Caffeine augments the increase in circulating concentrations of the pleiotropic cytokine interleukin (IL-) 6 in response to high-intensity and/or long-duration exercise in male individuals (1–7). The rationale for these previous studies has typically pertained to the role of IL-6 in the regulation of inflammation, immune function, and/or exercise-induced skeletal muscle damage. More recently, an argument has been presented that suggests that the IL-6 response to exercise could be of appreciable benefit to clinical populations, such as people with cancer and/or cancer–cachexia (8), and/or adults with visceral obesity (9). These proposed benefits include decreasing inflammation (10,11), decreasing visceral adiposity (9), promoting skeletal muscle hypertrophy and attenuation of sarcopenia (12), and improving glucose tolerance and insulin sensitivity (13,14). Unfortunately, high-intensity and/or long-duration exercise is not always feasible for all people. No prior studies have determined if caffeine can augment the IL-6 response to more manageable, relatively short-duration, moderate-intensity exercise.
One of the mechanisms thought to contribute to IL-6 release from exercising skeletal muscle is lactate production. Evidence has been accumulated from several species. In rodents, lactate injection into skeletal muscle increased IL-6 mRNA and serum IL-6 concentration, and inhibition of lactate-stimulated protease activity lowered IL-6 secretion after exercise (15). In humans, end-exercise plasma lactate concentration is positively correlated with postexercise plasma IL-6 concentration (15–17).
In addition to its influence on the IL-6 response to exercise, caffeine is also known to increase circulating concentrations of lactate during exercise, including moderate-intensity exercise (18–24). Thus, it seems feasible that through its actions on lactate, caffeine may also augment the IL-6 response to moderate-intensity exercise. Such an effect may be of particular benefit to the health of patient populations unable to perform high-intensity, long-duration exercise. Accordingly, the purpose of the current study was to provide proof of concept that caffeine, ingested before moderate-intensity exercise, would lead to greater circulating concentrations of both lactate and IL-6. In addition, to further extend previous observations (1–7) and provide novel insight into the presence or absence of potential sex differences, the study was conducted in a population comprising both male and female individuals. We hypothesized that caffeine, ingested before moderate-intensity exercise, would lead to greater circulating concentrations of lactate and IL-6 in both male and female individuals.
To avoid the burden of repeated laboratory-based exercise in a potentially vulnerable clinical population, adult male and female individuals considered healthy, but otherwise untrained or recreationally active, were invited to participate in this proof-of-concept study. The project was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Colorado State University (Protocol No. 20-10002H). Written informed consent was provided by all participants. Inclusion criteria consisted of age between 18 and 75 yr, and willingness to complete two 30-min bouts of moderate-intensity cycle ergometer exercise. Exclusion criteria included previous diagnosis of cancer, tobacco use, any recurring injury-limiting exercise, pregnancy or breast-feeding, a contraindication to exercise identified during a graded exercise test incorporating 12-lead ECG assessment, and contraindications to caffeine including unusual heart rhythm, unmedicated high blood pressure, and/or use of medications known to interact with caffeine (such as quinolones, theophylline, duloxetine, ephedra or guarana, rasagiline, or tizanidine).
This was a double-blind, randomized, repeated measures, placebo-controlled, crossover study. After screening and assessment of baseline physiological characteristics, participants reported to the laboratory on two separate occasions to perform 30 min of moderate-intensity stationary cycle ergometer exercise. One hour before exercise, participants ingested caffeine or placebo. Blood was sampled for the determination of lactate and IL-6 concentration. Indirect calorimetry was used to quantify gas exchange during exercise.
Screening and baseline physiological characteristics
Before study enrollment, potential participants completed a detailed electronic medical history questionnaire. Responses requiring additional queries were addressed either in-person, via telephone, or video conference. Body size and composition were assessed using dual-energy x-ray absorptiometry (Hologic, DiscoveryW, QDR Series, Bedford, MA), and a physician’s digital scale and stadiometer, as previously described (25,26). A supervised exercise stress test consisting of a 12-lead ECG and indirect calorimetry (Parvo Medics, Sandy, UT) to determine peak oxygen uptake (V̇O2peak) was completed, as previously described (27). V̇O2 at ventilatory threshold was determined using established methods (28).
