Clenbuterol and Meat Contamination

Originally released April 2011Updated August 2016

Clenbuterol and the World Anti-Doping Agency (WADA) Prohibited List

Clenbuterol is a powerful drug sometimes used for performance-enhancement by athletes to increase lean muscle mass and reduce body fat. Listed on the World Anti-Doping Agency (WADA) Prohibited List, clenbuterol is classified under the category of other Anabolic Agents because it promotes muscle growth through anabolic properties.

Clenbuterol is not legally distributed in the U.S. and is not approved by the Food and Drug Administration (FDA). Athletes should also be aware and use extreme caution knowing that clenbuterol may still be prescribed clinically by physicians in some countries as a bronchodilator beta-2 agonist medication.

Clenbuterol and Meat Contamination

Further, there have been reports of clenbuterol use to promote growth in livestock, including cattle, lamb, poultry and swine. Such use is illegal in the U.S. and in Europe.

Consistent with numerous prior reported cases globally, the issue of illicit administration of clenbuterol to animals destined for food production can result in, under specific conditions, a positive sample from an athlete. WADA has issued specific warningsabout this problem in China and Mexico. Unfortunately, anti-doping authorities have no control over agricultural and food safety practices in these countries, and inadvertent ingestion remains an ongoing issue for athletes.

Clenbuterol and Athlete Risk Outside the U.S.

USADA wants to help athletes and athlete support personnel understand the potential risks. To USADA’s knowledge, due to strict regulatory and meat certification practices, a clenbuterol positive athlete sample has never been reported after consumption of meat produced in the U.S.

USADA urges athletes to use the utmost care and caution if eating meat while traveling abroad, and to be aware of the potential for contamination.

To reduce your risk of unintentionally ingesting clenbuterol through contaminated meat:

• Choose foods from a reputable food source.
• Avoid eating liver or liver derived products while overseas.
• Avoid eating unusual or exotic meat products.

Clenbuterol and Results Management

Despite the continuously improving analytical methods in sports drug testing, especially using sensitive mass spectrometry, it remains difficult to determine if clenbuterol has been deliberately administered or unintentionally ingested through contaminated meat.

Under the World Anti-Doping Code, clenbuterol is a non-threshold non-specified substance, meaning that any amount of clenbuterol detected in an athlete urine sample is reported as a positive test. Thus, it’s important to note that strict liability dictates an athlete has ultimate responsibility for what is in his/her system, regardless of its origin.

USADA will continue to keep the sport community aware of new developments regarding this issue as they develop.

References

Thevis M, Geyer L, Geyer H, Guddat S, Dvorak J, Butch A, Sterk SS, Schänzer W. Adverse analytical findings with clenbuterol among U-17 soccer players attributed to food contamination issues. Drug Test Anal. 2013 May;5(5):372-6.

WADA statement on Clenbuterol, June 15, 2011.

WADA statement on Clenbuterol, “Athletes must show caution due to contaminated meat.” November 23, 2011.

WADA Testing Figures, Accessed August 9, 2016.

Substance Profile: Kratom

ts

Historically, agricultural workers in southeast Asia chewed Kratom leaves to increase work output and offset fatigue. Since those days, Kratom – known scientifically as Mitragynine speciosa – has also been used as a substitute for opium, and as a way to manage the symptoms of opioid withdrawal. Because of its demonstrated opioid activity, mitragynine is now being evaluated as a new drug for pain relief.

What is Kratom?

Kratom is a plant that produces several compounds that have opioid-like effects, with mitragynine being the active compound in Kratom that’s present in the highest concentrations. At low doses, mitragynine has stimulant effects similar to cocaine, but at higher dosages it has an effect more like morphine.

Is Kratom prohibited in sport?

As of 2017, Kratom is not a prohibited substance on the World Anti-Doping Agency (WADA) Prohibited List, but mitragynine has been on the WADA Monitoring program since 2014 as a narcotic. Given that narcotics are only prohibited in-competition, WADA labs screen samples for the presence of mitragynine only on drug tests that take place in-competition.

With this analysis, WADA can determine if substances that aren’t presently prohibited should be added to the Prohibited List because they are being abused for performance-enhancement in sport. Since it was added to the monitoring program in 2014, mitragynine has been detected in the samples of four strength-sport athletes from countries outside the U.S.

While Kratom is not currently prohibited, athletes are advised to steer clear of Kratom for health reasons.

What are the health risks associated with Kratom?

