Friday, 26 October 2018

Pseudoephedrine: does it work and why is it banned in sport?

I have just published an analysis of the scientific literature on the effectiveness of the banned stimulant pseudoephedrine in sport [1]. The full paper is free to read and can be accessed via this link: rdcu.be/8EtB Like most research it was a team effort. The original research was undertaken by two talented ex-undergraduate students of mine - Maria Gheorghiev and Farzad Hosseini - as part of their University of Essex degree. An Essex PhD student Jason Moran (now at Hartbury University) re-analysed and re-interpreted the data, adding greatly to the final outcome.  

Being a scientific paper, I was forced to write in a somewhat formal style and rein in some of my more florid expressions. However, hopefully it should still make interesting reading for the intelligent layperson. 

The key points from my paper were 

·      Pseudoephedrine use increases heart rate during exercise, but there is no significant effect on time trial performance, perceived effort, or biochemical markers (blood glucose and blood lactate).

·      A small performance benefit could not be completely ruled out, especially in the younger and well-trained athletes of most concern to anti-doping agencies, 

·      However, any performance benefit of pseudoephedrine is marginal and certainly less than that obtained through permitted stimulants such as caffeine

For those of you who are unfamiliar with pseudoephedrine it is the safest and most effective nasal decongestant available. It clears up the symptoms of blocked nose and sinuses during colds and flu, although it has no effect on the overall progress of the disease. Although available in most countries over the counter, its use is restricted, primarily over concerns that it is used as a precursor in the production of the recreational drug “crystal meth”. For those of you familiar with the TV show “Breaking Bad”, it is the “pseudo” that the characters use to make meth in their RV, before switching to more productive precursors when they move to industrial level production. 

In sport, as outlined in my article, the regulation of pseudoephedrine has a chequered history. It has been banned, unbanned and then banned again. As I say in my book, the most tragic case was that of the sixteen-year-old Rumanian gymnast Andreaa Răducan. At the 2000 Sydney Olympics the Rumanian women’s gymnastics team obtained a clean sweep of medals in the overall event. Răducan took the gold. However, she subsequently tested positive for pseudoephedrine; her gold medal was withdrawn. The drugs test was as a result of a cold that had struck many members of the Rumanian team. The team doctor had prescribed the painkiller Nurofen, which in its form as a cold medication contains pseudoephedrine. The minimum level of pseudoephedrine allowed in a urine drugs test is not corrected for body mass. Răducan, being the lightest gymnast, registered over the limit; her teammate Simona Amanar, who finished second, also tested positive for pseudoephedrine, but was below the banned level. Amanar was consequently awarded the gold medal – but she then boycotted the medal ceremony claiming that Răducan was the true champion. 

Given what we know was going on at the Sochi 2014 Winter Olympics games, it is rather ironic that the most high profile positive test actually reported at the Games was not for anabolic steroids or blood doping, but a humble nasal decongestant. The Swedish ice hockey team were deprived of the use of the star player Nicklas Backstrom, just before the gold medal ice hockey game. Shorn of their star player, Sweden were convincingly beaten by Canada 3-0. Backstrom had tested positive for pseudoephedrine. He was taking (and declared on his doping control form) Zyrtec-D, a pill that contains both an anti histamine and pseudoephedrine. It seems that he had been taking it every day for seven years. WADA does have a lower limit of pseudoephedrine that does not result in a ban. When tested, Backstrom’s pill put him just over this limit. There are a issues about the timing of the Backstrom ban (just before the ice hockey final) that have caused a lot of upset in Sweden. The controversy did not end after the Games. Originally not awarded a silver medal, the IOC reinstated him and awarded his medal in March 2014. WADA then appealed this decision to the Court of Arbitration for Sport in November 2014. Finally in January 2015, the dispute was settled and Backstromended with a reprimand, but was allowed to retain his medal.

I know WADA have more pressing issues to deal with at the moment (to put it mildly!). But it does seem to me that the WADA banned list could do with some significant pruning to remove these drugs and medicines such as pseuodoephedrine that - even if they are potentially performance enhancing - are clearly not “game changing” compared to current, legitimate supplements and methods that athletes are allowed to make use of. The asthma medication Salbutamol, as used by Chris Froome in the Vuelta a Espana -  could probably also fall into this category. But that is a subject for my next blog. 


Wednesday, 18 October 2017

“Gender doping”: should women with high testosterone be allowed to compete in athletics?

