Abstract
thletes are increasingly relying on natural supplements to improve athletic performance. Echinacea, a common herbal supplement, has been studied for its potential erythropoietin-enhancing effects, with mixed results in the literature. The purpose of this meta-analysis is to determine whether echinacea supplementation has erythropoietic or ergogenic effects in athletes. A search strategy was developed to identify trials studying the impact of echinacea supplementation on erythropoiesis and maximal oxygen uptake. The database search yielded 502 studies, 496 of which were excluded in the two-reviewer screening process. Six studies with a total of 107 athletes were included in the analysis. For hemoglobin and hematocrit levels, there were small, positive effect sizes when comparing the difference in pre- and post-intervention levels between the echinacea and placebo groups, at 0.38 (p= 0.02, 95% CI−0.04–0.80,I 2 = 70%) and 0.34 (p< 0.01, 95% CI−0.10–0.78,I 2 = 86%), respectively, though they did not reach statistical significance. There was also no statistically significant change in erythropoietin (effect size−0.29,p= 0.05, 95% CI−0.75–0.17,I 2 = 67%) or maximal oxygen uptake (effect size−0.20,p= 0.95, 95% CI−0.60–0.21,I 2 = 0%). Echinacea supplementation did not influence erythropoietin, hemoglobin, hematocrit, or maximal oxygen
2 = 70%) and 0.34 (p< 0.01, 95% CI−0.10–0.78,I 2 = 86%), respectively, though they did not reach statistical significance. There was also no statistically significant change in erythropoietin (effect size−0.29,p= 0.05, 95% CI−0.75–0.17,I 2 = 67%) or maximal oxygen uptake (effect size−0.20,p= 0.95, 95% CI−0.60–0.21,I 2 = 0%). Echinacea supplementation did not influence erythropoietin, hemoglobin, hematocrit, or maximal oxygen uptake in athletes; however, the evidence base is limited. Keywords:dietary supplementation; performance enhancement; athletic performance 1. Introduction Echinacea purpureais a member of the sunflower family that has long been used for its anti-inflammatory and pro-immunity effects, with a myriad of uses in holistic medicine ranging from a common cold remedy to anxiolytic psychotropic effects [1]. Echinacea’s most well-studied application is for the prevention and treatment of the common cold; a systematic review encompassing 14 studies and 1600 patients concluded that echinacea proved beneficial in decreasing both the incidence and duration of the common cold [2]. While echinacea’s role in immune health is well-characterized, it has also been investigated for possible ergogenic and erythropoietic properties. The mechanism of echinacea’s impact on erythropoiesis is poorly understood, however the basic science literature has shown an increase in pro-inflammatory cytokines (i.e., IL-1, TNF-alpha, IL-6) and oxygen radicals by macrophages exposed to echinacea vs. control [3,4]. Erythropoiesis is influenced by cytokines such as IL-6 and TNF-alpha, which possess pro-inflammatory qualities; the body’s inflammatory response has been studied as a catalyst for an alternative “stress erythropoiesis” pathway for increased red blood cell production during periods of phys- ical stress [5,6]. Animal studies have demonstrated convincing findings with respect to echinacea’s erythropoietic potential; for example, in a double-blind, placebo-controlled crossover study conducted in horses, 42 days of echinacea supplementation to the horse feed increased both the size and concentration of peripheral red blood cells as well as Nutrients2024,16, 1991.
