Dr. Don H. Catlin and Performance-Enhancing Drug Tests

The Development of Key Performance-Enhancing Drug Tests

Since founding the UCLA Olympic Analytical Laboratory in 1982 and serving as its director for 25 years, Don H. Catlin, M.D., has been instrumental in discovering new performance-enhancing drugs and establishing methods to uncover athletes’ use of various substances. His research, while both conducting doping control and simply focusing on new and evolving drugs, has been vital in the creation of many of the tests currently used to detect performance-enhancing drugs. As the New York Times noted in 2007, “Some call Dr. Don Catlin… the father of drug testing in sports.”

He and his son, executive Oliver Catlin, founded the well-regarded supplement certification provider BSCG (Banned Substances Control Group) in 2004. The Catlins’ expertise is unparalleled and often sought on the more complicated issues facing both anti-doping research and supplement testing. Here, we’ll take a brief look at some of Dr. Catlin’s key performance-enhancing drug (PED) breakthroughs and where more information can be found about them.

Dr. Don Catlin, anti-doping pioneer

Renowned anti-doping pioneer Dr. Don H. Catlin in his Los Angeles laboratory in 2008. (Photo from The Catlin Consortium.)

Developed the CIR Technique to Distinguish Natural from Artificial Testosterone

In the late 1990s, Dr. Don Catlin was the first to develop and offer the carbon isotope ratio, or CIR, test to determine whether testosterone or an anabolic steroid has been made naturally by the body or has come from a prohibited substance. This highly accurate test was the first technique capable of detecting synthetic testosterone, rather than simply gauging the body’s reaction to the substance. Dr. Catlin used for comparison a person’s endogenous reference compound (ERC) such as cholesterol to help determine the body’s natural carbon make-up. The testosterone CIR test was considered revolutionary and has proven useful and highly reliable; despite many challenges by athletes testing positive over the years, the Court of Arbitration for Sport has never found any fault with it.

More Info

See an info-graph about his test put together in 2006 for the New York Times: http://www.nytimes.com/imagepages/2006/08/01/sports/02landis-graphic.html

Academic Publication

Catlin DH, Hatton CK, Starcevic S. Issues in detecting xenobiotic anabolic steroids and testosterone by analysis of athletes’ urine. Clinical Chemistry 1997;43:1280-1288.

First Reported Use of a Form of EPO (Darbepoetin Alfa) in Sport

While overseeing the drug testing at the 2002 Winter Olympic Games in Salt Lake City, Dr. Catlin revealed the use of a form of EPO, or erythropoietin, (darbepoetin alfa), for the first time in sport. He used a new test developed by French scientist Dr. Françoise Lasne to detect this long-lasting form of EPO, a then newly approved drug for anemia patients that helps boost red blood cells and aids in endurance but can lead to serious health outcomes such as heart attack and stroke. Three Olympic cross-country skiers, including gold medalists Larissa Lazutina of Russia and Johann Muehlegg of Spain, were suspended and their medals stripped after they were found using the substance in Olympic competition.

More Info

For a thorough introductory account of this story, read the nonfiction book “The Night Olympic Team” (Boyds Mills Press, 2008), written for older kids by Caroline Hatton, Ph.D., one of the scientists working in the Olympic lab under Dr. Catlin.

Academic Publication

Catlin DH, Breidbach A, Elliott S, Glaspy J. Comparison of the isoelectric focusing patterns of darbepoetin alfa, recombinant human erythropoietin, and endogenous erythropoietin from human urine. Clinical Chemistry 2002. 48: 2057-9. Full Text PDF

First Reported Designer Steroid, Norbolethone

In 2002, Dr. Catlin was the first to report the use of a designer anabolic steroid in sport. He identified norbolethone (or norboletone) for the first time in an athlete’s urine sample. Norbolethone had been developed in the 1960s as a treatment for growth and weight gain but was deemed harmful and never brought to market. Patrick Arnold and Victor Conte introduced it to athletes through the Bay Area Laboratory Co-operative (BALCO). Dr. Catlin’s discovery of the substance was a wake-up call that some athletes were abusing designer steroids. The Chicago Tribune named Catlin Sportsman of the Year for 2002.