At the University of Essex we have just started a new MSc. in Sports and Exercise Science [1]. As part of my drugs in sport module, I am getting my students to examine a “hot” research paper each week. They do the background reading and then we discuss the paper together asking the questions: Why was the research done? What did the research find? What were the problems and limitations of the study? What are the consequences for sport?

I am really enjoying this type of small group teaching. The nine students are a mix of UK and overseas, some straight from undergraduate degrees and others with real world experience. The discussions are lively and they all bring different ideas to the table.

The first paper we discussed [2] was one about a condition called hyperandrogenism  - where someone has excess levels of the natural anabolic steroid testosterone. The paper is about to play a key role in the upcoming (any day now!) verdict from the Court of Arbitration of Sport with regards to the IAAF’s hyperandrogenism regulation. Approved in 2011 [3], the “Regulations Governing Eligibility of Females With Hyperandrogenism to Compete in Women's Competition” state that any female athlete with a level of testosterone above a stated value (i.e. in the “male range”) will not be allowed to compete until they had taken measures to reduce this value (usually this would require hormone treatment). The IAAF argument was that the difference in sporting performance between elite men and women is predominantly due to higher levels of testosterone in men. This is why women tend to get excess benefits by doping with anabolic steroids (such as testosterone) when compared to men. Therefore it is “unfair” for someone with a natural high level of testosterone to compete as it gives them benefits akin to doping. Note that at no point did the IAAF blame a “hyperandrogeic” athlete nor argue that they were not a woman - just that they are not allowed to compete in elite women’s sport (there is a distinction here if you look hard enough I guess).

An Indian sprinter – Dutee Chand – refused to take treatment to lower her testosterone and challenged the legality of the regulations at the Court of Arbitration for Sport (CAS). On 24 July 2015 CAS issued an Interim Award in the arbitration procedure [4]. They suspended the regulations for two years to give the IAAF the opportunity to provide scientific evidence about the quantitative relationship between enhanced testosterone levels and improved athletic performance in hyperandrogenic athletes. I can recommend reading the full award; it is a fascinating discussion of this difficult area [5]. However, to summarise a long case, essentially the IAAF had argued that natural (endogenous) testosterone gave a female athlete the equivalent benefit of unnatural added (exogenous) testosterone. The IAAF did not dispute this idea in principle, but wanted to see proof. Hence the two-year study that culminated in the research paper I discussed with my students [1, 2]. In the meantime with the regulations suspended Dutee Chand and other hyperandrogenic athletes were allowed to compete with their natural (high) levels of testosterone [6].

The IAAF and WADA funded study was published in the British Journal of Sports Medicine [2]. The study looked at over two thousand observations from elite athletes competing at the 2011 and 2013 IAAF World Championships. Measurements were made of blood levels of testosterone and comparisons made to performance. I have some potential issues with the statistics used in that they seemed a bit too generous towards finding a performance association, but perhaps that is a story for another day. The key finding, that no doubt will be forwarded to CAS, is that after dividing the athletes into thirds – high, medium and low testosterone – women in the highest testosterone category performed significantly better in 400m, 400m hurdles, 800m, hammer throw, and pole vault with margins of 2.73%, 2.78%, 1.78%, 4.53%, and 2.94%, respectively. This pattern was not seen in any male events.  

So what did my students think of it? Well they made some great observations. Perhaps the most interesting was that the effects were restricted to so few events. Results in many power-based events showed no association with increased testosterone. Indeed in the 100m, 100m hurdles and 200m those with the highest testosterone performed worse than those with the lowest testosterone. The difference was not scientifically significant, but clearly is heading in the wrong direction for the IAAFs case. However, it could be legally significant given Dutee Chand  - who bought the case after all – is a 100m sprinter! 

Actually what was not observed is almost as important as what was. Across female track and field events there was no association of testosterone levels with discipline i.e. elite female athletes in strength events such as shot putters and sprinters do not have higher testosterone than those competing in distance events like the 10,000m and marathon. Even more surprising (at least to me as an oxygen “expert”), the levels of the oxygen carrying protein hemoglobin were not greater in the “aerobic” events. This result is hidden away in Supplementary Table 8 if you want to find it. There is a trend for sure, but I would have expected the difference to be more evident, given that we know that long distance runners are doing all they can within the rules (altitude training, sleeping in low oxygen tents) and without the rules (EPO, blood doping) to increase their hemoglobin; something sprinters don’t bother with at all.