After initial screening, participants returned to the laboratory on two separate occasions separated by at least 72 h. Participants arrived at the laboratory approximately 1 h after consuming a standardized breakfast (Ensure Original Nutrition Shake; Abbott Laboratories, Lake Bluff, IL; 220 kcal, 16% protein, 24% fat, 60% carbohydrate) and having abstained from caffeine for the previous 48 h to allow for sufficient washout from previous caffeine consumption, consistent with other studies (1,2). On arrival, a venous catheter was placed into a dorsal hand vein, and the hand and forearm were wrapped in a heated blanket for the sampling of arterialized venous blood (29).
After baseline measurements of heart rate and blood pressure, participants ingested 6 mg·kg−1 of caffeine or placebo (dextrose) in the form of preprepared capsules. Approximately 25 mL of arterialized venous blood was sampled before caffeine/placebo ingestion (minute 0) and again at 60, 95, and 125 min. Blood intended for IL-6 analysis was immediately transferred into chilled tubes coated with ethylenediaminetetraacetic acid, and blood intended for lactate analysis was transferred into chilled tubes coated with sodium fluoride and potassium oxalate. Samples were placed on ice for up to 30 min before isolation of plasma via chilled (4°C) centrifugation for 10 min. Aliquots (1 mL) of plasma were stored at −80°C until analysis.
Stationary cycle ergometer (electrically braked; Corvial Cpet, Lode BV, Groningen, the Netherlands) exercise began 60 min after caffeine/placebo ingestion to facilitate absorption of caffeine (1–4,30). The exercise consisted of a 5-min warm-up of near load-less cycling, followed by 30 min of cycling at a work rate corresponding to a targeted metabolic rate equivalent to 60% of V̇O2peak. To confirm the actual metabolic rate, exhaled gasses were analyzed during minutes 5–10 and 25–30.
Determination of lactate and IL-6
Lactate analysis was completed in duplicate via an automated analyzer (YSI 2900; Xylem Inc., Rye Brook, NY). IL-6 analysis was undertaken using an enzyme-linked immunosorbent assay (HS600C; R&D Systems Inc., Minneapolis, MN) according to the manufacturer’s instructions; samples were analyzed in duplicate.
Statistical analysis was completed using commercially available software (SigmaStat 3.0; Systat Software Inc., San Jose, CA). Differences in baseline physiological characteristics between male and female participants were analyzed using one-way ANOVA. Differences in plasma lactate and IL-6 concentrations were calculated using a two-way ANOVA (treatment–time) with repeated measures (time). Tukey tests were used to further investigate identified main effects. Relations between end-exercise plasma lactate and postexercise IL-6 concentrations were explored using Pearson product–moment correlations. All data, unless otherwise stated, are expressed as mean ± SD. The criterion for significance is an α value of <0.05.
The progress of all participants throughout the trial (from screening and enrollment through to completion) is presented in Figure 1. Twenty-six adults volunteered to participate in this study. Six participants withdrew or were excluded. Reasons for withdrawal/exclusion included failure to respond to scheduling requests after initial screening (n = 2), contraindications to exercise identified on the ECG stress test (n = 1), failure to meet the inclusion/exclusion criteria (n = 2), and exposure to COVID-19 combined with failure to reschedule final laboratory visit after quarantine (n = 1). Baseline physiological characteristics for the 20 remaining participants are presented in Table 1 and were typical for healthy but otherwise untrained or recreationally active men and women. When differentiated by sex, several potentially relevant differences between men and women were noted, including body composition and absolute V̇O2peak (i.e., unadjusted for body mass). V̇O2 at the ventilatory threshold, expressed as a percent of V̇O2peak, was not different between men and women, implying similar endurance training status.