Nutrients2024,16, 1991 2 of 10 hemoglobin (Hb) concentration compared to the placebo group [7]. In another study in rab- bits, a dose-dependent, statistically significant increase in Hb concentration was observed during 3 months of echinacea supplementation; compared to the control rabbit population Hb level of 10.56 mg/dL, the low, medium, and high-dose echinacea groups were found to have average Hb levels of 11.19, 11.72, and 13.11 mg/dL, respectively [8]. Erythropoietin (EPO) and erythropoiesis-stimulating agents (ESAs) have been shown to positively influence aerobic capacity via the stimulation of red blood cell production, resulting in improved oxygen delivery to peripheral tissue. Maximal oxygen uptake (VO2 Max), which is the maximal rate at which oxygen is used by muscle tissue during exercise, is a commonly used metric to quantify aerobic fitness and has predictive value with respect to race performance in runners [9–11]. EPO and its downstream effects on Hb and hematocrit (Hct) levels are directly linked to VO2Max, particularly for trained endurance athletes, as VO2Max in muscle tissue has been shown to change from utilization limitation to diffusion limitation in response to endurance training [12]. A recent meta-analysis including 10 studieswith 238 patients demonstrated a benefit of EPO supplementation compared to placebo across a variety of athletic performance metrics including clinical measures such as hematological changes and pulmonary capacity as well as performance-related metrics like maximal power output and time to exhaustion; these effects were observed predominantly during maximal exercise intensities [13]. Consequently, EPO and ESAs have garnered particular attention in the athletic community as a means of performance enhancement, with the World Athletic Anti-Doping Agency (WADA) designating substances known to increase EPO as banned in and out of competition under substance category S2, class 1 [14]. Further complicating WADA’s efforts for clean sport, novel, effective, and increasingly difficult to detect ESAs are being developed [15]. As a result, athletes are increasingly relying on supplements for a safe, natural, and WADA-compliant alternative to procure a competitive advantage, with 45% of a sample of NCAA Division I athletes reporting regular supplement use; this number increases in endurance athletes, with 78% of a sample
clean sport, novel, effective, and increasingly difficult to detect ESAs are being developed [15]. As a result, athletes are increasingly relying on supplements for a safe, natural, and WADA-compliant alternative to procure a competitive advantage, with 45% of a sample of NCAA Division I athletes reporting regular supplement use; this number increases in endurance athletes, with 78% of a sample of elite college endurance runners reporting supplement use during training and competition [16,17]. In a study of Canadian high- performance athletes, a staggering 87% endorsed using three or more supplements in the past 6 months [18]. Echinacea supplementation provides an attractive option for per- formance enhancement as a well-tolerated natural supplement. However, the literature regarding echinacea’s erythropoietic effects in human clinical trials offers mixed results. For example, Whitehead et al. (2012) found significant increases in EPO, VO2Max, and running economy after 4 weeks of echinacea supplementation in a small sample of healthy young men; conversely, several other controlled trials have reported no change in these outcomes [19–22]. In addition, a recent literature review including five randomized con- trolled trials concluded that echinacea does not have EPO- or performance-enhancing qualities [23]. Importantly, further research has been conducted since this review was published in 2016, and a meta-analysis of the literature has not been conducted to date. The purpose of the present study is to understand whether echinacea supplementation enhances aerobic capacity and erythropoiesis through its effect on EPO, Hb, and Hct levels in the blood, as well as its impact on athlete VO2Max. 2. Materials and Methods This meta-analysis was registered with Prospero prior to initiation of research PROS- PERO 2023 CRD42023437889 Available from: display_record.php?ID=CRD42023437889. Accessed on 19 June 2024. 2.1. Search Strategy To capture all articles relevant to echinacea supplementation and sports performance, a search strategy was developed based on the General Methods for Cochrane reviews. In accordance with the Cochrane guidelines, we included the use of synonyms, related terms, and variant spellings in our terms (i.e., hemoglobin and haemoglobin) and employed the
and sports performance, a search strategy was developed based on the General Methods for Cochrane reviews. In accordance with the Cochrane guidelines, we included the use of synonyms, related terms, and variant spellings in our terms (i.e., hemoglobin and haemoglobin) and employed the