The fact that a biochemical marker like hemoglobin that athletes can manipulate and that is known to affect performance shows such a poor association with performance, does question the whole idea of these kind of “association studies” even when they include so many athletes.

Of course the real problem with this study is that it is – quite rightly - limited by ethics. None of the female testosterone values in this study were in the “male” range. Otherwise the athletes would have been banned at that time of course. The best way to prove that hyperandrogenism is equivalent to testosterone doping is to dope elite athletes with testosterone for a short time. Then look at their performance when they are on and off the steroids. Does the increase and decrease mirror those seen when a hyperandrogenic athlete comes on and off hormone therapy to vary their natural levels of testosterone? Good luck getting that study through a university ethics committee!

One final point is that the paper also looked at male athletes. Unlike with women, the study did find that male sprinters had increased testosterone levels compared to other events. However, in no event was there any association of an individual’s testosterone level with performance in that event. In the discussion the authors’ suggest there is “sigmoidal” curve associating testosterone levels and performance. For women this means that increasing testosterone can have a large effect on performance (the association curve is steep), but at the higher values seen in men the relationship smooths out and is undetectable. Of course this begs the question. Why is taking testosterone and other anabolic steroids banned for male athletes, if the performance benefit is so marginal as to be unmeasurable? I am not sure the IAAF and WADA can have things both ways. If associations with performance can be used to ban female hyperandrogenic athletes from performing, then surely the lack of such an association can be used to unban male anabolic steroid dopers? I think Shakespeare called this being hoist on your own petard [see Hamlet Act 3, scene 4).

What ever CAS decides, at least my students enjoyed discussing the paper. “Much better than my undergraduate teaching said one”. Given I taught him as an undergraduate, this was a somewhat back handed compliment, but I’ll take it anyway!  

Onwards and upwards ….next week we are discussing a controversial paper that suggests  that  blood doping does not increase performance in long distance aerobic sports events such as cycling [7]. Can’t wait……


[1] MSc. in Sports and Exercise Science, University of Essex, UK


[2] Bermon S, Garnier PY (2017) Serum androgen levels and their relation to performance in track and field: mass spectrometry results from 2127 observations in male and female elite athletes. Br. J. Sports Med. 51:1309-1314.


The paper can be downloaded from the IAAF web page: https://www.iaaf.org/news/press-release/hyperandrogenism-research


[3] IAAF to introduce eligibility rules for females with hyperandrogenism ; IAAF news April 2011


[4]  CAS media release: CAS suspends the IAAF hyperandrogenism regulations Lausanne, July 27, 2015


[5]  Dutee Chand v IAF and IAAF, Interim Arbitral Award delivered by the Court of Arbitration of Sport,  July 27, 2015


[6] The most famous current elite female athlete is the South African World and Olympic 800 m champion, Caster Semenya. Since the lifting of the IAAF regulations her success has come under some criticism from fellow athletes.


However, it was notable that this is not necessarily shared by the athletics watching public. I was at the London Olympic Stadium two months ago when the crowd were right behind her during her race, in her post racer interview and during the medal ceremony.



[7]  [Heuberger J, Rotmans JI, Gal P et al (2017) Effects of erythropoietin on cycling performance of well trained cyclists: a double-blind, randomised, placebo-controlled trial. Lancet Haematol 4:e374-e386.


Friday, 21 October 2016

DENY, DENY, DENY. Gene doping: the future of theatre?

Deny, Deny, Deny is written by Jonathan Maitland and is due to open at the Park Theatre, London on November 2nd. I was the scientific advisor for this play, which deals with a female sprinter tempted into experimenting with gene doping. I wrote a short piece for the program notes, which I reproduce below [note that the last line does not mean I particularly think any athlete is currently gene doping, although this possibility can’t be ruled out entirely].

“In 2006 anti doping agencies got the information they had always feared.  Police raiding the home of famous German athletics coach, Thomas Springstein, found this email on his computer: The new Repoxygen is hard to get. Please give me new instructions soon so that I can order the product before Christmas.” Repoxygen was an experimental drug developed by UK biotechnology company Oxford Biomedica. It was designed to treat anaemia by injecting extra copies of the human erythropoietin (EPO) gene.