More Info

More about norbolethone and Dr. Catlin’s original test can be found on PubChem, a website of the U.S. National Library of Medicine: https://pubchem.ncbi.nlm.nih.gov/compound/norbolethone#section=Top

Academic Publication

Catlin DH, Ahrens BD, Kucherova Y. Detection of norbolethone, an anabolic steroid never marketed, in athletes’ urine. Rapid Communications in Mass Spectrometry 2002. 16:1273-5.

Second Reported Designer Steroid, THG

In 2003, Dr. Catlin identified and developed a test for THG, or tetrahydrogestrinone, the second reported designer anabolic steroid. This discovery famously came from a sample contained in a used syringe delivered anonymously to USADA (United States Anti-Doping Agency), who subsequently passed it along to Dr. Catlin for testing. THG was the active ingredient in “The Clear,” a previously “undetectable steroid” created and distributed by BALCO to some top American and British Olympic and professional athletes. Dr. Catlin credited his large team of capable researchers and chemists with finding the substance and developing a new test for it, saying the accomplishments “took all the skills that are represented in this lab.” In 2009, Newsweek magazine named coach Trevor Graham’s decision to send the syringe to USADA one of the decade’s “Top-10 History-Altering Decisions.”

More Info

For more about Dr. Catlin and the BALCO story, read this 2004 Washington Post article by Amy Shipley: “One Mastermind Behind Two Steroids,” July 29, 2004. http://www.washingtonpost.com/wp-dyn/articles/A22151-2004Jul28.html

Academic Publication

Catlin DH, Sekera MH, Ahrens BD, Starcevic B, Chang YC, Hatton CK. Tetrahydrogestrinone: discovery, synthesis, and detection in urine. Rapid Communications in Mass Spectrometry 2004. 18: 1245-9.

Third Reported Designer Steroid, Madol or DMT

In 2004, Dr. Catlin identified madol, the third reported designer anabolic steroid. Madol, short for methylandrostenol, and also known as DMT, or desoxymethyltestosterone, (not to be confused with dimethyltryptamine) was the active ingredient in the third generation of “The Clear,” found during a raid of the BALCO lab in 2003. The steroid, a potent testosterone derivative that can seriously damage the liver and heart, was designed in the early 1960s but never made it to market. After being discovered in dietary supplements, DMT was made a controlled substance in the United States in 2010.

More Info

For more about DMT, THG, and BALCO, see the news article “Athletics: New steroid designed to fool drug-testers,” from Reuters, The New Zealand Herald, Feb. 2, 2005. http://m.nzherald.co.nz/sport/news/article.cfm?c_id=4&objectid=10009252

Academic Publication

Sekera MH, Ahrens BD, Chang YC, Starcevic B, Georgakopoulos C, Catlin DH. Another designer steroid: discovery, synthesis, and detection of ‘madol’ in urine. Rapid Communications in Mass Spectrometry 2005. 19: 781-4.

Multiple Reports of New Anabolic Steroids

In 2005, Dr. Catlin discovered five new designer anabolic steroids in dietary supplements sent to him for testing by the Washington Post. One substance found in the supplement Halodrol-50 closely resembled oral turinabol, the principal anabolic steroid abused by East German Olympic athletes in the 1960s and ’70s. Some 800 athletes later reported serious ailments after taking that steroid, referred to as “the blue bean.” Halodrol-50 was discontinued but a version called Halodrol resurfaced online in 2016.

Dr. Catlin also found the new designer steroid methasterone in the supplement Superdrol. This discovery prompted anti-doping authorities to focus on curtailing the sale and use of pro-hormone supplements, often toxic to the liver. WADA (the World Anti-Doping Agency) soon added the compound to its list of banned substances in sport, and in 2009 the U.S. Food & Drug Administration (FDA) raided Bodybuilding.com in part over the sale of the compound, which represented the largest enforcement action up to that time in the supplement industry.

More Info

See early Washington Post story, “Steroids Detected In Dietary Tablets,” by Amy Shipley, Nov. 30, 2005: https://www.washingtonpost.com/archive/sports/2005/11/30/steroids-detected-in-dietary-tablets/938990b4-5956-48a5-8804-7f5ae6d561e3/?utm_term=.9d357da69081

“Designer Steroids: Hide and Seek” by Amy Shipley, Bonnie Berkowitz, and Christina Rivero, Washington Post, Oct. 18, 2005. http://www.washingtonpost.com/wp-dyn/content/graphic/2005/10/18/GR2005101800648.html

“Forgotten victims of East German doping take their battle to court,” by Luke Harding, The Guardian, Oct. 31, 2005: https://www.theguardian.com/sport/2005/nov/01/athletics.gdnsport3

“Bodybuilding.com, LLC and Jeremy DeLuca Plead Guilty in Federal Court to Violating FDCA,” FDA News Release, May 22, 2012. https://www.fda.gov/ICECI/CriminalInvestigations/ucm305494.htm

Academic Publication

Catlin DH. Anabolic steroids. In DeGroot LJ, Jameson JL, eds. Endocrinology Elsevier Saunders 2006; 5th Edition: 3265-82. (Book chapter.)