TABLE 1 -
||25 ± 7
||27 ± 9
||24 ± 3
||170.8 ± 7.5
||175.4 ± 5.6
||166.2 ± 6.4
||74.7 ± 14.3
||83.0 ± 15.1
||66.5 ± 7.2
||25.2 ± 3.7
||26.5 ± 4.1
||23.8 ± 2.8
|Fat mass (kg)
||20.3 ± 5.8
||19.9 ± 6.9
||20.7 ± 4.9
|Lean mass (kg)
||52.1 ± 10.9
||60.5 ± 9.1
||43.7 ± 3.5
||27.1 ± 5.7
||23.5 ± 4.3
||30.8 ± 4.4
||42.2 ± 7.6
||44.6 ± 7.3
||39.7 ± 7.5
||3.09 ± 0.70
||3.60 ± 0.52
||2.59 ± 0.44
|V̇O2 at TVE (% of V̇O2peak)
||52.3 ± 9.4
||50.3 ± 10.8
||54.3 ± 7.9
Data are mean ± SD.
TVE, ventilatory threshold.
Cardiopulmonary responses to exercise
The cardiopulmonary responses to the 30-min bouts of stationary cycle ergometer exercise, with and without caffeine, are presented in Table 2. As intended, during the early stages of the exercise, the intensity was approximately 60% of V̇O2peak or 120% of the V̇O2 at ventilatory threshold. Throughout the exercise, despite no adjustment of the work rate, the metabolic response increased (main effect of time; P = 0.01), such that during the final 5 min, the intensity was approximately 65% V̇O2peak or 125% of the V̇O2 at ventilatory threshold. Caffeine did not influence this response (main effect of condition (placebo vs caffeine); P = 0.051). Consistent with the small increase in V̇O2, heart rate also increased throughout the exercise session. In contrast, respiratory exchange ratio (RER) was lower during the final 5 min of exercise compared with minutes 5–10. Caffeine did not seem to influence any of these respiratory responses except for greater ventilation at both time points. The only time–caffeine versus placebo interaction was for heart rate, as evidenced by a greater increase with caffeine across the 30 min (P = 0.048).
TABLE 2 -
Cardiorespiratory responses during exercise.
||148 ± 22
||156 ± 20
||147 ± 23
||157 ± 23
|SBP (mm Hg)
||151 ± 13
||153 ± 15
||152 ± 16
||153 ± 16
|DBP (mm Hg)
||71 ± 9
||71 ± 10
||74 ± 7
||76 ± 8
|MAP (mm Hg)
||98 ± 8
||98 ± 10
||100 ± 9
||101 ± 9
||59.6 ± 14.6
||64.5 ± 17.6
||62.4 ± 15.9
||68.0 ± 18.7
||0.95 ± 0.07
||0.90 ± 0.05
||0.94 ± 0.07
||0.90 ± 0.06
||1.84 ± 0.35
||1.96 ± 0.46
||1.90 ± 0.39
||1.99 ± 0.39
||1.74 ± 0.36
||1.74 ± 0.40
||1.77 ± 0.37
||1.78 ± 0.36
||60 ± 8
||64 ± 11
||62 ± 10
||66 ± 10
HR was recorded at minute 10 and minute 30. Blood pressure was recorded at minute 15 and minute 30. Data are mean ± SD.
HR, heart rate.
Blood pressure and rating of perceived exertion (RPE) were determined at minutes 15 and 30. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial (MAP) pressure did not change between minutes 15 and 30 (all P > 0.4). There was a main effect of condition (higher with caffeine) for DBP (P = 0.018) and MAP (P = 0.046) but not for SBP (P = 0.264; Table 2). RPE was greater (P < 0.001) at minute 30 (placebo: 14 ± 2 vs caffeine: 14 ± 2) compared with minute 15 (placebo: 13 ± 1 vs caffeine: 12 ± 1) but was unaffected by caffeine (P = 0.172). Importantly, all participants were able to complete all exercise sessions, indicating that the prescribed intensity was manageable.
Circulating lactate and IL-6 responses to caffeine and exercise
Circulating lactate concentrations are presented in Figure 2A. There was an interaction between caffeine and placebo over time (P < 0.001). Preexercise (minute 60) lactate concentration was unaffected by placebo or caffeine. However, at end-exercise, lactate concentration was appreciably increased above rest (P < 0.001), and the magnitude of increase was greatest in the caffeine condition resulting in end-exercise lactate concentrations of 5.12 ± 3.67 and 6.45 ± 4.40 mmol·L−1, in placebo and caffeine, respectively (P < 0.001). After 30 min of inactive recovery, lactate had decreased but was still higher in the caffeine condition (1.83 ± 1.59 vs 2.32 ± 2.09 mmol·L−1; P = 0.006).
