Thursday, August 2, 2012

Medicine - Pseudoephedrine Study Draft 2010

Pseudoephedrine (PSE) is a readily available over-the-counter nasal decongestant which is a sympathomimetic amine. Specifically PSE activates adrenergic receptors in presynaptic neurons causing muscle contraction in blood vessels, also known as vasoconstriction. This results in decreased inflammation and mucous production which relieves the symptoms of the common cold. This study in particular considers one of its alternative uses as an ergogenic aid.

As an ergogenic aid it was banned from use in sports competition as doping is illegal in most realms of professional sports. However, it is debatable whether or not PSE is capable of generating any ergogenic effect, and so there was a period from 2004-2010 where PSE was not on the banned substances list due to WADA’s list replacing the IOC’s list of banned substances.

Despite potential risks, and uncertainty on the ergogenic effects of PSE, athletes have still been known to abuse the use of pseudoephedrine in hopes of gaining an edge on their competitors. Data generated and recorded in the doping control laboratory of Cologne between 1996 and 2003 that included a total of 52,347 in-competition analyses yielded 33 AAFs for pseudoephedrine, which amounts to an average of 4.1 positive controls per year. In 2007 and 2008, that is, 3 years after pseudoephedrine was removed from the prohibited list, the prevalence of pseudoephedrine and ephedrine was determined in 16,335 in competition doping control samples. The analyses resulted in 102 cases of pseudoephedrine use or misuse. In particular there have been a high number of cyclists who have abused this drug in hopes of an edge in competition, out of those 102 cases of pseudoephedrine use, 44 came from cyclists (Thevis et. al).

The potential ergogenic effects that athletes believe PSE can provide is as a stimulant and to increase muscle performance. This is one of the points of controversy between studies, as a boost to muscle performance has yet to be confirmed. PSE’s use as a stimulant is also controversial as its effect on the nervous system is relatively minor and will probably only affect sensitive individuals. This use of PSE is likely due to its association with ephedrine and methamphetamine both of which do have significant effects on the nervous system to increase concentration. The association from ephedrine is due to the plant Ephedra sinica which contains both and is used as a traditional herbal remedy in Chinese medicine. The association with methamphetamine is because pseudoephedrine is used as a chemical precursor in the illicit creation of methamphetamine.

The purpose of this systematic review is to quantitatively consolidate the results of studies relating to the ergogenic effect of Pseudoephedrine in order to determine the validity of its ban from competition. Previous studies have yet to resolve these conflicting results even when using the same testing methods. Chu et. al 2002 found no ergogenic effect while performing a 30 second Wingate test, and yet Gill et. al found that there was an ergogenic effect with the very same Wingate test.

In consultation with 2 research librarians, we developed search strategies to identify potentially relevant studies from the MEDLINE, and EMBASE databases. We sought reports of randomized control trials, including crossover trials, in relation to pseudoephedrine use for its ergogenic effect. From medline, our first search strategy retrieved 100 articles between the time period 1950-2010. Our second search strategy retrieved 42 articles between 1950-2010. From embase, our first search strategy retrieved 159 articles between the time period 1980-2010. Our second search strategy retrieved 80 articles between the 1980-2010.

One author and a peer then reviewed the titles and abstracts through our search and retrieved potentially relevant studies. Studies that were excluded in this process included those with co-interventions with other drugs. In particular, for the purposes of data abstraction, articles that related to Ephedra, ma huang were excluded due to it containing ephedrine. Out of those possibly relevant articles we retrieved 16 but were unable to retrieve two. However, as will be explained later, from reading the abstracts those studies just verified what is already established about PSE’s ergogenic effect. Also, out of those two, one of the articles studied the effects of PSE with the additional variable of diving, which is not as relevant to this study. Out of those 16 articles, only 8 were found to be relevant trials devoted solely to studying the ergogenic effects of PSE.

The same author and peer then independently abstracted data into abstraction forms. We resolved abstraction differences by repeated review and consensus. Similarly the same author and peer assessed risk of bias through the use of both the Jadad scale and the Cochrane collaboration’s tool for assessing risk of bias, once again resolving differences by repeated review and consensus. It was determined that articles with a jaded scale of less than 3 would be removed from the study, however all 8 studies were found to have a passing score.

Table 1 summarizes the results gathered from the 8 relevant retrieved articles. Displayed are the results of main tests of each trial, the significance of their results, as well as the quality of the studies. As these studies did not have results in which PSE produced a significant decrease in performance, significant outcomes signify that the study was able to find some kind of ergogenic effect while testing their subjects.

The participants in these studies were primarily male, females accounted for only 9.7% out of the total pool of subjects. Participants were on average 24.38 years of age, and in general good health. In total, the studies examined 93 individuals. 7 out of the 8 studies examined the ergogenic effect of a single dose of pseudoephedrine; the remaining study was a multiple dose trial.