First Report of the Designer Stimulant Methylhexaneamine

In 2006, in another analysis of a dietary supplement at the behest of the Washington Post, Dr. Catlin was first to identify the designer stimulant methylhexaneamine, a potentially deadly amphetamine-like substance. This compound was found in Ergopharm’s Ergolean AMP, a product formulated by BALCO chemist Patrick Arnold, who was then awaiting sentencing for his role there. The product was pulled from the market, but in 2011 USADA issued an official warning to athletes to avoid the dangerous stimulant in a range of supplement products after a rash of positive test results. Unlike some problematic supplement ingredients, this compound often could be found in supplement ingredient lists—under the names methylhexaneamine, 1,3-dimethylamylamine (DMAA), dimethylpentylamine (DMP) 4-methylhexan-2-amine, Geranamine, and geranium oil, extract, or stems and leaves.

More Info

For more information, see the original Washington Post story “Chemist’s New Product Contains Hidden Substance,” by Amy Shipley, May 8, 2006. http://www.washingtonpost.com/wp-dyn/content/article/2006/05/07/AR2006050700913_2.html

USADA Advisory “Beware: Your Supplement Could Cause a Positive Test,” June 16, 2011. http://www.usada.org/athlete-advisory-methylhexaneamine-and-dietary-supplements/

A Multitude of Contributions

Dr. Catlin’s contributions to detecting PEDs have extended beyond these remarkable breakthroughs. Among other things, he determined the pharmacokinetics of steroids such as androstenedione (“andro,” formerly sold over the counter) and DHEA, provided analytical consulting as part of government action to identify and expose designer drugs like the aromatase inhibitor 6-OXO and the designer steroid Tren in supplement products, and succeeded at adapting a test for the potent blood-boosting drug CERA (sold under the brand name Mircera) for equines.

More Info

For more information about Dr. Don Catlin and his current work safeguarding supplements, visit the BSCG website at http://www.bscg.org/.

Note: The term “designer steroid” is defined as a synthetic steroid derived by simple chemical modification from another steroid, often an anabolic steroid. The word “designer,” however, can refer to compounds that are either novel or recycled and repurposed as performance-enhancers. Today these problematic substances sometimes find their way into legally sold supplement products.

— Joseph Taylor

New Sports Doping Agent FG-4592 Not the Only HIF Drug Available to Athletes

fg-4592 What drugs are athletes using to dope? This is one of the most commonly asked questions in the realm of sports anti-doping. Recently the answer has been provided in glaring form. During the week of July 29, Dr. Don Catlin, BSCG’s chief science officer and former longtime director of the UCLA Olympic Analytical Laboratory, was interviewed by the New York Times regarding a new drug called FG-4592, which was detected in tests of at least two elite cyclists.

AstraZeneca, one of the drugs’ developers, summarizes FG-4592 as “a small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase. HIF is a protein that responds to oxygen changes in the cellular environment and meets the body’s demands for oxygen by inducing erythropoiesis, the process by which red blood cells are produced.”

FG-4592 is available in pill form and is orally active, unlike its cousin, recombinant erythropoietin, or EPO, which must be injected. Some have dubbed FG-4592 as oxygen in pill form. This new drug is a breakthrough for anemia treatment and other similar blood ailments.  doping-271623_640Unfortunately, an effective blood boosting drug in pill form is also the Holy Grail for endurance dopers. Though FG-4592 remains in third-stage clinical trials around the world, it is widely available as a research chemical on the Internet. Its apparent arrival in elite sport is troubling, yet predictable.