Circulating IL-6 concentrations are presented in Figure 2B. Data from 2 of the 20 participants (2 of the men) were excluded from final analysis because of technical issues during the enzyme-linked immunosorbent assay. There was a significant interaction (P = 0.028). IL-6 concentration did not change for either condition between baseline and preexercise for either placebo or caffeine. At end-exercise, IL-6 concentration was appreciably increased above rest, but was not different between caffeine and placebo. Circulating IL-6 concentration was greatest 30 min after exercise compared with all other time points (P < 0.004) and greater with caffeine compared with placebo (2.88 ± 2.05 vs 4.18 ± 2.97 pg·mL−1; P < 0.001).
There seemed to be considerable variability between participants in response to exercise and caffeine. To further explore this variability, individual participant end-exercise circulating plasma lactate and postexercise circulating plasma IL-6 concentrations in placebo and caffeine conditions were plotted and are displayed in Figures 2C and D, respectively. End-exercise lactate concentration was greater with caffeine compared with placebo in 17 of the 20 participants, and postexercise IL-6 concentration was greater in caffeine compared with placebo in 15 of 18 participants. Closer inspection of these panels revealed that, compared with placebo, caffeine resulted in greater end-exercise lactate concentration in 8 of the 10 men and 9 of the 10 women, and greater postexercise IL-6 concentration in 7 of the 8 men and 8 of the 10 women. Inclusion of sex as an independent variable in our general linear model revealed that IL-6 was greater in men compared with women (main effect; P = 0.016). When we repeated our analysis in men and women separately, the influence of caffeine on the response to exercise seemed to be subject to sex differences. In men, there were interactions between caffeine versus placebo and time (P = 0.005) for lactate and for IL-6 (P < 0.001; Fig. 3A). In women, on the other hand, there was an interaction between caffeine versus placebo and time for lactate (P < 0.001), but not for IL-6 (P = 0.991; Fig. 3B). Importantly, the end-exercise intensity when expressed as a percent of the V̇O2 at ventilatory threshold was not different between men and women for either the placebo (men vs women, 128% ± 16% vs 119% ± 7%; P = 0.12) or caffeine (men vs women, 129% ± 18% vs 124% ± 10%; P = 0.42) condition.
There are two novel and potentially clinically relevant findings of this study. First, caffeine augmented the lactate and IL-6 response to 30 min of moderate-intensity exercise in a group comprising men and women. Second, separate analysis of men and women showed that caffeine increased exercise-induced circulating concentrations of lactate in both sexes, but only augmented the IL-6 response in men. Collectively, these data imply that the IL-6–mediated health benefits of high-intensity/long-duration exercise potentially may be extended to more manageable moderate-intensity, short-duration exercise in men after ingestion of caffeine. Our data also highlight a potentially important sex difference with respect to the interaction of IL-6, moderate exercise, and caffeine.
The influence of caffeine on the IL-6 response to exercise has been studied using a variety of different exercise protocols and modalities, including 1 h of treadmill exercise at 70% maximal V̇O2 (3), 2 h of cycling at 65% maximal V̇O2 (5), a 15-km running race (1,2), sprint interval training (4), a maximal treadmill test (7), and a combination of high-intensity intermittent treadmill exercise and resistance training (6). Collectively, these long-duration and/or high-intensity protocols may be beyond the capabilities of clinical populations for whom IL-6–mediated benefits may be particularly relevant, including people with cancer and/or cancer–cachexia (8) and/or potentially adults with visceral obesity (9). In the current study, we demonstrate that caffeine was able to augment the IL-6 response to 30 min of moderate-intensity, weight-supported, cycle ergometer exercise in untrained and recreationally active adults. Moreover, in most of these previous studies (1–7), caffeine augmented the IL-6 response to exercise by a magnitude ranging between approximately 0 to 1.6 pg·mL−1. These values are comparable to those observed in the current study (i.e., increase with caffeine of approximately 0.8 pg·mL−1). Importantly, the magnitude by which caffeine augmented the response to exercise may have clinical relevance. In a previous study, with concomitant administration of an IL-6 receptor antibody (tocilizumab), the decrease in visceral mass mediated by 12 wk of exercise was abrogated (9). In the control group assigned to exercise and placebo (i.e., no interference with IL-6 signaling), decreased visceral fat was accompanied by an acute, exercise-mediated increase of IL-6 of 0.37 pg·mL−1 and a long-term increase in resting IL-6 of 0.15 pg·mL−1 (9). Accordingly, it seems that only small increases in IL-6 are necessary to evoke meaningful and beneficial adaptations to exercise.