Nutrients2024,16, 1991 3 of 10 use of Boolean operators. Search strategies documented by previous literature reviews that identified publications related to echinacea were built upon [2]. The search terms “Echi- nacea” OR “coneflower” in the Title/Abstract field were combined using AND Boolean operator with the following terms in all fields: sport, athlete, athletic, performance, aerobic, anaerobic, exercise, oxygen, threshold, VO2Max, capacity, erythropoietin, epoetin alfa, erythropoiesis, hemoglobin, hematocrit, red blood cell, and doping (Figure).Nutrients 2024, 16, x FOR PEER REVIEW 3 of 11 2. Materials and Methods This meta-analysis was registered with Prospero prior to initiation of research (PROSPERO 2023 CRD42023437889 Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023437889. Accessed on 19 June 2024 . 2.1. Search Strategy To capture all articles relevant to echinacea supplementation and sports performance, a search strategy was developed based on the General Methods for Cochrane reviews. In accordance with the Cochrane guidelines, we included the use of synonyms, related terms, and variant spellings in our terms (i.e., hemoglobin and haemoglobin) and employed the use of Boolean operators. Search strategies documented by previous literature reviews that identified publications related to echinacea were built upon [2]. The search terms “Echinacea” OR “coneflower” in the Title/Abstract field were combined using AND Boolean operator with the following terms in all fields: sport, athlete, athletic, performance, aerobic, anaerobic, exercise, oxygen, threshold, VO 2 Max, capacity, erythropoietin, epoetin alfa, erythropoiesis, hemoglobin, hematocrit, red blood cell, and doping (Figure 1). Figure 1. The search strategy employed was the following: (terms in Box A combined using OR present in title/abstract) AND (terms in Box B combined using OR present in all fields). * Indicates that the term includes multiple spellings or endings of a word. Four databases (PubMed, CINAHL, Embase, and SPORTDiscus) were queried. Filters for “Human Subjects” and “Clinical Trial” study type were used as available in each database due to a high volume of animal studies and irrelevant study types (i.e., reviews, opinion articles, book chapters) identified during search strategy development. Each database query included all studies up to the date of the search (15 July 2023). 2.2. Study Screening and Data Extraction Screening for relevant
and “Clinical Trial” study type were used as available in each database due to a high volume of animal studies and irrelevant study types (i.e., reviews, opinion articles, book chapters) identified during search strategy development. Each database query included all studies up to the date of the search (15 July 2023). 2.2. Study Screening and Data Extraction Screening for relevant articles was conducted based on title and abstract using the systematic review management system Covidence (Covidence systematic review software, Veritas Health Innovation, Melbourne, Australia. Available at Figure 1.The search strategy employed was the following: (terms in Box (A) combined using OR present in title/abstract) AND (terms in Box (B) combined using OR present in all fields). * Indicates that the term includes multiple spellings or endings of a word. Four databases (PubMed, CINAHL, Embase, and SPORTDiscus) were queried. Filters for “Human Subjects” and “Clinical Trial” study type were used as available in each database due to a high volume of animal studies and irrelevant study types (i.e., reviews, opinion articles, book chapters) identified during search strategy development. Each database query included all studies up to the date of the search (15 July 2023). 2.2. Study Screening and Data Extraction Screening for relevant articles was conducted based on title and abstract using the systematic review management system Covidence (Covidence systematic review software, Veritas Health Innovation, Melbourne, Australia. Available at). All records were screened by two reviewers (S.D., C.B.). Disputes were reviewed by a third author (K.P.). Following the initial screen for relevance, each remaining record was further assessed to determine whether the study met the inclusion criteria. Criteria for inclusion in the analysis included all randomized, placebo-controlled or controlled pre-post trials that evaluated the impact of echinacea supplementation on EPO, Hb, Hct, or VO2Max in a study population of adult (age > 18) humans. The included studies underwent data extraction for variables of interest related to the study design (dosage of echinacea supplementation, length of supplementation, study population and demographics) as well as outcome measures of interest (pre- and post-intervention EPO, Hb, Hct, and VO2Max). In addition, a CONSORT score was
Hct, or VO2Max in a study population of adult (age > 18) humans. The included studies underwent data extraction for variables of interest related to the study design (dosage of echinacea supplementation, length of supplementation, study population and demographics) as well as outcome measures of interest (pre- and post-intervention EPO, Hb, Hct, and VO2Max). In addition, a CONSORT score was calculated for all studies based on the 25-item 2010 CONSORT Checklist, which is a guideline for reporting clinical trial data in a transparent and reproducible manner [24,25]. Each checklist item was assigned equal weight (1 point). Risk of bias was also evaluated for each study using the Cochrane Risk of Bias Tool [26].