Contrary to the apparent controversy over whether or not PSE can generate an ergogenic effect, the results of these studies seem fairly consistent. There appears to be a threshold value at which it becomes possible to detect the ergogenic effect of pseudoephedrine. The studies considered here can be separated into a relatively low dosage group and a high dosage group. Those below 120 mg, including the trial run by Swain et. al, as well as the sole multiple dose trial run by Chester et. al, fall into the low dosage group, which report no ergogenic effect of any sort. As was mentioned in the methods section there were articles found that were unable to be retrieved, however the abstracts of those articles only confirm this result. Below this dosage, it is definitive that no ergogenic effect can be found, and this range is well above that needed for a therapeutic dose.

Those trials with dosages above this value report finding some sort of ergogenic effect. The trial run by Gill et. al was able to find a significant increase in anaerobic performance while running a 30 second Wingate test, as well as an increase in isometric leg extension. The PSE group in this study had a mean +- SD of 1262.5+-48.5 over the placebo group which had a mean+-SD of 1228.4+-47.1 in peak power measured in watts for the Wingate test. The values in the leg extension test were 321.1+-62.0 in the PSE group over 295.7+-72.4 in the placebo group. However, they were unable to find any benefit in the bench press test, which showed that the possible ergogenic effects would be limited to the lower portion of the body. It’s important to note that while ingestion of PSE resulted in an increase in peak power that did not correspond to a significant increase in total work performed, which corresponds to a higher average power as the time was kept constant in these 30 second Wingate tests. However, there was a trend towards this result, so this study verifies an anaerobic ergogenic effect produced by PSE in high dosage.

The next two studies evaluated the possibility of an aerobic ergogenic effect produced by PSE. Hodges’ 2006 study noted a 5.8 second/2.1% decrease in time to completion in a 1500 m trial. This was noted as significant decrease in time, which would correlate to an increase in average power, which somewhat contradicts Gill’s result should anaerobic vs aerobic comparison be deemed valid. This report was odd in that 8 people were included in study 1 to determine the efficacy of the 1500m test, but only 7 people participated in the study 2 which was the RCT crossover with placebo study. It was not mentioned whether or not participants in study 2 overlapped with those in study 1 which would result in a baseline that nulls the results of the crossover study as the baseline time to completion was lower than either the placebo or PSE group by .3% with significance set at .5%. It is also important to note that all participants showed some sort of improvement when dosed with PSE.

The study done by Pritchard-Peschek et. al in 2010 confirms the trial run by Hodges in 2006. In this study a 180 mg dose of PSE was shown to provide a 5.1% decrease in cycling time set at the same significance level of .5%. Once again all participants showed some sort of improvement when dosed with PSE, as in the trial done by Hodges. In light of the study done by Hodges and Gill, it is confirmed that both an anaerobic and aerobic ergogenic effect is produced by the ingestion of high doses of PSE in the lower portion of the body.

Table 1

StudyDesignSubject descriptionPseudoephedrine dosageMain OutcomesOutcome results
Gillies et. al 1996RCT crossover, single dose10 male cyclists120 mg 90 minutes prior to testingTime to completion,
Isometric muscle test
Not significant,
Not significant
Swain et. al 1997RCT crossover, single dose20 male cyclists, 10 relevant to pse1mg/kg, 2mg/kg 60 minutes prior to testingTime to exhaustionNot significant
Gill et. al 2000RCT crossover,
Single dose
22 male athletes180 mg 45 minutes prior to testingWingate test, Isometric leg extension, bench pressSignificant, Significant,
Not significant
Chester et. al 2002RCT crossover, multiple dose8 male endurance runners60 mg,6 doses over 36 hours, 4 hours prior to testing5000m time trial, steady state exercise
Statistical data not reported
Not significant,
Not significant
Chu et. al 2002RCT crossover, single dose10 male, 9 female healthy university students120 mg, 2 hours prior to testingWingate test, MVC grip test, dorsi-flexion testNot significant, Not significant,
Not significant
Hodges et. al 2003RCT crossover, single dose11 male athletes60 mg, 90 minutes prior to testing40% submaximal cycling, 60% submaximal cycling, Wingate testNot significant, Not significant,
Not significant
Hodges et. al 2006RCT crossover, single dose7 male athletes from a university’s athlete club2.5 mg/kg, 90 minutes prior to testing1500 m time trialReported as significant
Pritchard-Peschek et. al 2010RCT crossover, single dose6 male cyclists or triathletes180 mg, 60 minutes prior to testing70kJ/kg standardized work time trialSignificant

Table 1 cont.