As you can see in the table below, there are a number of dangerous side effects associated with Kratom. Even worse, the DEA is aware of at least 15 deaths associated with the use of Kratom between 2014 and 2016.

In August 2016, the DEA announced that it planned to place Kratom on Schedule 1 (the most restrictive schedule) under the Controlled Substances Act. At this time, the DEA has temporarily withdrawn its proposal to schedule Kratom until it has conducted more research on the plant and considered all of the comments received from the public.

Adverse/Toxicological Effects of Kratomfrom Cinosi et al (2015) [8]
Short term use side effects	Nausea, constipation, sleep problems, temporary erectile dysfunction, itching, or sweating
Long term use side effects	Anorexia, dry mouth, problems in diuresis, darker skin, and hair loss
Withdrawal symptoms	Hostility, aggression, aching of muscles and bones, jerky movements of the limbs, anorexia and weight loss, and insomnia
Infrequent effects	Seizures (individuals using high doses of kratom, either alone or combined with other drugs), intrahepatic cholestasis, psychotic symptoms, Adult Respiratory Distress Syndrome, and hypothyroidism
Fatalities	Kratom mixed with other substances: O-desmethyltramadol; propylhexedrine; over-the-counter cold medications and benzodiazepines; venlafaxine, diphenhydramine, and mirtazapine; zopiclone, citalopram, and lamotrigine

Is Kratom legal outside of sport?

Over the last few years, Kratom has been in the news because abuse of this plant by recreational drug users has increased dramatically. In light of the current epidemic of opioid abuse in the United States, the medical community and law enforcement officials are very concerned about the increased use of Kratom.

Unfortunately, Kratom is readily available on the internet and is often marketed as a “legal high,” but such advertising is not completely accurate. It’s true that unlike heroin, Kratom (or mitragynine) is not a scheduled drug under the Controlled Substances Act. However, that does not mean it is entirely legal.

For example, the FDA issued an import alert in February 2014 stating that imported dietary supplements and bulk dietary ingredients that contain Kratom can be seized. As such, a shipment of Kratom was recently seized by US Marshalls in California with the explanation that Kratom products are unapproved and misbranded drugs under the Federal Food, Drug, and Cosmetic Act.

Resources

[1] E. Cinosi, G. Martinotti, P. Simonato, D. Singh, Z. Demetrovics, A. Roman-Urrestarazu, F. S. Bersani, B. Vicknasingam, G. Piazzon, J. H. Li, W. J. Yu, M. Kapitany-Foveny, J. Farkas, M. Di Giannantonio, O. Corazza. Following “the Roots” of Kratom (Mitragyna speciosa): The Evolution of an Enhancer from a Traditional Use to Increase Work and Productivity in Southeast Asia to a Recreational Psychoactive Drug in Western Countries. Biomed Res Int. 2015, 2015, 968786.

[2] DrugFacts: Kratom (2016). National Institute on Drug Abuse. Available at: https://www.drugabuse.gov/publications/drugfacts/kratom [Accessed on Oct 25 2016].

[3] A. Varadi, G. F. Marrone, T. C. Palmer, A. Narayan, M. R. Szabo, V. Le Rouzic, S. G. Grinnell, J. J. Subrath, E. Warner, S. Kalra, A. Hunkele, J. Pagirsky, S. O. Eans, J. M. Medina, J. Xu, Y. X. Pan, A. Borics, G. W. Pasternak, J. P. McLaughlin, S. Majumdar. Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit beta-Arrestin-2. J Med Chem. 2016, 59, 8381-97.

[4] N. Harun, Z. Hassan, V. Navaratnam, S. M. Mansor, M. Shoaib. Discriminative stimulus properties of mitragynine (kratom) in rats. Psychopharmacology (Berl). 2015, 232, 2227-38.

[5] W. C. Prozialeck, J. K. Jivan, S. V. Andurkar. Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effects. J Am Osteopath Assoc. 2012, 112, 792-9.

[6] S. Guddat, C. Gorgens, V. Steinhart, W. Schanzer, M. Thevis. Mitragynine (Kratom) – monitoring in sports drug testing. Drug Test Anal. 2016,

[7] C. Ingraham. The DEA is withdrawing a proposal to ban another plant after the Internet got really mad. Washington Post, 2016. https://www.washingtonpost.com/news/wonk/wp/2016/10/12/the-dea-is-reversing-its-insane-decision-to-ban-the-opiate-like-plant-kratom-for-now/ [Accessed on Oct 14 2016].

