Our results quantitatively demonstrate that PSE causes a small increase in HR during exercise. In terms of the other parameters studied, there were trivial improvements in time trial performance, a trivial reduction in RPE and trivial decreases in GLU and LAC levels during exercise. It could be argued that these equivocal findings suggest a meta-analysis would better wait until a larger number of studies have been performed, thus leading to a more robust conclusion. However, the intriguing subgroup analyses argue against this. Effect sizes tended to be larger in just those athletes of most concern to anti-doping agencies (younger and well-trained athletes). They also suggest an optimal time and activity to take the drug, indicating PSE is most effectively administered less than 90 min before a short bout of exercise of less than 25 min. Of particular concern is that our subgroup analysis confirms the qualitative review [3] that larger doses (> 170 mg) are likely to be the most effective in improving performance. However, this was accompanied by a larger effect on increasing HR. A recent study looking at neuromuscular performance effects using these more effective higher PSE doses (180 mg) noted adverse side effects such as tachycardia and heart palpitations 24 h after exercise [18]. This suggests it will be increasingly difficult to get ethical approval to test the most effective doses of PSE, making it important to carry out the most complete analysis of the studies that have already been performed.

Comparison to previous systematic reviews

The initial search for our systematic review was carried out at approximately the same time as that of the recent systematic review by Trinh et al. [3] and subsequent searches uncovered no additional studies of interest. However, the studies deemed appropriate for detailed analysis were different. Whilst our search confirmed and agreed with the many of the studies chosen by Trinh et al. [3], we included some additional publications. As our enhanced sample enabled the meta-analysis that Trinh et al., [3] felt not to be justified, we feel it is important to justify the rationale for the additional papers chosen.

Both reviews focused on the performance effects of PSE using a randomised-controlled trial approach. As our study was designed to enable a meta-analysis, it was restricted to sports performances that had a time trial component and/or included quantitative measures that could inform potential underlying mechanisms (such as LAC, GLU, HR, and RPE). This biased our search to include only those studies that focused on sports events with an aerobic component. This approach ruled out one article included by Trinh et al. [3], a study by Chu et al. [10] showing that a moderate dose (120 mg) of PSE did not alter muscle action strength or anaerobic power. It also ruled out a recent study published after both systematic searches. In 2015, Pallarés et al. [18] measured bench press and full squat exercise performance against four incremental loads (25%, 50%, 75%, and 90% one repetition maximum). No effects were seen except in the highest dose studied (180 mg) where PSE seemingly increased lower body muscle contraction velocity.

Trinh et al. [3] conducted their analysis on only 10 studies and concluded that the data were insufficient and too variable to enable a meta-analysis. We feel that, at least in part, this conclusion is based on the combination of a flawed search strategy and an overly restrictive view of which articles to select from that search. We found seven additional papers omitted by Trinh et al. [3], all of which used randomised placebo designs to assess the effect of PSE on aspects of performance. On this basis, these studies could, in principle, fit the criteria used by Trinh et al. [3]. These articles are highlighted in Table 1 and owing to their importance to our final meta-analysis, it is crucial that we justify their inclusion individually (see discussion in Table 4).

Table 4 Characteristics of studies included in this meta-analysis that were not included in Trinh et al. [3] systematic review Full size table

Given that Trinh et al. [3] only included 10 articles in their final qualitative synthesis, the exclusion of seven relevant studies represents a significant fraction of the available literature. Crucially, all seven studies excluded showed no effect of PSE on performance. This may not be related to a dose effect as three studies [6, 8, 22] were at low (clinically approved) doses and four were at supratherapeutic doses [19, 20, 23, 24]. It is possible that excluding such a large fraction of data biased the final conclusion of that review, particularly the comment that “qualitative analysis showed overall positive results in favour of PSE over placebo for PSE doses ≥180 mg or 2.5 mg/kg”. Of the 10 studies included by Trinh et al. [3], all three high dose studies showed an ergogenic effect, and all seven lower dose studies showed PSE to be ineffective, making their conclusion reasonable. However, adding the seven omitted studies would significantly weaken this argument as only 3 out of 7 high dose studies demonstrate a positive effect of PSE. Therefore, although there is clearly an increase in HR during exercise due to PSE, we are more equivocal than Trinh et al. [3] about the drug’s positive ergogenic effects, even at high doses. Including these new articles does, however, strongly favour the conclusion that when taken at clinically recommended doses, PSE has only a very minor effect on HR and no ergogenic effect in terms of performance.