Study# of Subjects recruited# of Subjects completedJadad scaleCochrane risk of bias
Gillies et. al 199610104 randomization sequence not describedAcceptable
Swain et. al 199720205Acceptable
Gill et. al 200022224 randomization sequence not describedAcceptable
Chester et. al 20021284/ randomization sequence not described, reason for drop outs acceptableAcceptable
Chu et. al 200219194 randomization sequence not describedAcceptable
Hodges et. al 200311114 randomization sequence not describedAcceptable
Hodges et. al 20068 or 15 or 773 randomization sequence not described, dropouts not made clearAssuming subjects recruited is 7, Acceptable
Pritchard-Peschek et. al 2010664 randomization sequence not describedAcceptable

Perhaps one of the most confusing aspects in studying the ergogenic effect of PSE is attempting to explain just how it could possibly produce an ergogenic effect. As mentioned in Prtichard-Pescheck et al.’s paper there is speculation (Chester et al., 2003; Gill et al., 2000; Gillies et al., 1996; Hodges et al., 2006; Swain et al., 1997) that PSE exerts an effect through “central” pathways and that the potential mechanisms of action may be related to one of the many sympathetic actions of NE, including increased fuel mobilization or stimulation of the central nervous system.
Hodges et al. (2006) alluded to the possibility that dopamine is involved in PSE’s mechanism of action. However, studies have yet to be done to confirm or deny these possibilities. In relation to its ban from use in competition, as was shown in the sole multiple dose study, no ergogenic effect was found even at the maximal therapeutic dose. The only effects were shown in single dose studies with at least triple that amount. In a study done by Chester et. al in 2004, it was shown that the maximal therapeutic dose done in a 36 hour time period had urine tests results of 149+-72 mg/L. This ranks above the current limits of testing which is 125 mg/L. Considering that there seems to be a threshold value at which ergogenic effect can be made possible, which is far above that of the maximal therapeutic dose, it is recommended that there is once again a raise in the limit of testing for PSE. It is also recommended that further studies be done to evaluate the potential mechanisms of action of PSE in relation to its ergogenic effect for the lower portion of the body.


Chester, N., T. Reilly, and D. R. Mottram. "Physiological, Subjective and Performance Effects of Pseudoephedrine and Phenylpropanolamine During Endurance Running Exercise." International Journal of Sports Medicine 24.1 (2003): 3-8. Print.

Chester, Neil, David R. Mottram, Thomas Reilly, and Mark Powell. "Elimination of Ephedrines in Urine following Multiple Dosing: the Consequences for Athletes, in Relation to Doping Control." British Journal of Clinical Pharmacology 57.1 (2004): 62-67. Print.

Chu, Kelly S., Timothy J. Doherty, Gianni Parise, Jamie S. Milheiro, and Mark A. Tarnopolosky. "A Moderate Dose of Pseudoephedrine Does Not Alter Muscle." Clinical Journal of Sport Medicine (2002): 387-90. Print.

Gill, Nicholas D., Anthony Shield, Anthony J. Blazevich, Shi Zhou, and Robert P. Weatherby. "Muscular and Cardiorespiratory Effects of Pseudoephedrine in Human Athletes." British Journal of Clinical Pharmacology 50.3 (2000): 205-13. Print.

Gillies, Hunter, Wayne E. Derman, Timothy D. Noakes, Peter Smith, Alicia Evans, and Gary Gabriels. "Pseudoephedrine Is without Ergogenic Effects during Prologned Exercise." Journal of Applied Physiology 81 (1996): 2611-617. Print.

H. Hodges, Alastair N., Brenna M. Lynn, Jonathan E. Bula, Meghan G. Donaldson, Marc O. Dagenais, and Donald C. Mckenzie. "Effects of Pseudoephedrine on Maximal Cycling Power and Submaximal Cycling Efficiency." Medicine & Science in Sports & Exercise 35.8 (2003): 1316-319. Print.

Hodges, Kate, Sarah Hancock, Kevin Currell, and Asker Jeukendrup. "Pseudoephedrine Enhances 1500 M Running Performance." Medicine & Science in Sports & Exercise 37.Supplement (2005): S43. Print.

Pritchard-Peschek, Kellie R., David G. Jenkins, Mark A. Osborne, and Gary J. Slater. "Pseudoephedrine Ingestion and Cycling Time-Trial Performance." International Journal of Sport Nutrition and Exercise Metabolism 20 (2010): 132-38. Print.

Swain, Randall A., David M. Harsha, John Baenziger, and Robert M. Saywell. "Do Pseudoephedrine or Phenylpropanolamine Improve Maximum Oxygen Uptake and Time to Exhaustion?" Clinical Journal of Sport Medicine 7.3 (1997): 168???173. Print.

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