Skip to main content
Log in

Beta2-Agonist Doping Control and Optical Isomer Challenges

  • Current Opinion
  • Published:
Sports Medicine Aims and scope Submit manuscript

A Correction to this article was published on 23 January 2018

This article has been updated

Abstract

The World Anti-Doping Agency (WADA) currently allows therapeutic use of the beta2-agonists salbutamol, formoterol and salmeterol when delivered via inhalation despite some evidence suggesting these anti-asthma drugs may be performance enhancing. Beta2-agonists are usually administered as 50:50 racemic mixtures of two enantiomers (non-superimposable mirror images), one of which demonstrates significant beta2-adrenoceptor-mediated bronchodilation while the other appears to have little or no pharmacological activity. For salbutamol and formoterol, urine thresholds have been adopted to limit supratherapeutic dosing and to discriminate between inhaled (permitted) and oral (prohibited) use. However, chiral switches have led to the availability of enantiopure (active enantiomer only) preparations of salbutamol and formoterol, which effectively doubles their urine thresholds and provides a means for athletes to take supratherapeutic doses for doping purposes. Given the availability of these enantiopure beta2-agonists, the analysis of these drugs using enantioselective assays should now become routine. For salmeterol, there is currently only a therapeutic dose threshold and adoption of a urinary threshold should be a high priority for doping control.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Change history

  • 23 January 2018

    Page 1789, table 1, ‘Carmoterol’ row: The cell entry in the ‘Stereochemistry’ column, which previously read.

References

  1. Decramer ML, Hanania NA, Lotvall JO, et al. The safety of long-acting beta2-agonists in the treatment of stable chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2013;8:53–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Meyer HH. Biochemistry and physiology of anabolic hormones used for improvement of meat production. APMIS. 2001;109:1–8.

    Article  CAS  PubMed  Google Scholar 

  3. Marchant-Forde JN, Lay DCJ, Marchant-Forde RM, et al. The effects of R-salbutamol on growth, carcass measures, and health of finishing pigs. J Anim Sci. 2012;90:4081–9.

    Article  CAS  PubMed  Google Scholar 

  4. Hamby PL, Stouffer JR, Smith SB. Muscle metabolism and real-time ultrasound measurement of muscle and subcutaneous adipose tissue growth in lambs fed diets containing a beta-agonist. J Anim Sci. 1986;63:1410–7.

    Article  CAS  PubMed  Google Scholar 

  5. McElligott MA, Barreto A Jr, Chaung LY. Effect of continuous and intermittent clenbuterol feeding on rat growth rate and muscle. Comp Biochem Physiol C. 1989;92:135–8.

    Article  CAS  PubMed  Google Scholar 

  6. Lynch GS, Ryall JG. Role of beta2-adrenoceptor signaling in skeletal muscle: implications for muscle wasting and disease. Physiol Rev. 2008;88:729–67.

    Article  CAS  PubMed  Google Scholar 

  7. Pluim BM, de Hon O, Staal JB, et al. beta-Agonists and physical performance: a systematic review and meta-analysis of randomized controlled trials. Sports Med. 2011;41:39–57.

    Article  PubMed  Google Scholar 

  8. Goubault C, Perault MC, Leleu E, et al. Effects of inhaled salbutamol in exercising non-asthmatic athletes. Thorax. 2001;56:675–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Le Panse B, Collomp K, Portier H, et al. Effects of short-term salbutamol ingestion during a Wingate test. Int J Sports Med. 2005;26:518–23.

    Article  PubMed  Google Scholar 

  10. Le Panse B, Arlettaz A, Portier H, et al. Short term salbutamol ingestion and supramaximal exercise in healthy women. Br J Sports Med. 2006;40:627–31.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Dickinson J, Molphy J, Chester N, et al. The ergogenic effect of long-term use of high dose salbutamol. Clin J Sports Med. 2014;24:474–81.

    Article  Google Scholar 

  12. Kalsen A, Hostrup M, Bangsbo J, et al. Combined inhalation of beta -agonists improves swim ergometer sprint performance but not high-intensity swim performance. Scand J Med Sci Sports. 2014;24:814–22.

    Article  CAS  PubMed  Google Scholar 

  13. Hostrup M, Kalsen A, Auchenberg M, et al. Effects of acute and 2-week administration of oral salbutamol on exercise performance and muscle strength in athletes. Scand J Med Sci Sports. 2016;26:8–16.