In the current study, the moderate exercise was well tolerated by the untrained and recreationally active adults. A potential additional benefit of caffeine for our study population pertains to the ability of caffeine to lower the perception of exertion during exercise (21,31–34), therefore potentially promoting exercise adherence. However, the influence of caffeine on RPE during exercise is not consistent across all studies (20,35–38), and in the current study, RPE was unaffected by caffeine.
Consistent with many other investigations (23,32,34,37–39), in the current study, caffeine increased ventilation and lowered RER. We speculate that the lower RER could be, in part, attributed to greater ventilation rather than increased reliance of fat oxidation, especially in the face of increased blood lactate concentration, another frequently reported observation in caffeine studies (18–24,35).
To our knowledge, we are the first to report potential sex differences with respect to the influence of caffeine on the IL-6 response to exercise. Six of the seven previous studies examining the IL-6 response to exercise with/without caffeine were completed in men only (1–6). We, perhaps naively, assumed that men and women would respond in a similar manner. Our data demonstrate that a sex difference may exist. Although IL-6 increases in both men and women in response to exercise, in women it does not seem to increase to a greater extent with caffeine. Future follow-up studies may wish to place greater emphasis on matching men and women for cardiorespiratory fitness and body composition, and also consider the potential influence of menstrual cycle. However, in regard to the latter, several studies have demonstrated similar ergogenic effects of caffeine in a variety of different exercise protocols, including aerobic cycling, sprinting, and resistance exercise, in eumenorrheic women in all phases of the menstrual cycle (40–42). Thus, menstrual phase may not necessarily be a critical consideration for future studies.
Previously, it has been suggested that nutritional status may partially determine the IL-6 response to exercise (43). Evidence comes from reports of greater circulating IL-6 concentrations after exercise in the fasted state, compared with exercise completed after ingestion of carbohydrate-rich meals designed to promote preexercise skeletal muscle glycogen content, or with exercise accompanied by nutrient ingestion (i.e., refueling) (44). In the current investigation, we provided the same preexercise meal to each of the participants to alleviate the potential confound of variable baseline nutritional status. A single serving of a commercially available liquid meal was administered. It is plausible that, on account of appreciable sex differences in body mass and therefore presumably energy needs, by providing the same absolute energy, we may have inadvertently introduced experimental bias as the number of administered kilocalories per kilogram of body mass was lower in the men compared with women. Our approach could be considered a study limitation; however, post hoc analysis of a subset of the heaviest women (n = 4; body mass, 73.4 ± 2.7 kg) matched with the lightest men (n = 4; body mass, 71.8 ± 8.9 kg) revealed that the magnitude of the caffeine-mediated increase in the IL-6 response to exercise remained greater (P = 0.04) in men (1.7 ± 0.5 pg·mL−1) compared with women (0.6 ± 0.6 pg·mL−1). This small subset comparison implies that the sex differences we observed in the complete study population were not mediated by differences in body mass, and by extension, differences in the caloric value of the preexperiment meal. Related to this issue, it has also been suggested that strategies used to promote glycogen sparing during exercise diminish the IL-6 exercise response (43). In the context of the current study, this is a curious observation as we, consistent with others (1–7), have shown that caffeine increases the IL-6 response to exercise, whereas caffeine has also been reported to spare muscle glycogen during exercise (23,45). These apparently divergent observations suggest that the influence of caffeine on the IL-6 response to exercise may override the potential interaction between glycogen depletion and IL-6 secretion.