[8] Import Alert: DETENTION WITHOUT PHYSICAL EXAMINATION OF DIETARY SUPPLEMENTS AND BULK DIETARY INGREDIENTS THAT ARE OR CONTAIN MITRAGYNA SPECIOSA OR KRATOM. FDA.gov, 2014. http://www.accessdata.fda.gov/cms_ia/importalert_1137.html [Accessed on Oct 17, 2016].

[9] C. Ingraham. The DEA is withdrawing a proposal to ban another plant after the Internet got really mad. Washington Post, 2016. https://www.washingtonpost.com/news/wonk/wp/2016/10/12/the-dea-is-reversing-its-insane-decision-to-ban-the-opiate-like-plant-kratom-for-now/ [Accessed on Oct 14 2016].

[9] Kratom seized in California by US Marshals Service. FDA.gov, 2016. [Accessed on Oct 17, 2016].

USADA Retests Samples for Unapproved and Abused Blood Booster

In the fight against doping in sport, USADA is using newly developed and cutting-edge detection methods to retest stored urine samples for prohibited substances, including a newly-abused blood booster.

A new class of drugs, called HIF-stabilizing agents, mimic the natural response to hypoxia, or insufficient oxygen, and result in increased production of red blood cells (RBCs). While a number of related pharmaceutical products are being developed to assist in the treatment of legitimate diseases, such as anemia, these same agents can be abused in sport. Athletes can use these products to increase their red blood cell count, which is a very effective doping technique that increases the delivery of oxygen to working muscles to increase endurance performance.

One such blood boosting drug is called FG-4592 (Roxadustat), a HIF-stabilizer currently in clinical trials, but not approved for human use. HIF-stabilizers like FG-4592 increase oxygen-carrying capacity bypassing traditional low oxygen sensing pathways, resulting in the increased expression of native erythropoietin (EPO). Traditionally, dopers have used injections of recombinant EPO or erythropoiesis stimulating agents (ESAs) for performance-enhancement. All HIF-stabilizers, like other forms of blood-doping, have been banned by the World Anti-Doping Agency (WADA).

Based on several tips about athlete abuse of FG-4592, USADA helped launch research at the SMRTL and Cologne WADA-accredited laboratories to develop a mass spectrometry-based method for FG-4592 detection. With this technology, USADA recently retested 61 urine samples that had been frozen following initial analysis in 2011. All of the 61 stored samples from U.S. athletes were negative for FG-4592 upon retesting, although globally a number of athletes have tested positive, including a race walker in France and a Chilean cyclist from the 2015 Pan Am Games.

Urinary drug tests have also proven effective at detecting HIF-stabilizers, and ongoing advances in detection technology have resulted in longer detection windows, enabling USADA to more effectively and routinely screen for HIF-stabilizers and retest frozen samples as part of its detection and deterrence-based anti-doping strategy.

Substance Profiles

for Substances Clarified

on the

2017 Prohibited List

Each year, the World Anti-Doping Agency (WADA) publishes an updated Prohibited List of Substances and Methods, which outlines nine categories of substances and three categories of methods that are prohibited at all times, in-competition only, or in particular sports.

On January 1, the 2017 WADA Prohibited List goes into effect and it includes a number of clarifications that are pertinent to athletes and their support personnel. It is always important to keep in mind that athletes are subject to a standard of strict liability, and as such, should take the time to review the summary of the major changes to the 2017 WADA Prohibited List to understand the updates. In order to make it easier to interpret, USADA has also developed an online summary of the major changes to the 2017 WADA Prohibited List.

The following article further highlights important information on a few substances that athletes should be aware of before the 2017 Prohibited List goes into effect:

 S2 PEPTIDE HORMONES, GROWTH FACTORS, RELATED SUBTANCES, AND MIMETICS

Molidustat (HIF-stabilizer BAY 85-3934)

• History: In the early 2000’s, Molidustat was established as an anti-anemic drug, but researchers have since determined that its actions are similar to the prohibited HIF-stabilizer FG-4592.

• Clinical Utility: As an anti-anemic drug, Molidustat is used to increase erythropoietin (EPO) production to help anemic patients who lack the right amount of healthy red blood cells. Molidustat is in clinical trials and currently has no government regulatory approvals for human clinical use in the United States.

• Performance-Enhancing Actions: Similar to FG-4592 and other HIF-stabilizers, Molidustat can boost the production of red blood cells, which effectively increases an athlete’s endurance level.