Nutrients2024,16, 1991 4 of 10 2.3. Statistical Analysis The mean difference for each outcome of interest was calculated based on the re- ported pre- and post-intervention means. The standard deviations for each pre- and post-intervention outcome were pooled. Next, the difference in change in each outcome of interest was compared between study and control populations. The magnitude of dif- ference between control and treatment groups was measured using Hedges method for effect size (Hedges’ g) due to the small sample size within studies. Studies that did not include the outcome of interest for a particular analysis were excluded from that analysis. A fixed effects model was used to analyze the data given the small number of studies included in the analysis (n= 6) [27]. With respect to the VO2Max outcome, one study (Bellar et al., 2014 [22]) did not include a control group. For this study, the control groups of the other studies were averaged as a surrogate for the control population and given equal weight to the intervention group. In addition, one study (Whitehead et al., 2012 [19]) reported the VO2Max outcome as a percentage change from baseline; consequently, the raw data for the post-intervention VO2Max were extrapolated from the reported baseline. Two studies (Whitehead et al., 2007 [28], Whitehead et al., 2012 [19]) included the same patient population; consequently, the patients were only included in analysis once for each outcome of interest. Stevenson et al. [29] studied double-dose echinacea supplementation (16,000 mg) vs. 8000 mg vs. placebo; for simplification of the analyses and for improved comparison between studies, the 16,000 mg group was excluded from the present study. Analyses were conducted using Meta-Mar (v3.5.1), a free online meta-analysis service, and repeated using R Statistical Software (v4.3.3; R Core Team 2024) using the “meta” analysis package [30]. 3. Results The search strategy yielded 502 studies for screening once duplicates (n= 154) were removed. Of these, 493 were excluded based on title and abstract screening. Nine studies underwent full text review with three studies failing to meet inclusion criteria. After screening and full text review, six studies were included in
Team 2024) using the “meta” analysis package [30]. 3. Results The search strategy yielded 502 studies for screening once duplicates (n= 154) were removed. Of these, 493 were excluded based on title and abstract screening. Nine studies underwent full text review with three studies failing to meet inclusion criteria. After screening and full text review, six studies were included in the final analysis (Figure).Nutrients 2024, 16, x FOR PEER REVIEW 5 of 11 Figure 2. PRISMA Flow Diagram. Adapted from Covidence (Covidence systematic review software, Veritas Health Innovation, Melbourne, Australia. Available at www.covidence.org). Combining the participants within all included studies, a total of 107 athletes were considered in the analysis. The length of supplementation between pre- and post- intervention measurements varied between study, ranging from 28 to 42 days. All studies dosed the echinacea at 8000 mg daily. The included studies are summarized in Table 1. Table 1. Study design of included studies. Study n Population Female n Intervention Length of Intervention Intervention n Placebo n Outcomes of Interest Baumann et al., 2013 [20] 16 distance runners not reported 8000 mg daily ech 42 days 9 7 VO 2 Max, Hb, Hct Stevenson et al., 2016 [29] 30 endurance- trained athletes 15 8000 mg daily ech 35 days 15 15 VO 2 Max, Hb, Hct, EPO Martin et al., 2019 [21] 24 above- average aerobic fitness 0 8000 mg daily ech 42 days 12 12 Hb, Hct, EPO Whitehead et al., 2007 * [28] 24 recreational athletes 0 8000 mg daily ech 28 days 12 12 Hb, Hct, EPO Figure 2.PRISMA Flow Diagram. Adapted from Covidence (Covidence systematic review software, Veritas Health Innovation, Melbourne, Australia. Available at).
