An analysis of the long-term effects of performance-enhancing drugs

Our celebrities have meltdowns, chop off their hair, interrupt awards shows, and get pulled over driving drunk. And, for punishment, they get to tour the talk-show circuit, sign new contracts, and revitalize their careers. Politicians sleep with interns, misappropriate funds, email pictures of their less-public sides, and, sometimes, still win elections. Even when our athletes cheat on their wives repeatedly, their “brands” are often salvaged by means of a simple “image readjustment.”

In cycling, however, forgiveness is a foreign concept.

A first offense for doping — what would amount to sitting on the bench for a few NFL games — often brings a two-year ban in cycling. It can end a career. And for those who do return, they are sometimes faced with cold shoulders and limited contract opportunities. Lately, even our heroes are rewarded for their grand tour victories with cries of “not normal” and demands for power files and blood profiles.

It doesn’t quite seem fair. If Toyota can build cars with life-endangering flaws, then apologize, offer a factory recall, and be forgiven, how hard is it, really, to excuse a few pro cyclists?

Some claim that there is good reason not to forgive. While WADA bestows a two-year suspension, partially to ensure any gains from doping have cleared an athlete’s system, some believe that a temporary ban, no matter how long, isn’t long enough.

Years of cycling while doped, the thinking goes, allowed athletes to train abnormally hard, resulting in increased capillary and mitochondrial density and improved oxygen delivery, all of which are permanent benefits. Some believe these athletes would have an unfair advantage no matter when they returned.

“That is the most ridiculous thing,” said Christian Vande Velde (Garmin-Sharp) when asked if the effects of doping were permanent. Like his Garmin teammates Tom Danielson and Dave Zabriskie, Vande Velde served a six-month, off-season ban from the sport after admitting to doping while supporting the United States Anti-Doping Agency investigation into Lance Armstrong. “I didn’t dope that much. It was just a few times. It didn’t even help that much … but it’s crazy to think that there’s some long-term effect or benefit.”

Proponents of lifetime bans are quick to counter with the fact that many cyclists, such as Zabriskie, Vande Velde, and Levi Leipheimer, enjoyed their best results after they claimed to have stopped doping. “It shouldn’t add up that these riders, who improved with doping, would continue to perform at a much higher level after doping,” pointed out one Velo reader. (And, of course, this assumes that they all actually stopped doping when they said they did.)

Jonathan Vaughters, Garmin-Sharp team manager and an admitted former user of PEDs, attributes those performance increases to the sport cleaning itself up. These riders are only better relative to other, now-clean cyclists. Zabriskie also attributes it to a change in approach. Where athletes used to just focus on what to take and when, now it’s about adhering to legitimate training science. “Me and Christian… we never trained as hard as we train now,” Zabriskie said in August, at the USA Pro Challenge, before announcing his retirement. “It’s not the same. It wasn’t the same level. There weren’t guys like [physiologist] Allen Lim out there measuring lactate, figuring out inflammatory diets, with rice cakes and special electrolyte drinks,” he said.

This debate is heated and emotionally charged, with members of each side claiming strong science to back their beliefs. But the fact is, as Vaughters puts it, the science is imperfect. “We’re relying on studies from rats and cancer patients,” he said. Few are willing to admit that their evidence is mostly anecdotal.

We’ll attempt to strip out the emotions and hyperbole and see what the science does and does not say. Then you can decide how forgiving you want to be.

Doping vs. The body

Possibly the best argument for forgiving our flawed heroes rests in the fundamental driving force of our physiology itself — homeostasis, or state of equilibrium. Simply put, homeostasis means that our bodies strive to stay in balance.

At the forefront of this “lasting-effects debate” are two researchers in Europe, Dr. Cristóbal Belda-Iniesta and Dr. Jo Bruusgaard. Belda-Iniesta is the head of the Biomarkers and Experimental Therapeutics for Cancer Group at Madrid’s University Hospital. His research on cancer markers has led to novel ways to identify doping even years after the fact. He looks for changes in homeostasis; according to Belda-Iniesta our bodies are, naturally, very well balanced. Almost everything in our bodies has an equilibrium point — a set body temperature, fluid volume, hematocrit, blood sugar, and countless others.

Our bodies respond to anything that stresses these levels. The classic example is our set 98.6-degree Fahrenheit body temperature. When it gets hot, we’ll sweat, and when it gets cold, we’ll shiver, but our bodies attempt to stay at 98.6 degrees.

Homeostasis also explains our training adaptations. You may lift weights with the desire to get stronger and impress your friends, but that’s not what motivates your body. Lifting weights damages muscles, which is another homeostatic stress. Do enough damage and the body will say, “I don’t like this damage so I’m going to build the muscle back bigger and stronger. That way, the next time this stressor is thrown at me, I can homeostatically handle it.”