    Article  CAS  PubMed  Google Scholar 

  14. Hostrup M, Kalsen A, Bangsbo J, et al. High-dose inhaled terbutaline increases muscle strength and enhances maximal sprint performance in trained men. Eur J Appl Physiol. 2014;114:2499–508.

    Article  CAS  PubMed  Google Scholar 

  15. Hostrup M, Kalsen A, Onslev J, et al. Mechanisms underlying enhancements in muscle force and power output during maximal cycle ergometer exercise induced by chronic beta2-adrenergic stimulation in men. J Appl Physiol. 1985;2015(119):475–86.

    Google Scholar 

  16. Kalsen A, Hostrup M, Soderlund K, et al. Inhaled beta2-agonist increases power output and glycolysis during sprinting in men. Med Sci Sports Exerc. 2016;48:39–48.

    Article  CAS  PubMed  Google Scholar 

  17. Decorte N, Bachasson D, Guinot M, et al. Effect of salbutamol on neuromuscular function in endurance athletes. Med Sci Sports Exerc. 2013;45:1925–32.

    Article  CAS  PubMed  Google Scholar 

  18. Decorte N, Lamalle L, Carlier PG, et al. Impact of salbutamol on muscle metabolism assessed by 31P NMR spectroscopy. Scand J Med Sci Sports. 2015;25:e267–73.

    Article  CAS  PubMed  Google Scholar 

  19. Martindale. Martindale: the complete drug reference. London Pharmaceutical Press; 2014. https://www.medicinescomplete.com/mc/martindale/current/.

  20. Fragkaki AG, Georgakopoulos C, Sterk S, et al. Sports doping: emerging designer and therapeutic beta2-agonists. Clin Chim Acta. 2013;425:242–58.

    Article  CAS  PubMed  Google Scholar 

  21. World Anti-Doping Agency. WADA Prohibited List 2016. World Anti-Doping Code International Standard. 2016. https://wada-main-prod.s3.amazonaws.com/resources/files/wada-2016-prohibited-list-en.pdf.

  22. World Anti-Doping Agency. 2014 Anti-Doping Testing Figures Report. 2015. https://www.wada-ama.org/en/resources/laboratories/anti-doping-testing-figures.

  23. Aavikko A, Helenius I, Alaranta A, et al. Asthma medication is increasingly prescribed for Finnish Olympic athletes for a reason? J Asthma. 2012;49:744–9.

    Article  PubMed  Google Scholar 

  24. Couto M, Horta L, Delgado L, et al. Impact of changes in anti-doping regulations (WADA Guidelines) on asthma care in athletes. Clin J Sports Med. 2013;23:74–6.

    Article  Google Scholar 

  25. McKenzie DC, Fitch KD. The asthmatic athlete: inhaled Beta-2 agonists, sport performance, and doping. Clin J Sports Med. 2011;21:46–50.

    Google Scholar 

  26. van Baak MA, Mayer LH, Kempinski RE, et al. Effect of salbutamol on muscle strength and endurance performance in nonasthmatic men. Med Sci Sports Exerc. 2000;32:1300–6.

    Article  PubMed  Google Scholar 

  27. Harcourt LJ, Schertzer JD, Ryall JG, et al. Low dose formoterol administration improves muscle function in dystrophic mdx mice without increasing fatigue. Neuromuscul Disord. 2007;17:47–55.

    Article  PubMed  Google Scholar 

  28. Pearen MA, Ryall JG, Lynch GS, et al. Expression profiling of skeletal muscle following acute and chronic beta2-adrenergic stimulation: implications for hypertrophy, metabolism and circadian rhythm. BMC Genom. 2009;10:448.

    Article  Google Scholar 

  29. Sullo N, Roviezzo F, Matteis M, et al. Skeletal muscle oxidative metabolism in an animal model of pulmonary emphysema: formoterol and skeletal muscle dysfunction. Am J Respir Cell Mol Biol. 2013;48:198–203.

    Article  CAS  PubMed  Google Scholar 

  30. Busquets S, Toledo M, Marmonti E, et al. Formoterol treatment downregulates the myostatin system in skeletal muscle of cachectic tumour-bearing rats. Oncol Lett. 2012;3:185–9.