As noted, there seemed to be considerable between-participant variability within our data. This variability may represent an unintended consequence of selecting a percent of V̇O2peak as our target exercise intensity rather than prescribing the intensity proportional to ventilatory (or lactate) threshold. Although the use of % V̇O2peak for exercise prescription is common, metabolic responses to exercise, including blood lactate concentration, are determined by the intensity of exercise relative to the ventilatory (or lactate) threshold (46). In this regard, end-exercise V̇O2 for almost all participants, in both conditions, was above the ventilatory threshold (~125% of the V̇O2 at ventilatory threshold). Noteworthy, there were no sex differences in the end-exercise intensities when expressed relative to ventilatory threshold for either the placebo or caffeine conditions. This implies that the observed sex differences in the caffeine mediated IL-6 response to exercise are unlikely to be explained by differences in the exercise intensities. However, additional correlational analysis (data not shown) revealed that end-exercise V̇O2 expressed as a percent of ventilatory threshold seems to be related to postexercise IL-6 concentration and the magnitude of increase in IL-6 concentration from rest to postexercise in the caffeine condition only. In addition, when considered separately, this relation only held true for women. An explanation for this final point is not immediately forthcoming and may warrant future study.
In the current investigation, we studied (mostly) young, untrained and recreationally active adults who were otherwise healthy. The implications of our findings are perhaps most relevant for clinical populations who are unable to complete high-volume exercise but who stand to gain the biggest benefit from regular physical activity. Future follow-up studies could, conservatively, repeat the current study in a clinical population, or less conservatively, incorporate caffeine versus placebo in a short-term training study; one might hypothesize that caffeine ingestion may augment the IL-6–mediated benefits of moderate exercise. Additional and important considerations include the risks associated with combining caffeine and exercise for clinical populations (arrhythmias, etc.), and the delivery of the caffeine. In the current study, a pharmaceutical preparation of caffeine was used. If the end goal is for a practical intervention, then pharmaceutical preparation of caffeine may not always be feasible, and delivery mechanisms such as coffee, soda, or caffeinated gum may be more realistic. Finally, we did not collect data pertaining to habitual caffeine use. It is plausible that the magnitude of influence of caffeine on the lactate and IL-6 responses to exercise may have been partially determined by normal daily caffeine consumption, and perhaps also by history (duration) of daily use. Data from a recent meta-analysis (47) suggest that, at least from an ergogenic perspective, habitual caffeine consumption does not determine the acute responses to caffeine. It is unclear if the potential acute clinical benefits of caffeine are also independent of habitual caffeine consumption; thus, the absence of data pertaining to habitual caffeine use is a limitation of the current work.
In response to moderate-intensity exercise, caffeine evoked greater circulating lactate concentrations in men and women but only increased the IL-6 response to exercise in men. These findings suggest that for men unwilling or unable to perform high-intensity and/or long-duration exercise, caffeine may augment the IL-6–mediated health benefits of relatively short, moderate-intensity exercise.
The authors thank the volunteers for their participation and cooperation. This study was funded by an Undergraduate Research Award given to K. S. S. A. by the Rocky Mountain Chapter of the American College of Sports Medicine. Conception and design of the study, together with all data collection and analysis, and manuscript preparation were completed at Colorado State University. At the time of manuscript submission, K. S. S. A. had relocated to the University of Oregon.
The authors declare that they have no conflicts of interest regarding the publication of this article. There are no financial conflicts of interest to disclose. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. The results of the present study do not constitute an endorsement by the American College of Sports Medicine.
Author Contributions: conception and design of the experiment: K. S. S. A. and C. B; data collection: K. S. S. A., T. R. E., M. C. B., and H. M. B.; analysis of data: K. S. S. A. and C. B.; interpretation of data: K. S. S. A. and C. B.; writing the first draft: K. S. S. A.; revision of the manuscript: all authors. All authors have read and approved the final version of the manuscript.
Data Availability: The data that support the findings of this study are available from the corresponding author upon reasonable request.
