amphetamines can cause physiologic dependence and lead to addiction. The more you take, the more you need, and if you stop, withdrawal symptoms occur. And as the ergogenic effects decrease, the potentially harmful side effects increase. For example, although amphetamines may initially improve alertness and elevate mood, as tolerance mounts and users need more and more to achieve the same effects, fatigue and depression often result.
Amphetamines are dangerous drugs. In addition to drug addiction, regular use can cause anxiety, hallucinations, and paranoid behavior. Single doses can cause cardiac arrhythmias (irregular beating of the heart), high blood pressure, and dehydration. Additionally, the combination of increased aggression and decreased sensation of pain on the playing field might lead to more serious personal injuries as well as the potential harm of other players, officials, or spectators. Case in point. As if there’s just a lot of coffee and Red Bull in the locker room now, right?
Conclusion
Any self-respecting anything wants to do better. Comedians want to be funnier; models want to be more attractive; medical students want to score better on tests; and athletes want to run faster, hit harder, or be more focused. And with the widespread availability of chemicals that claim to improve performance on all different sorts, it is no surprise that drug abuse exists. It is also extremely unlikely that despite testing efforts, ergogenic aids in sports will ever go away. It is therefore critical that players, teams, and trainers are able to ask the right questions about available products. Does the substance enhance performance? Are there serious health side effects? What about in five years? Can I get addicted? None of the drugs discussed in this article are benign – and some don’t have much evidence to support their ability to improve performance. So, in the same way physicians must be cautious of pharmaceutical marketing ploys when making prescribing decisions, we must make efforts to insure that our athletes are truly making informed choices. Otherwise, the chemical drive to do better will remain fueled on empty promises and huge risks. Yield wisely.
References
Sportsology
You probably didn’t learn about the scientific method in your junior high gym class, and not too many post-game interviews touch on quantum theory. But don’t be fooled: the athletic and scientific worlds are not such strange bedfellows. Boxing, for instance, is often called “the sweet science.” And no less an expert than Ted Williams, perhaps baseball’s greatest batter, described his craft in his book, The Science of Hitting. We turn our focus to this intriguing relationship here in Sportsology, where we endeavor to examine the world of sports with a scientific eye. Sportsology will explore athletic topics you never knew you cared about, from the physics of the curveball to Olympic abstinence. We hope to arm you with knowledge to, at the very least, make you the most annoying person at the sports bar.
Companion Piece - “To Catch a Cheat: Testing in the Steroid Era” by Tom Hummer