    Article  CAS  PubMed  Google Scholar 

  31. Gehrig SM, Koopman R, Naim T, et al. Making fast-twitch dystrophic muscles bigger protects them from contraction injury and attenuates the dystrophic pathology. Am J Pathol. 2010;176:29–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ryall JG, Schertzer JD, Alabakis TM, et al. Intramuscular beta2-agonist administration enhances early regeneration and functional repair in rat skeletal muscle after myotoxic injury. J Appl Physiol. 1985;2008(105):165–72.

    Google Scholar 

  33. Ryall JG, Schertzer JD, Lynch GS. Attenuation of age-related muscle wasting and weakness in rats after formoterol treatment: therapeutic implications for sarcopenia. J Gerontol A Biol Sci Med Sci. 2007;62:813–23.

    Article  PubMed  Google Scholar 

  34. Conte TC, Silva LH, Silva MT, et al. The beta2-adrenoceptor agonist formoterol improves structural and functional regenerative capacity of skeletal muscles from aged rat at the early stages of postinjury. J Gerontol A Biol Sci Med Sci. 2012;67:443–55.

    Article  PubMed  Google Scholar 

  35. Ametller E, Busquets S, Fuster G, et al. Effects of formoterol on protein metabolism in myotubes during hyperthermia. Muscle Nerve. 2011;43:268–73.

    Article  CAS  PubMed  Google Scholar 

  36. Koopman R, Gehrig SM, Leger B, et al. Cellular mechanisms underlying temporal changes in skeletal muscle protein synthesis and breakdown during chronic {beta}-adrenoceptor stimulation in mice. J Physiol. 2010;588:4811–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Riiser A, Tjorhom A, Carlsen KH. The effect of formoterol inhalation on endurance performance in hypobaric conditions. Med Sci Sports Exerc. 2006;38:2132–7.

    Article  CAS  PubMed  Google Scholar 

  38. Tjorhom A, Riiser A, Carlsen KH. Effects of formoterol on endurance performance in athletes at an ambient temperature of −20 degrees C. Scand J Med Sci Sports. 2007;17:628–35.

    Article  CAS  PubMed  Google Scholar 

  39. Stewart IB, Labreche JM, McKenzie DC. Acute formoterol administration has no ergogenic effect in nonasthmatic athletes. Med Sci Sports Exerc. 2002;34:213–7.

    Article  CAS  PubMed  Google Scholar 

  40. Carlsen KH, Hem E, Stensrud T, et al. Can asthma treatment in sports be doping? The effect of the rapid onset, long-acting inhaled beta2-agonist formoterol upon endurance performance in healthy well-trained athletes. Respir Med. 2001;95:571–6.

    Article  CAS  PubMed  Google Scholar 

  41. Canto ND, Ribeiro JP, Neder JA, et al. Addition of tiotropium to formoterol improves inspiratory muscle strength after exercise in COPD. Respir Med. 2012;106:1404–12.

    Article  PubMed  Google Scholar 

  42. Lee P, Day RO, Greenfield JR, et al. Formoterol, a highly beta2-selective agonist, increases energy expenditure and fat utilisation in men. Int J Obes (Lond). 2013;37:593–7.

    Article  CAS  Google Scholar 

  43. Greig CA, Johns N, Gray C, et al. Phase I/II trial of formoterol fumarate combined with megestrol acetate in cachectic patients with advanced malignancy. Support Care Cancer. 2014;22(5):1269–75.

    Article  CAS  PubMed  Google Scholar 

  44. Morton AR, Joyce K, Papalia SM, et al. Is salmeterol ergogenic? Clin J Sports Med. 1996;6:220–5.

    Article  CAS  Google Scholar 

  45. McDowell SL, Fleck SJ, Storms WW. The effects of salmeterol on power output in nonasthmatic athletes. J Allergy Clin Immunol. 1997;99:443–9.

    Article  CAS  PubMed  Google Scholar 

  46. Fredsted A, Gissel H, Ortenblad N, et al. Effects of beta(2)-agonists on force during and following anoxia in rat extensor digitorum longus muscle. J Appl Physiol. 1985;2012(112):2057–67.

    Google Scholar 

  47. Moore NG, Pegg GG, Sillence MN. Anabolic effects of the beta 2-adrenoceptor agonist salmeterol are dependent on route of administration. Am J Physiol. 1994;267:E475–84.