Relevance for putative mechanism of any performance benefit

Our analysis suggests that only at high doses does PSE have the potential to enhance sports performance. It also sheds some light on to the possible mechanism that could be operating. A previous meta-analysis demonstrated that, at rest, PSE caused a statistically significant small increase in systolic blood pressure (1 mmHg) and HR (3 beats/min), although diastolic blood pressure did not change. We found 11 studies reporting HR changes following PSE ingestion during exercise. Our data showed that this mean HR increase is maintained during exercise with the largest increase being 13 beats/min [20]. The subgroup analyses showed that the biggest effect sizes were seen at high doses and in athletes with high maximal oxygen uptake (VO 2 max). Three individual studies showed a performance effect [13,14,15]. Gill et al. [13] showed that HR increased significantly from 166 to 175 beats/min, and Hodges et al. [14] demonstrated a non-significant increase from 185 to 190 beats/min. Similarly, Pritchard-Peschek et al. [15] also reported a non-significant increase was from 176 to 180 beats/min. Given that studies that showed no performance increase showed at least as large and as significant HR increases during exercise, it seems unlikely that—in and of itself—changes in HR underpin any performance enhancement.

In relation to RPE, GLU, and LAC levels in exercise, a lack of data is more challenging to overcome with only between five and seven studies reporting sufficient information. We observed a small, trivial decrease in all of these parameters. However, it is worth exploring the individual studies, as the statistical power of pairing individuals in a crossover study is lost during a meta-analysis.

For RPE, none of the five studies included showed meaningful differences between PSE and placebo [8, 12, 15, 22, 23]. An additional study did not report values, but did state that there were no significant differences [7]. Glucose levels were not significantly different in four of the five studies included in the meta-analysis [6, 7, 14, 23]. An additional study, not part of the analysis as it reported no values, again stated a lack of any PSE effect on GLU [25]. However, one study did report increased GLU levels post exercise following PSE treatment [15]. This was one of the few studies that also showed a performance effect (decreased time in cycling TT). Interestingly in this case, it was the pre-exercise GLU level that correlated with the increased performance in the cycling time trial. Lactate levels did not significantly change in five of the seven studies included in the meta-analysis [7, 13,14,15, 23]. However, they did significantly decrease in two studies [19, 24]. In one study, LAC levels were not reported, the authors nonetheless stating there was no significant change [25].

Given that only 3 of the 16 studies included in our analysis showed a performance benefit, it is worth exploring in detail, which secondary parameters changed in these studies to see if this can inform mechanism. Gill et al. [13] measured an increase in maximum torque in an isometric knee extension and an improvement in peak power during maximal cycle performance in 22 healthy male volunteers. In terms of lung function, small, but significant, increases were seen in forced vital capacity (FVC) and forced expired volume in 1 s (FEV) following ingestion of PSE. These are consistent with the well-characterised role of PSE in stimulating the sympathetic nervous system and acting as a bronchodilator [33]. This is unlikely to explain the effect on peak power observed here, nor is a small increase in FVC and FEV likely to improve sports performance in endurance events given the lack of consistent ergogenic effect of drugs that are far more effective in increasing lung function such as salbutamol [34].

Hodges et al. [14] found that PSE significantly decreased time to completion of a 1500 m time trial in 7 healthy male subjects. However, no other measured parameters (HR, LAC, GLU, arterial O 2 partial pressure, arterial carbon dioxide partial pressure and arterial oxygen saturation) were significantly altered.

Pritchard-Peschek et al. [15] reported a significant improvement in a cycling TT performance following PSE in six trained male cyclists and triathletes. As previously noted, this study reported increased post exercise GLU levels following PSE treatment. No significant PSE effect was found on LAC, blood pH, substrate oxidation, RPE, or HR. PSE did significantly increase plasma norepinephrine concentrations, an expected outcome for a drug that has indirect agonist activity on cardiac β receptors and peripheral α 1 receptors, through release of norepinephrine from the cytoplasmic pool [14]. However, the validity of any ergogenic effects of this increased β receptor activity is undermined by the two subsequent similar studies from this group, which used larger sample sizes (n = 10) and showed no performance benefit despite an increase in plasma norepinephrine [24, 25].