Similar to EPO, HIF drugs like FG-4592 help increase oxygen carrying capacity by spurring the production of red blood cells. Some researchers believe HIF stabilizers might be even more effective than EPO as they can help stimulate iron absorption and suppress the inflammation of cytokines.[1] FG-4592 was recently added to the WADA (World Anti-Doping Agency) Prohibited List for 2015, as have cobalt and other HIF stabilizers and activators in general.  No other HIF drugs are named though they would be prohibited if they are detected.

According to PubChem’s listing of Chemical Vendors, there are 18 suppliers of FG-4592 worldwide . One of the vendors, the Houston-based company APExBIO, has eight HIF-related biochemicals available on its website including BAY 87-2243, 2-Methoxyestradiol, PX 12, ML 228, KC7F2, Chetomin, DMOG, and its top seller, IOX2 (Glycine). On PubChem, there are 251 Related Compounds with Annotation to explore.

Recent positive drug tests of two elite cyclists suggest athletes have managed to obtain FG-4592 for use as a performance-enhancer. Though the chemical vendors listed on PubMed are not marketing the drug to athletes, another site does not seem as scrupulous, as it sells research peptides like FG-4592 alongside an array of “performance enhancers.”  Some research peptides at www.superhumanstore.com overlap the list of performance enhancers. Numerous drugs on the WADA Prohibited List are available on this site including Aicar, CJC-1295 (a growth hormone secretagogue), Erythropoietin-mimetic peptide 17 (EMP17), GHRP-2, Sermorelin, Thymosin Beta- 4 and more. Similar drugs are available that are not included on the WADA Prohibited List by name, like BAY 87-2243 and Follistatin 344 (a myostatin inhibitor).

The average cyclists pictureprofessional cyclist in the UCI Tour makes $142,000, according to Ernst & Young.  Top riders can earn up to $5 million. Currently, the average dose of FG-4592 is recommended at 1-2mg/kg, 3 times a week, so $780 for 500mg will buy a two- week’s supply. An athlete could buy a year’s supply for around $20,280. This is a relatively affordable rate, even to an average Tour rider. With the difference between the average salary and the top salaries in elite cycling so significant, the financial incentives to use this new drug, or its cousins, remains high.

The good news is FG-4592 is detectable with drug tests. Similar developing drugs will undoubtedly be pursued and tried by athletes in the not-too-distant future. Whether these other options, particularly those not specified on the WADA Prohibited List, are detectable only time will tell. One thing history has proven, these will not be the last athletes to test positive for a new sports doping agent.

By Oliver Catlin and Joe Taylor

[1] Medscape  (http://www.medscape.org/viewarticle/548667)

The Monetary Gap – One Reason for the Lance Armstrong Affair

LA photo from TVYesterday much of the world had to watch Oprah to see Lance Armstrong confess his doping for the first time.  Even Lance agrees that should have happened long ago. 

One of the most troubling elements of all of this is that drug testing began in the Olympics in 1968 more than 44 years ago and yet the system is still unable to distinguish who is a clean athlete.  Every decade we are faced with a groundbreaking scandal, and multiple times a year we are faced with an ordinary scandal resulting from doping in sport.  Just last week we finished a baseball hall of fame vote where a whole generation of players got snubbed largely because of doping, and yet it seemed ordinary. 

Lance Armstrong, Ben Johnson, Marion Jones, Tim Montgomery, Barry Bonds, Roger Clemens… the list is long and spans all sports and generations when it comes to sport heroes and champions who have fallen, some even sacrificing their lives like Tommy Simpson, from using performance-enhancing drugs.  The question facing us all is why and what should we do about it, in much the same way we ask why and what to do about gun violence after witnessing the Newtown disaster. 

Now some may say hold on, you are way out of line.  There is no way to compare innocent children dying in a horrifying massacre to the performance-enhancing drug problem.  While we would agree with that in large part, we also point out that children are tragically affected by performance-enhancing drugs, figuring they have to use them to compete.  Sadly, some of our children even sacrifice their lives in pursuit of steroids and other drugs.  Just ask the Hooton’s, or the Garibaldi’s, or the Marrero’s or the other parents that have paid the ultimate price in losing a child to the use of performance-enhancing drugs. 