1. Tauler P, Martinez S, Martinez P, Lozano L, Moreno C, Aguiló A. Effects of caffeine supplementation on plasma and blood mononuclear cell interleukin-10 levels after exercise. Int J Sport Nutr Exerc Metab
2. Tauler P, Martínez S, Moreno C, Monjo M, Martínez P, Aguiló A. Effects of caffeine on the inflammatory response induced by a 15-km run competition. Med Sci Sports Exerc
3. Rodas L, Martinez S, Aguilo A, Tauler P. Caffeine supplementation induces higher IL-6
and IL-10 plasma levels in response to a treadmill exercise test. J Int Soc Sports Nutr
4. Ferreira GA, Felippe LC, Bertuzzi R, et al. The effects of acute and chronic sprint-interval training on cytokine
responses are independent of prior caffeine intake. Front Physiol
5. Walker GJ, Finlay O, Griffiths H, Sylvester J, Williams M, Bishop NC. Immunoendocrine response to cycling
following ingestion of caffeine and carbohydrate. Med Sci Sports Exerc
6. Rossi FE, Panissa VLG, Monteiro PA, et al. Caffeine supplementation affects the immunometabolic response to concurrent training. J Exerc Rehabil
7. Salicio VMM, Fett CA, Salicio MA, et al. The effect of caffeine supplementation on trained individuals subjected to maximal treadmill test. Afr J Tradit Complement Altern Med
8. Daou HN. Exercise as an anti-inflammatory therapy for cancer cachexia: a focus on interleukin-6 regulation. Am J Physiol Regul Integr Comp Physiol
9. Wedell-Neergaard AS, Lang Lehrskov L, Christensen RH, et al. Exercise-induced changes in visceral adipose tissue mass are regulated by IL-6
signaling: a randomized controlled trial. Cell Metab
10. Steensberg A, Fischer CP, Keller C, Møller K, Pedersen BK. IL-6
enhances plasma IL-1ra, IL-10, and cortisol in humans. Am J Physiol Endocrinol Metab
11. Starkie R, Ostrowski SR, Jauffred S, Febbraio M, Pedersen BK. Exercise and IL-6
infusion inhibit endotoxin-induced TNF-α production in humans. FASEB J
12. Serrano AL, Baeza-Raja B, Perdiguero E, Jardí M, Muñoz-Cánoves P. Interleukin-6 is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy. Cell Metab
13. Carey AL, Steinberg GR, Macaulay SL, et al. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes
14. Ellingsgaard H, Hauselmann I, Schuler B, et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat Med
15. Hojman P, Brolin C, Nørgaard-Christensen N, et al. IL-6
release from muscles during exercise is stimulated by lactate-dependent protease activity. Am J Physiol Endocrinol Metab
16. Cullen T, Thomas AW, Webb R, Hughes MG. Interleukin-6 and associated cytokine
responses to an acute bout of high-intensity interval exercise: the effect of exercise intensity and volume. Appl Physiol Nutr Metab
17. Minetto MA, Rainoldi A, Gazzoni M, Ganzit GP, Saba L, Paccotti P. Interleukin-6 response to isokinetic exercise in elite athletes: relationships to adrenocortical function and to mechanical and myoelectric fatigue. Eur J Appl Physiol
18. Graham TE. Caffeine and exercise: metabolism, endurance and performance. Sports Med
19. Glaister M, Gissane C. Caffeine and physiological responses to submaximal exercise: a meta-analysis. Int J Sports Physiol Perform
20. Hodgson AB, Randell RK, Jeukendrup AE. The metabolic and performance effects of caffeine compared to coffee during endurance exercise. PLoS One
21. Suvi S, Timpmann S, Tamm M, Aedma M, Kreegipuu K, Ööpik V. Effects of caffeine on endurance capacity and psychological state in young females and males exercising in the heat. Appl Physiol Nutr Metab
22. Oberlin-Brown KT, Siegel R, Kilding AE, Laursen PB. Oral presence of carbohydrate and caffeine in chewing gum: independent and combined effects on endurance cycling
performance. Int J Sports Physiol Perform
23. Cruz RS, de Aguiar RA, Turnes T, Guglielmo LG, Beneke R, Caputo F. Caffeine affects time to exhaustion and substrate oxidation during cycling
at maximal lactate steady state. Nutrients