Nutrients2024,16, 1991 5 of 10 Combining the participants within all included studies, a total of 107 athletes were con- sidered in the analysis. The length of supplementation between pre- and post-intervention measurements varied between study, ranging from 28 to 42 days. All studies dosed the echinacea at 8000 mg daily. The included studies are summarized in Table. Table 1.Study design of included studies. Study n Population Female n Intervention Length of Intervention Intervention n Placebo n Outcomes of Interest Baumann et al., 2013 [20] 16 distance runners not reported 8000 mg daily ech 42 days 9 7 VO2Max, Hb, Hct Stevenson et al., 2016 [29] 30 endurance-trained athletes 15 8000 mg daily ech 35 days 15 15 VO2Max, Hb, Hct, EPO Martin et al., 2019 [21] 24 above-average aerobic fitness 0 8000 mg daily ech 42 days 12 12 Hb, Hct, EPO Whitehead et al., 2007 * [28] 24 recreational athletes 0 8000 mg daily ech 28 days 12 12 Hb, Hct, EPO Whitehead et al., 2012 * [19] 24 recreational athletes 0 8000 mg daily ech 28 days 12 12 VO 2Max Bellar et al., 2014 [22] 13 recreational athletes 0 8000 mg daily ech † 30 days 13 0 VO 2Max * Studies completed using same participants; † no placebo group. The average CONSORT grade for all studies was 13. The Cochrane risk of bias for each study are summarized in Figure.Nutrients 2024, 16, x FOR PEER REVIEW 6 of 11 Whitehead et al., 2012 * [19] 24 recreational athletes 0 8000 mg daily ech 28 days 12 12 VO 2 Max Bellar et al., 2014 [22] 13 recreational athletes 0 8000 mg daily ech † 30 days 13 0 VO 2 Max * Studies completed using same participants; † no placebo group. The average CONSORT grade for all studies was 13. The Cochrane risk of bias for each study are summarized in Figure 3. Figure 3. Cochrane risk of bias [19–23]. Outcome data by study are summarized in Table 2. Table 2. Outcome data by study. Echinacea Group Placebo Group EPO mean (SD) Hb mean (SD) Hct
participants; † no placebo group. The average CONSORT grade for all studies was 13. The Cochrane risk of bias for each study are summarized in Figure 3. Figure 3. Cochrane risk of bias [19–23]. Outcome data by study are summarized in Table 2. Table 2. Outcome data by study. Echinacea Group Placebo Group EPO mean (SD) Hb mean (SD) Hct mean (SD) VO2 Max mean (SD) EPO mean (SD) Hb mean (SD) Hct mean (SD) VO2 Max mean (SD) pre post pre post pre post pre post pre post pre post pre post pre post Baumann 2013 [20] - - 14.93 (1.27) 15.55 (0.80) 43.57 (2.38) 42.85 (1.46) 67.37 (4.62) 67.23 (5.82) - - 15.4 7 (0.9) 15.8 3 (0.7) 44.6 1 (2.4) 43.5 (1.34) 65.17 (6.60) 66.25 (6.23) Stevenso n 2016 [29] 6.2 (0.6) 6.2 (0.8) 14.4 (0.3) 14.3 (0.3) 42.4 (0.8) 42.8 (0.7) 59.3 (1.95) 62 (1.80) 9.7 (0.8) 9.8 (0.6) 14.7 (0.3) 14.5 (0.3) 43.1 (0.9) 43.2 (0.9) 61.0 (1.45) 63.8 (1.50) Martin 2019 [21] 7.92 (1.13) 8.86 (1.54) 14.8 (0.3) 14.8 (0.2) 42.9 (0.9) 42.7 (0.5) - - 9.21 (1.3) 9.74 (1.81) 15.0 (0.3) 15.1 (0.2) 43.2 (0.9) 43.6 (0.6) - - Whitehea d 2007/2012 [19,28] 12.37 (0.87) 10.32 (0.51) 14.5 (0.2) 14.6 (0.2) 41.9 (0.5) 42.9 (0.5) 43.8 (1.70) 43.8 (1.70) * 10.63 (0.68) 9.54 (0.98) 14.7 (0.1) 14.5 (0.2) 42.5 (0.3) 42.3 (0.5) 40.7 (1.3) 41.31 (1.3) * Bellar 2014 [22] - - - - - - 51 (6.8) 51.8 (6.5) - - - - - - x x Figure 3.Cochrane risk of bias [19–23]. With respect to EPO, the small, negative effect size of−0.29 (p= 0.05, 95% CI −0.75–0.17,I 2 = 67%) demonstrated no difference between the echinacea and placebo groups. There were small, positive effect sizes when comparing the difference in pre- and post-intervention Hb and Hct levels between the echinacea and placebo groups, at 0.38 (p= 0.02, 95% CI−0.04–0.80,I 2 = 70%) and 0.34 (p< 0.01, 95% CI−0.10–0.78,I 2 = 86%), respectively; however, this did not reach statistical significance. Change in VO2Max was not significantly different between echinacea supplementation and control
Description
This meta-analysis evaluates the effects of echinacea supplementation on athletic performance.