We consider the annual budget of the World Anti-Doping Agency at ~$28 million annually and the United States Anti-Doping Agency at $14 million.  We assume UK Sport and Australian Sports Anti-Doping Authority are equivalent to USADA for another $28 million.  The NFL spent $10 million in 2011.  We will put MLB at $10 million as well although their updated new program likely will come with additional cost.  The sport of cycling was estimated to spend $4.7 million and tennis (ITF) $1.3 million per year in 2011 for another $6 million.  If we assume there are 150 other countries and sporting bodies spending an average of $1-2 million annually on anti-doping, that adds another $150-300 million.  All said we estimate the total annual anti-doping budget worldwide to be $246-396 million, which compares to the budget of a small pharmaceutical company – and our estimate is probably on the high side. 

At the same time, you consider that Lance Armstrong made an estimated $17.5 million in endorsements alone in 2005.  Alex Rodriguez, another previous doper, makes $29 million per year in salary alone.  Annual budgets for professional cycling teams range from several million up to $25 million for a team like Sky.  The median team payroll in Major League Baseball is around $90 million while the total payroll for the league is a staggering $2.94 billion.  The total payroll in the NFL is even higher at almost $3.4 billion.  Finally consider the $3.2 billion in endorsement contracts for Nike athletes alone over the next 5 years.  All told, professional and Olympic athletes and teams have easily more than $10 billion in annual resources. 

When Lance Armstrong’s endorsements plus A-Rod’s salary alone totals more than $46.5 million, eclipsing the WADA and USADA annual budgets by $4.5 million.  When the drug-testing programs for MLB and NFL represent 0.3% of annual player salaries.  When the estimated annual amount spent worldwide on anti-doping testing, legal matters and research at ~$246-396 million represents 2-4% of the more than $10 billion in resources available to athletes perhaps we begin to see the scope of the problem.  Those who want to dope can afford to beat the system; at present the monetary gap is simply too great for the system to overcome. 

Now we consider the response.  There have already been countless hours of media content alone dedicated to Lance Armstrong.  We tried to estimate the dollars spent and considered 500 media outlets spending an average of $10,000 each on the coverage.  That would be $5 million alone spent covering the issue worldwide, by the end of this whole affair it is likely to be 10 or 50 times that amount, and our estimate is likely conservative. 

Those of us in the anti-doping community don’t expect $6 billion to be dropped off anytime soon, but it would be nice to see the resources available to anti-doping double or triple at least.  If we can’t afford to give anti-doping a fighting chance by providing the movement with the financial resources needed to effectuate change, then we are part of the problem and we can settle in for a continuing parade of scandals. 

It is up to sport and those that care about it to ensure adequate resources are available to establish and maintain a reality of clean competition.  The athletes, sport, and the next generations of athletes and sports fans deserve a drug testing system that can deliver to the world clean sporting champions, ones we can believe in and trust.  With an outmatched system that can’t expose dirty athletes, even athletes who want to compete clean feel they have to dope to win, and we simply can’t accept that reality.  The risks are too great to sport and the individuals who dedicate their lives to it. 

But it is not just about the money, it is about finding real solutions that can improve the drug-testing system and approach in place today, with or without more resources.  Stay tuned as our dinner conversations have been generating some interesting ideas….

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New Zealand cyclist Adam Stewart banned for two years for attempted use of EPO and hCG

cyclists picture Unfortunately, another story has come out regarding the attempted use of the banned substances EPO and hCG, this time by Adam Stewart, a cyclist from New Zealand. It is attempted use, because the drugs were found during a customs search, not as the result of a positive drug test. On the surface this seems like just another story about doping in cycling, but there are some harsh realities hidden within this story.

The cycling community has done a great deal to clean up the sport by implementing the passport program and taking an aggressive stance on doping as a whole. Some teams even pay for independent testing to add a further layer of protection. Comments by Floyd Landis recently have caused the community to evaluate whether EPO doping is part of the past or whether it continues to be used today. Landis has suggested that it is possible to engage in micro-dosing with EPO combined with traditional blood doping and not test positive in the current drug-testing system. Regardless of what you think about Landis and his allegations, these questions remain as significant concerns and must be answered and evaluated by the scientific community.

What the Adam Stewart situation does answer is a sad but true reality: EPO and its many analogues continue to be sought out and used today by elite cyclists. If Mr. Stewart was caught possessing the drug, one has to think that he had been using it for some time and not testing positive or producing blood values that are suspicious in the passport program. Or, perhaps this is the first time Mr. Stewart got the drug and he had not used it yet? One does have to wonder. If this was not the first time he used the drug then the question needs to be asked, why did he not get caught by the drug-testing system? If he was using EPO and not getting caught then we must look at why and try to address the cause.