EPO is a small protein that increases the number of oxygen carrying red blood cells in the body. Activating the EPO gene increases the levels of EPO protein, increasing the number of red blood cells, enhancing oxygen delivery and improving performance in long distance “aerobic” sports. Clean athletes try to increase their own levels of EPO by altitude training. Others, like the cyclist Lance Armstrong, injected synthetic EPO directly - a process explicitly banned by the World Anti Doping Agency. Synthetic EPO is detectable, albeit with difficulty. It also needs multiple injections. How much better coach Springstein thought to inject the EPO gene itself? This gene would continue to make increased undetectable levels of EPO, creating a gene doped super athlete!

We don’t know whether Springstein ever got hold of his black market Repoxygen. We do know that Oxford Biomedica stopped making it; a combination of poorer than expected animal trials and the ready availability of new versions of cheap, synthetic EPO protein made further development uneconomic. Market forces, rather than the vigilance of anti doping agencies saved the day for clean sport in this instance.

Gene doping sits at the heart of Deny, Deny, Deny. So what is it and is the plot scientifically feasible? Gene doping is the bastard child of gene therapy. It uses the same molecular tools but aims at different outcomes. Whilst gene therapy attempts to cure genetic diseases such as cystic fibrosis and thalassemia, gene doping aims to improve how well elite athletes can run, swim or throw.

In the 1970s gene therapy was touted as heralding a new age of medicine. Is gene doping a similar game changer in sports cheating? The basic science is scarily cheap. You can teach students the principle in a school project and even get them to make a “dummy” gene construct. There is an analogy here with nuclear weapons. Everyone knows the basic theory of how to make one. But the problem - and expense - lies in the fine details of the engineering. In gene therapy the multi million pound expense is not in creating the new gene, but in making the final product effective and safe. As a result there are only a handful of genetic diseases that are currently treated by gene therapy; the cost of gene therapy per patient runs into the hundreds of thousands of pounds.


It is easy to envisage gene doping increasing the speed of female sprinters. It would only require injecting a gene that causes a slight increase in levels of testosterone – the natural male anabolic steroid - to increase female muscle mass and enable a sprinter to power to victory in the 100m or 200m. But given the costs is gene doping too expensive and impractical to be successful without the backing of Big Pharma or a rogue state? I think not. If you had “looser” ethics and were willing to trade off safety for low cost and high performance, it is easy to envisage an unscrupulous coach persuading a scientist to inject a gene that would increase the performance of a female sprinter. Perhaps they already have …….”

Wednesday, 31 August 2016

Bloody Olympics: Rio, 2016, and the history of illegal blood doping

The below is a reprint of a bog I wrote for Oxford University Press to coincide with the Olympics. Nothing new really, but it was nice to put things in a historical context. To see the original story (with pictures) go to http://blog.oup.com/2016/08/rio-2016-history-blood-doping/

Throughout history blood has been imbued with magical properties. Drinking blood was viewed as a source of power for many mythical beasts centuries before the invention of the modern vampire myth. In Greek mythology Odysseus can revive the dead by giving them blood to drink. But all blood is not the same – the blood from the veins on the left side of the snake-headed Gorgon Medusa is deadly, that from the right side is life-giving. In 1489 the Italian philosopher Marsilio Ficino, proposed that drinking the blood of healthy young men could rejuvenate the sick and elderly. Indeed it seems that an attempt was made to cure Pope Innocent VIII of his stroke by giving him blood from three ten year old boys. More dramatically the Hungarian princess and serial killer, Countess Elizabeth of Bathory, was alleged to have drained all the blood from over 600 young girls to feed her restorative blood baths.

Drinking fresh blood was supposed to give you strength, maybe eternal life if you were a vampire. Even in the post-enlightenment age, the first blood transfusions had nothing to do with the modern notion of enhancing oxygen supply; instead they were supposed to heal by replacing old bad blood with strong healthy animal blood.

Sport has long had a fascination with blood. The blood of the Roman gladiators, moppped by a sponge from the arena, fed a profitable business; perhaps the athlete’s ultimate commitment to promoting their brand? Today blood is even more relevant to sport. Indeed arguably its use and abuse in sport today has come close to destroying the Olympic movement.