24. Gaesser GA, Rich RG. Influence of caffeine on blood lactate response during incremental exercise. Int J Sports Med
25. Williams NNB, Ewell TR, Abbotts KSS, et al. Comparison of five oral cannabidiol preparations in adult humans: pharmacokinetics, body composition, and heart rate variability. Pharmaceuticals (Basel)
26. Ewell TR, Abbotts KSS, Williams NNB, et al. Pharmacokinetic investigation of commercially available edible marijuana products in humans: potential influence of body composition and influence on glucose control. Pharmaceuticals (Basel)
27. Ewell TR, Harms KJ, Abbotts KSS, Bell C. Scheduling sprint interval training at a constant rather than variable time of day does not influence the gains in endurance performance. J Exerc Nutr
28. Beaver WL, Wasserman K, Whipp BJ. A new method for detecting anaerobic threshold by gas exchange. J Appl Physiol (1985)
29. Forster HV, Dempsey JA, Thomson J, Vidruk E, DoPico GA. Estimation of arterial PO2
, pH, and lactate from arterialized venous blood. J Appl Physiol
30. Magkos F, Kavouras SA. Caffeine use in sports, pharmacokinetics in man, and cellular mechanisms of action. Crit Rev Food Sci Nutr
31. Costill DL, Dalsky GP, Fink WJ. Effects of caffeine ingestion on metabolism and exercise performance. Med Sci Sports
32. Stadheim HK, Kvamme B, Olsen R, Drevon CA, Ivy JL, Jensen J. Caffeine increases performance in cross-country double-poling time trial exercise. Med Sci Sports Exerc
33. Stadheim HK, Spencer M, Olsen R, Jensen J. Caffeine and performance over consecutive days of simulated competition. Med Sci Sports Exerc
34. Giles D, Maclaren D. Effects of caffeine and glucose ingestion on metabolic and respiratory functions during prolonged exercise. J Sports Sci
35. Yeo SE, Jentjens RL, Wallis GA, Jeukendrup AE. Caffeine increases exogenous carbohydrate oxidation during exercise. J Appl Physiol (1985)
36. Acker-Hewitt TL, Shafer BM, Saunders MJ, Goh Q, Luden ND. Independent and combined effects of carbohydrate and caffeine ingestion on aerobic cycling
performance in the fed state. Appl Physiol Nutr Metab
37. Casal DC, Leon AS. Failure of caffeine to affect substrate utilization during prolonged running. Med Sci Sports Exerc
38. Jenkins NT, Trilk JL, Singhal A, O’Connor PJ, Cureton KJ. Ergogenic effects of low doses of caffeine on cycling
performance. Int J Sport Nutr Exerc Metab
39. Bruce CR, Anderson ME, Fraser SF, et al. Enhancement of 2000-m rowing performance after caffeine ingestion. Med Sci Sports Exerc
40. Lara B, Gutiérrez-Hellín J, García-Bataller A, Rodríguez-Fernández P, Romero-Moraleda B, Del Coso J. Ergogenic effects of caffeine on peak aerobic cycling
power during the menstrual cycle. Eur J Nutr
41. Romero-Moraleda B, Coso J Del, Gutiérrez-Hellín J, Lara B. The effect of caffeine on the velocity of half-squat exercise during the menstrual cycle: a randomized controlled trial. Nutrients
42. Lara B, Gutiérrez Hellín J, Ruíz-Moreno C, Romero-Moraleda B, Del Coso J. Acute caffeine intake increases performance in the 15-s Wingate test during the menstrual cycle. Br J Clin Pharmacol
43. Hennigar SR, McClung JP, Pasiakos SM. Nutritional interventions and the IL-6
response to exercise. FASEB J
44. Keller C, Keller P, Marshal S, Pedersen BK. IL-6
gene expression in human adipose tissue in response to exercise—effect of carbohydrate ingestion. J Physiol
. 2003;550(Pt 3):927–31.
45. Rush JW, Spriet LL. Skeletal muscle glycogen phosphorylase a kinetics: effects of adenine nucleotides and caffeine. J Appl Physiol (1985)
46. Colosio AL, Caen K, Bourgois JG, Boone J, Pogliaghi S. Bioenergetics of the VO2
slow component between exercise intensity domains. Pflugers Arch
47. Carvalho A, Marticorena FM, Grecco BH, Barreto G, Saunders B. Can I have my coffee and drink it? A systematic review and meta-analysis to determine whether habitual caffeine consumption affects the ergogenic effect of caffeine. Sports Med