Detraining is just the reverse. Remove the constant stressor and your body will no longer feel a need to maintain such large muscle tissue. Soon enough, you’ll have to head back to the gym.

And how does homeostasis accomplish this amazing balance? Hormones. Sensors throughout our body detect any imbalance and tell the brain to release the appropriate hormones to make us sweat, feel thirsty, release glucose, or whatever may be needed to restore balance. Once the stressor is gone, the hormones break down.

Most doping products are just synthetic versions of our natural hormones. They use the body’s normal pathways, but they fool our bodies into responding to a bigger stress than what’s really there. They intentionally cause the body to get out of balance. But, as Belda-Iniesta pointed out, “Athletes don’t need to be balanced at the time of competition.”

“Our bodies try to balance even artificial changes in our bodies,” he said. So, once the athlete stops taking doping products, what’s left in the system will break down rapidly and the body will, over time, find its true levels again. The athlete will “detrain,” no differently than if he had simply reduced his training volume. When asked how long this would take, Belda-Iniesta replied, simply, “Months.”

All gains, honestly achieved or not, dissolve. Mitochondrial and capillary density, often cited as permanent benefits of doping, start decreasing within days. Slow-twitch muscle fibers convert back to fast twitch in short order, and improvements in VO2 max can be reversed in 12 weeks.

Doping vs. Muscle memory

In order for doping to get around homeostasis and have any lasting benefit, it would have to find a way to create a “memory” in our bodies. Look to our immune system for an example; we can only fall ill once from any specific virus before we generate antibodies.

And here, again, the science is mixed.

When a relatively new athlete detrains, he loses everything. But many studies have shown that when experienced, long-term athletes detrain, they lose a lot, but not all. Capillary density and VO2 max both remain above baseline. There appears to be a permanent shift in homeostatic balance.

Among strength athletes, there is something called “muscle memory.” These athletes find that if they build muscle mass and then let it atrophy, they can build it back much more rapidly, even years later.

Dr. Jo Bruusgaard and his team at the Department of Molecular Biosciences at the University of Oslo were studying muscle memory when they discovered a potentially permanent effect of testosterone doping.

Bruusgaard was studying myonuclei content, a fancy term for the number of nuclei in muscle cells. Nuclei are the protein factories of our bodies. Most cells have one nuclei, but muscle cells are huge, needing a lot of protein, so one cell can contain thousands of nuclei, according to Bruusgaard.

For a muscle cell to grow bigger and stronger, it has to first increase its myonuclei number to handle the larger protein demand — in essence, this constitutes a process called hypertrophy.

Bruusgaard studied this effect by administering a single dose of testosterone to mice. He found that the testosterone dramatically increased the effects of training on myonuclei numbers. In fact, testosterone alone had a bigger impact than training. After three months of detraining, the muscles shrunk, but the nuclei stuck around.

Bruusgaard pointed out that three months in the life of a mouse is equal to about 10 years in a human. “There is a good chance the increase in the nuclei is forever. There have been a lot of studies on the age of nuclei in humans and they seem to be as old as the humans carrying them,” he said.

The benefits of this testosterone-enhanced “muscle memory” is obvious for strength athletes, but what about for endurance athletes, for whom large muscles can be a disadvantage?

The slow-twitch fibers that we rely on actually have a naturally higher nuclei content. We need more of these little protein factories to handle all of our muscle recovery demands. According to Bruusgaard, a higher number provides a big advantage when we’re training hard and dealing with small damages in the muscles.

In his studies, testosterone had a greater impact on the myonuclei of slow-twitch muscles.

But before you go grabbing your pitchforks, remember that the most important question here is dosage. Cyclists who have doped with testosterone have done so with far lower doses than power lifters.

Testosterone was most typically used to address the fatigue at the end of three-week stage races, from Vaughters’ experience. “You’d be at a 200 to 300 range [of testosterone]. Using the patch for a short period of time would potentially increase that from 200 to 275, which is still a very low end of normal,” he said. Anything higher would immediately test positive. But he added, “This isn’t for a second, a justification to use testosterone.”

Bruusgaard reinforced this point, “In terms of cycling, I don’t know how much hypertrophy you’d want and I don’t know if these doses increase myonuclei. That is the question we are actually addressing here.” With research just beginning to ramp up, it could be years before the findings are published.

Doping vs. Genetics

Even more powerful than homeostasis, however, is our genetics. And our genetic makeup doesn’t change. Or does it?

Both Bruusgaard and Belda-Iniesta are looking at a branch of genetics called epigenetics in the fight against doping.

We’ve all seen pictures of our chromosomes as nicely organized Xs and Ys. The reality is they don’t normally fit in a cell like that. Instead, they are wound together. A better image of our genes would be a giant ball of twine (called the chromatin structure.) You might have a great gene for endurance sports, but if it’s at the middle of that ball, it doesn’t matter.