Readily available drugs used as decongestants that are not banned by WADA such as phenylephrine act directly on peripheral α receptors and have limited ability to cross the blood-brain barrier and/or act as a central stimulant [2]. PSE is more lipid soluble and is therefore more accessible to the central nervous system. Consequently, it can, in principle, act as both a peripheral or central stimulant. However, the biochemical, physiological, and psychological data in our systematic review and meta-analysis fail to give a consistent explanation to underpin a possible ergogenic mechanism. Heart rate did increase, however, in most studies there was no accompanying performance benefit; indeed in some studies which showed a performance benefit, there is no significant heart rate change. A few studies show plasma metabolite changes (GLU/LAC) that might suggest improved substrate or oxygen utilisation. However, other studies show no metabolite changes even when there is a performance benefit. Unlike other WADA banned stimulants such as amphetamines [35], perception of effort (RPE) is completely unchanged by PSE at low or high doses, irrespective of any performance benefit.

Rationale for WADA listing pseudoephedrine as a prohibited doping substance

The WADA Prohibited List may include any substance that satisfies any two of the following three criteria: (i) it has the potential to enhance or enhances sport performance; (ii) it represents an actual or potential health risk to the athlete; (iii) it violates the spirit of sport. Apparently, PSE fulfilled these criteria and was banned until 2004, did not fulfil them between 2004 and 2010 (when it was removed from the banned list), and then fulfilled them again after 2010 (when it returned to the banned list). Currently, PSE is only banned in competition. A doping offence is committed if an athlete has a urine PSE concentration of greater than 150 μg/ml. Even given the biological variability of single point measurements, this level is high enough that it should not be possible to produce a positive urine test if an athlete discontinues a therapeutic dose of PSE more than 24 h before competition. However, it is possible, though not guaranteed, to exceed these levels within 24 h of taking PSE at the normal therapeutic dose [9], and it is impossible not to exceed them when on a supratherapeutic dose [24].

WADA monitored PSE use in doping samples when it was not banned from 2004 to 2009. WADA’s case for reintroducing the PSE ban in 2010 was made in a Q and A statement published as part of the 2010 prohibited list [36]:

“Results of the Monitoring Program over the past five years have shown a sustained increase in samples containing pseudoephedrine. The program indicated clear abuse of this substance with high concentrations in a number of sports and regions. In addition, available literature shows scientific evidence of the performance-enhancing effects of pseudoephedrine beyond certain doses.”

Some increase in PSE use would be expected when the ban was lifted given that the best drug to treat nasal decongestion in competition was now freely available to athletes without the threat of sanction. Presumably, the geographic and sport-specific nature of the increase argued against this more benign interpretation. An additional concern, not specifically noted by WADA, but stated by some anti-doping researchers, is that one of PSE’s minor metabolites, norpseudoephedrine (cathine), was on the banned list during this period. Athletes could therefore claim a failed cathine doping result was a consequence of taking the now permitted PSE. PSE use would, therefore, mask cathine abuse [37].

However, our systematic review does question WADA’s statement that “available literature shows scientific evidence of the performance-enhancing effects of pseudoephedrine beyond certain doses.” A research article would need to have been published between 2004 and 2009 to inform this change of policy. In this period, our search uncovered three studies reporting no performance effect [7, 14, 23] and only one coming to the contrary view [14]. That study was published in 2006 and is the only paper WADA cite in the 2004–2009 period showing a performance benefit in justification of their decision [38]. It showed a performance benefit based on only six UK college 1500 m runners, the fastest running over 4:15 min for the distance. The International Association of Athletics Federations (IAAF) qualifying standard for this event in the 2016 Olympics was 3:36 min, making this subject group far from elite. Given that PSE is not banned out of competition, a WADA-approved study in elite athletes would be beneficial to support the current policy.

Given the difficulty of taking measurements in elite athletes, it is possible that WADA treat the systematic abuse of a drug by elite athletes as partial evidence for its efficacy in that subject group. The use of a higher than necessary dose of a medicine (or even the use at all of a medicine where there is no clinical need) is also considered to be against the “spirit of sport”. A similar rationale was presumably used for the more infamous 2016 banning of the cardiac drug meldonium once the extremely widespread use of it amongst Eastern European athletes became known [39], despite the poor evidence base for its performance-enhancing effect. In the case of PSE, there is the added concern, that in some countries, to get access to the higher doses, athletes need to circumvent government regulations designed to combat the production of illegal recreational drugs [2].