• Potential Side Effects: While Molidustat does have clinical utility, it also has the potential to alter blood viscosity, and consequently, may increase the risk of stroke or other cardiac and/or adverse circulatory events (e.g. blood clots).

S3 BETA-2 AGONISTS

Higenamine (Norcoclaurine)

• History: A substance found in a variety of plant sources, Higenamine was often used in traditional medicine, and now the supplement industry has started using it as a substitute for Dimethylamylamine (DMAA) and ephedrine. As such, USADA reminds athletes to check your supplement labels for Higenamine (also known as norcoclaurine) or Higenamine plant-based sources (Aconite, Annona squamosal, Nandina domestica, Tinospora crispa, and others).

• Clinical Utility: Higenamine can act as an anti-asthmatic and a cardiotonic, which means that it may strengthen the heart by increasing cardiac output. Pre-clinical studies suggest Higenamine may be used to help the heart recover after an adverse event like a myocardial infarct or heart failure. Many of these effects have been observed in in vitro studies and in animals, but have not been confirmed in humans.Higenamine currently has no government regulatory approvals for human clinical use in the United States. Higenamine or its synonyms may or may not be listed on labels of dietary supplement products. Some examples can be found on USADA’s Supplement 411 High Risk List.

• Performance-Enhancing Actions: Research indicates that Higenamine has mixed adrenergic receptor activity, meaning it may act as a general stimulant. It may be found in some pre-workout, energy, or weight-loss products.

• Potential Side Effects: In some circumstances, Higenamine may also alter blood pressure and cause irregular heartbeats.

S6 STIMULANTS

DMBA (1,3-dimethylbutylamine)

• History: DMBA is a stimulant studied in the 1940s shown to raise blood pressure. The supplement industry has since used DMBA, also listed by alternate names (like AMP Citrate), as a replacement for Dimethylamylamine (DMAA). Therefore, it’s important to screen your supplements for this ingredient. In addition, please be aware that there is another chemical called DMBA (7,12-dimethylbenz[a]anthracene) that has no relation to the aforementioned DMBADMBA is also known as:
  • 1,3-Dimethylbutylamine
  • 2-Amino-4-Methylpentane Citrate
  • 4-Amino-2-Methylpentane Citrate
  • 4-Amino Methylpentane Citrate
  • Amperall
  • AMP
  • AMP Citrate
  • 4-AMP Citrate
  • 4-Methyl-2-Pentanamine

• Clinical Utility: DMBA is a stimulant studied in animals with spinal cord injuries to improve their blood pressure. Currently, DMBA has no government regulatory approvals for human clinical use in the United States. The FDA has issued specific consumer information on DMBA in dietary supplements here.

• Performance Enhancing Actions: Research has shown that DMBA can act as an adrenergic beta-agonist, which leads to increased fat burning.

• Potential Side Effects: Despite its clinical utility, DMBA may negatively alter heart rate and blood pressure.

S7 NARCOTICS

Nicomorphine

• History: A powerful opioid, nicomorphine was developed in the early 1990’s in Europe to manage severe pain in patients with cancer and neuropathic pathologies.

• Pre-Clinical Utility: In some European countries, nicomorphine was used as a post-operative pain relief method. It’s important to note that nicomorphine currently has no government regulatory approvals for human clinical use in the United States, but it may be available internationally. Nicomorphine is a Schedule I Controlled Substance under the United States Code (USC) Controlled Substances Act.

• Performance Enhancing Actions: Similar to other narcotics, nicomorphine is a powerful painkiller that dulls the nervous system’s ability to detect pain, which could allow an athlete to mask pain or injury, and reduce stress or anxiety levels.

• Potential Side Effects: Nicomorphine can cause dependence, loss of concentration, itching, nausea and vomiting, respiratory depression, and fainting/dizziness.

For more information on the prohibited status of specific substances, visit GlobalDRO.com, an easy-to-use resource that athletes and support personnel can access at any time to search for medications purchased in Australia, Canada, Japan, the United Kingdom, Switzerland, and the United States.

WADA and USADA also recognize that athletes, like all people, may have conditions or illnesses that require them to take particular medications or undergo procedures. If that medication or method happens to be prohibited and they can’t use a non-prohibited alternative, an athlete can apply for a Therapeutic Use Exemption (TUE) that authorizes them to access the medical care they need while continuing to compete.