The modern fascination with blood in the Olympics arose from the new discipline of sports science in the 1960s and 1970s.  A key driver was the 1968 Mexico City Olympics where physiologists recognized the difficulty of getting sufficient oxygen to tissue in the rarefied 2km high air. Red blood cells transfusions increase the amount of oxygen given to people suffering from trauma or anaemia. It was therefore argued that healthy athletes could be given “excess” blood to increase their ability to deliver oxygen to tissue, and hence enhance their performance in endurance sport?

Scandinavian scientists were first to prove this - in 1972, Björn Ekblom at the Institute of Physiology of Performance in Stockholm, showed a 25% increase in stamina after a transfusion. It was subsequently alleged that Scandinavian athletes were putting this laboratory method into practice. Lasse Viren won double gold medals on the track in 5,000m and 10,000m at the 1972 and 1976 Olympics. Unproven allegations of blood doping dogged Viren, who always denied them claiming that altitude training and “reindeer milk” were the keys to his enhanced performance. Some of his teammates did later confess to blood doping, however, most notably Kaarlo Maaninka at the 1980 Olympics. Maaninka received no sanction, which might surprise today’s readers given that blood doping is one of the main reasons we will not see the Russian track and field team competing at these Olympics. However, although in the 1970s and 1980s blood doping was viewed as morally dubious, it did not break any rules. The anti doping effort of the time focussed more on amphetamines and anaboloic steroids.

This would change in the 1980s. The LA Olympics in 1984 was the watershed event. There was extensive use of blood transfusions including by several members of the highly successful US cycling team. Again no rules were broken, but the IOC had had enough and banned blood doping in 1985. However, they had no way of testing for this form of cheating, so it presumably continued in secret. In fact the ready availability of genetically engineered EPO in the late 1990s, a difficult to detect drug that increases the number of red blood cells more gradually and naturally than a blood transfusion, undoubtedly increased the use of banned methods. I could fill most of the rest of this article with a list of Olympic athletes who are confirmed or strongly suspected of using EPO and/or blood transfusions to aid their performance.

So where are we now? Blood is a part of the Olympics and always will be. Whilst not imbuing you with the mythical life giving properties of Odysseus, optimizing your number of red blood cells is a key part of success in endurance events. I can guarantee that every medal winner in a long distance endurance event will have had their blood measured frequently by support scientists to conform the success of their training program, whether that program uses permitted (altitude training, sleeping in low oxygen tents) or banned (EPO, blood transfusion) methods.

So much for Rio, what about PyeongChang and the Winter Olympics? This is, if anything, an even richer source of stories than the summer games.  There are claims of athletes chosen for ski teams solely so that are the right blood group to donate blood to their team leader; in 2006 a disgraced ex Austrian ski coach crashed his car into a roadblock in the Italian alps, whilst attempting to escape the police. But that’s a blog for two years time ……..

Rio Olympics 2016 and doping stories

Most of the interest for me happened pre the Games of course and the "will they, won't they" allow Russia to compete saga. Not surprisingly during the games my TV and radio interviews weren't about science, but about athletes response to other athletes. The extent of finger pointing was unusual for the Olympics,  but less extreme than has happened at some other events e.g. Paula Radcliffe unfurling her "EPO cheats out" banner at the 2001 World Championship [1]. Still it was the Olympics so news outlets inevitably focussed on incidents such as the finger wagging between Yulia Efimova and Lilly King [2]. Until of course the light relief/black comedy provided by Ryan Lochte and his co-conspirators [3].

The main story in my opinion though was the IPC being brave enough to ban Russia completely from the Paralympics. The world didn't end and the ban was even upheld by the Court of Arbitration for Sport.  This rather put the lie to the IOC's passing of the buck to the national sporting organisations with its ridiculous one week timescale and wilful misreading of the nature of the McLaren WADA report [3].

I didn't get asked much about the IPC decision  though I did try to bring the contrast with the IOC into some of my interviews. Still I am now really looking forward to the Paralympics. Not clean, but cleaner......

[1]  https://www.theguardian.com/sport/2001/aug/10/athletics1

[2] http://www.independent.co.uk/sport/olympics/rio-2016-yulia-efimova-and-lilly-king-show-how-swimmings-code-of-honour-is-shot-to-pieces-by-ioc-a7179891.html

[3] http://www.breitbart.com/video/2016/08/22/john-oliver-destroys-ryan-lochte-labels-him-americas-idiot-sea-cow/

[4] https://www.theguardian.com/sport/2016/aug/04/richard-mclaren-ioc-wada-russia-rio-2016-