Epigenetics is the study of how our bodies rearrange that ball, turning genes on and off, to improve how we maintain homeostasis. As Belda-Iniesta describes it, our genes are like computer programs. We still get to choose which programs we install on our computer to make it work better.

“Your epigenetic changes should be maintained all the time,” Belda-Iniesta said. “The epigenetic effects should be in the program of your cells.” These epigenetic changes are sometimes long lasting; studies have shown they can be passed on to your children. More importantly, scientists are demonstrating that both training and doping can potentially alter epigenetics.

In a recent study by Dr. Jonny St-Amand and his colleagues in Canada and Japan, endurance training increased the activity of several key genes and, after 12 weeks of detraining, these genes remained highly active. This led the researchers to conclude that changes in gene expression created “memories of previous training.”

But before we get too excited and petition to ban the children of dopers for life, remember that there are few studies of the effects of doping on epigenetics, let alone the long-term effects. Just like all things in the body, epigenetic changes can be reversed. This is very new science.

Doping vs. Bad memories

Even if the effects of doping are lasting, there is nothing saying they are all good. Vaughters was surprised when he first read about this debate. “When I saw this argument that there’s this permanent change in performance, my initial reaction was, ‘Yeah, there is, but it’s negative. Doesn’t everyone know that?’”

The drug of choice for cyclists over the past decade has been EPO, and it paints a grimmer long-term picture. EPO appears to produce no structural improvements even in the short run. It does not affect capillary density, muscle size, or muscle fiber type. It does not produce the sort of benefits that last.

“What I have anecdotally noticed is that while people are taking erythropoietin — while I was taking erythropoietin — there is certainly an increased training load possibility,” Vaughters said. “But I have also noticed that when you cease taking the drug, there is a sort of backlash — since your bone marrow receptors have been over-occupied with erythropoietin, your body basically shuts down red blood cell production for a while and the bone marrow isn’t as receptive to natural erythropoietin.”

Vaughters said he has seen riders drop well below their pre-EPO baseline abilities, and claims the effect last years in some cases.

The effect is called erythropoietin hyporesponsiveness. It’s well documented in cancer patients who take large quantities of EPO to stay alive. EPO receptors become desensitized and there can even be damage to bone marrow where red blood cells are produced.

More concerning still is a condition called pure red cell aplasia. When medical patients are maintained at high doses of EPO, the body can develop antibodies against EPO itself; these antibodies are unable to distinguish between natural and synthetic forms. The result is a permanent and sometimes dangerous reduction in red blood cells.

Of course, as Vaughters pointed out, the EPO he took over his entire career amounted to about the quantity a cancer patient would receive in one month. He saw these consequences far more in cyclists who rode in the mid-90s, before there was a 50-hematocrit limit and biological passports. These riders couldn’t compete after they stopped taking EPO. For later generations who micro-dosed, he admitted that these long-term consequences were less likely.

With the potential consequences, it’s interesting that in an anonymous study of why cyclists doped, many riders said they felt they needed it for their health. They were convinced that these products were necessary to survive the rigors of such a tough sport.

Doping vs. Opportunity

While the science behind the lasting physiological effects of doping is still in its infancy and unclear, there is one way in which doping clearly has a lasting effect — opportunity.

Most cyclists who used PEDs, because of their results while doped, were able to gain access to better teams, better doctors, and better coaches, not to mention more fame and its rewards. Many still have this access.

In his book The Secret Race, Tyler Hamilton wrote about how he was finishing in the third group on the road before he started doping. He also implied that doping ruined his career. But who would buy a book from a little-known clean rider who spent his career finishing at the back of the peloton? As Olympic champion Nicole Cooke pointed out, Hamilton made more money from his book on doping than she did during a career of clean racing.

Vaughters feels that changing the sport begins by forgiving, and allowing the truth to flourish. He pointed out that by helping past dopers be honest, we can learn the patterns of behavior and how to better identify them. You’re going to get there faster “than if you condemn anyone who’s ever admitted,” he said. “What’s the motivation for anyone to ever admit?”

Ultimately, it’s up to each of us, individually, whether we want to forgive, whether we feel these cyclists have had an unfair lasting advantage, be it physiological or in opportunity.

But perhaps what’s most important is the lasting effect on the sport itself. In the study on why cyclists doped, a key reason was because of pressure put on them by the elder statesmen of the sport. Now these past dopers are the elder statesmen. They have the opportunity to do something different: To come clean, serve as lessons, and work to create a culture of clean sport for the next generation.

If they can make that the true lasting effect of their doping, perhaps we can find it a little easier to forgive.

Trevor Connor is a long-time cycling coach and researches both exercise physiology and nutrition at Colorado State University. This story originally appeared in the February 2014 issue of Velo magazine.