    Article  CAS  PubMed  Google Scholar 

  48. Ryall JG, Sillence MN, Lynch GS. Systemic administration of beta2-adrenoceptor agonists, formoterol and salmeterol, elicit skeletal muscle hypertrophy in rats at micromolar doses. Br J Pharmacol. 2006;147:587–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Boulton DW, Fawcett JP. The pharmacokinetics of levosalbutamol - What are the clinical implications? Clin Pharmacokinet. 2001;40:23–40.

    Article  CAS  PubMed  Google Scholar 

  50. Morgan DJ, Paull JD, Richmond BH, et al. Pharmacokinetics of intravenous and oral salbutamol and its sulphate conjugate. Br J Clin Pharmacol. 1986;22:587–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Joyce KB, Jones AE, Scott RJ, et al. Determination of the enantiomers of salbutamol and its 4-O-sulphate metabolites in biological matrices by chiral liquid chromatography tandem mass spectrometry. Rapid Commun Mass Spectrom. 1998;12:1899–910.

    Article  CAS  PubMed  Google Scholar 

  52. Jacobson GA, Yee KC, Wood-Baker R, et al. SULT 1A3 single-nucleotide polymorphism and the single dose pharmacokinetics of inhaled salbutamol enantiomers: are some athletes at risk of higher urine levels? Drug Test Anal. 2015;7(2):109–13.

    Article  CAS  PubMed  Google Scholar 

  53. Mareck U, Guddat S, Schwenke A, et al. Determination of salbutamol and salbutamol glucuronide in human urine by means of liquid chromatography-tandem mass spectrometry. Drug Test Anal. 2011;3:820–7.

    Article  CAS  PubMed  Google Scholar 

  54. Guillemette C, Levesque E, Rouleau M. Pharmacogenomics of human uridine diphospho-glucuronosyltransferases and clinical implications. Clin Pharmacol Ther. 2014;96:324–39.

    Article  CAS  PubMed  Google Scholar 

  55. World Anti-Doping Agency. WADA Technical Document - TD2014DL. 2014. https://www.wada-ama.org/en/resources/science-medicine/td2014-dl.

  56. Berges R, Segura J, Ventura R, et al. Discrimination of prohibited oral use of salbutamol from authorized inhaled asthma treatment. Clin Chem. 2000;46:1365–75.

    CAS  PubMed  Google Scholar 

  57. Ventura R, Segura J, Berges R, et al. Distinction of inhaled and oral salbutamol by urine analysis using conventional screening procedures for doping control. Ther Drug Monit. 2000;22:277–82.

    Article  CAS  PubMed  Google Scholar 

  58. Schweizer C, Saugy M, Kamber M. Doping test reveals high concentrations of salbutamol in a Swiss track and field athlete. Clin J Sports Med. 2004;14:312–5.

    Article  Google Scholar 

  59. McKenzie DC. Salbutamol and the competitive athlete. Clin J Sports Med. 2004;14:316.

    Article  Google Scholar 

  60. Jacobson GA, Peterson GM, McLean S. Investigation of urinary levels of salbutamol in asthmatic patients receiving inhaled therapy. J Clin Pharm Ther. 1997;22:119–26.

    Article  CAS  PubMed  Google Scholar 

  61. Sporer BC, Sheel AW, McKenzie DC. Dose response of inhaled salbutamol on exercise performance and urine concentrations. Med Sci Sports Exerc. 2008;40:149–57.

    Article  CAS  PubMed  Google Scholar 

  62. Mazzarino M, de la Torre X, Fiacco I, et al. A simplified procedure for the analysis of formoterol in human urine by liquid chromatography-electrospray tandem mass spectrometry: application to the characterization of the metabolic profile and stability of formoterol in urine. J Chromatogr B Analyt Technol Biomed Life Sci. 2013;931:75–83.

    Article  CAS  PubMed  Google Scholar 

  63. Ventura R, Damasceno LM, Ramirez R, et al. Evaluation of the urinary threshold concentration of formoterol in sports drug testing. Drug Test Anal. 2013;5:266–9.

    Article  CAS  PubMed  Google Scholar 

  64. Deventer K, Pozo OJ, Delbeke FT, et al. Quantitative detection of inhaled formoterol in human urine and relevance to doping control analysis. Drug Test Anal. 2012;4:449–54.

    Article  CAS  PubMed  Google Scholar 

  65. Eibye K, Elers J, Pedersen L, et al. Formoterol concentrations in blood and urine: the World Anti-Doping Agency 2012 regulations. Med Sci Sports Exerc. 2013;45:16–22.

    Article  CAS  PubMed  Google Scholar 

  66. Deventer K, Pozo OJ, Delbeke FT, et al. Quantitative detection of inhaled salmeterol in human urine and relevance to doping control analysis. Ther Drug Monit. 2011;33:627–31.

    CAS  PubMed  Google Scholar 

  67. Hostrup M, Kalsen A, Elers J, et al. Urine concentrations of inhaled salmeterol and its metabolite alpha-hydroxysalmeterol in asthmatic and non-asthmatic subjects. J Sports Med Doping Stud. 2012;2(2):6.

    Google Scholar 

  68. Boulton DW, Fawcett JP. Enantioselective disposition of albuterol in humans. Clin Rev Allergy Immunol. 1996;14:115–38.

    Article  CAS  PubMed  Google Scholar 

  69. Boulton DW, Fawcett JP. Pharmacokinetics and pharmacodynamics of single oral doses of albuterol and its enantiomers in humans. Clin Pharmacol Ther. 1997;62:138–44.

    CAS  PubMed  Google Scholar 

  70. Handley DA, Senanayake CH, Dutczak W, et al. Biological actions of formoterol isomers. Pulm Pharmacol Ther. 2002;15:135–45.

    Article  CAS  PubMed  Google Scholar 

  71. Nials AT, Coleman RA, Johnson M, et al. The beta-adrenoceptor pharmacology of the enantiomers of salmeterol. Am Rev Respir Dis. 1994;149:A481.

    Google Scholar 

  72. Schmekel B, Rydberg I, Norlander B, et al. Stereoselective pharmacokinetics of S-salbutamol after administration of the racemate in healthy volunteers. Eur Respir J. 1999;13:1230–5.

    Article  CAS  PubMed  Google Scholar 

  73. Jacobson GA, Yee KC, Premilovac D, et al. Enantioselective disposition of (R/S)-albuterol in skeletal and cardiac muscle. Drug Test Anal. 2014;6:563–7.

    Article  CAS  PubMed  Google Scholar 

  74. Zhang M, Fawcett JP, Shaw JP. Stereoselective urinary excretion of formoterol and its glucuronide conjugate in human. Br J Clin Pharmacol. 2002;54:246–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Fried KM, Koch P, Wainer IW. Determination of the enantiomers of albuterol in human and canine plasma by enantioselective high-performance liquid chromatography on a teicoplanin-based chiral stationary phase. Chirality. 1998;10:484–91.

    Article  CAS  PubMed  Google Scholar 

  76. Akapo S, McCrea C, Gupta J, et al. Chiral HPLC analysis of formoterol stereoisomers and thermodynamic study of their interconversion in aqueous pharmaceutical formulations. J Pharm Biomed Anal. 2009;49:632–7.

    Article  CAS  PubMed  Google Scholar 

  77. Ward JK, Dow J, Dallow N, et al. Enantiomeric disposition of inhaled, intravenous and oral racemic-salbutamol in man—no evidence of enantioselective lung metabolism. Br J Clin Pharmacol. 2000;49:15–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Bream RN, Ley SV, Procopiou PA. Synthesis of the beta2-agonist (R)-salmeterol using a sequence of supported reagents and scavenging agents. Org Lett. 2002;4:3793–6.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors acknowledge Dr David Nichols (Central Science Laboratory, University of Tasmania) for providing the chemical structures.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Glenn A. Jacobson.

Ethics declarations

Funding

Glenn Jacobson has received funding from the World Anti-Doping Agency (WADA) to investigate the enantioselective pharmacokinetics of salbutamol (13D24GJ) and formoterol (14A32GJ) in urine and their application to doping control

Conflict of interest

Paul Fawcett declares he has no conflicts of interest relevant to the content of this article.

Additional information

A correction to this article is available online at https://doi.org/10.1007/s40279-018-0859-7.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jacobson, G.A., Fawcett, J.P. Beta2-Agonist Doping Control and Optical Isomer Challenges. Sports Med 46, 1787–1795 (2016). https://doi.org/10.1007/s40279-016-0547-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40279-016-0547-4

Navigation