The influence of citrus aurantium and caffeine complex versus placebo on the cardiac autonomic response: a double blind crossover design

The purpose of this study was to examine the resting ANS response to the ingestion (I1 – I2) of CA + C as well as its influence on the ANS response to an exhaustive exercise protocol (R1 – R2). During the ingestion period HR, lnLF, LFnu, E and NE significantly increased in the CA + C trial, indicating an enhanced sympathetic response to the supplementation. Interestingly, a significant decrease in HFnu was observed while no changes in lnHF or lnRMSSD occurred despite a significant increase in lnSDNN. All cardiac autonomic markers demonstrated a time-dependent shift towards baseline following the exercise protocol except for LFnu, HFnu, and LF/HF. Further points of consideration are provided below.

Ingestion period

Resting HR is a primary marker in cardiac autonomic activity and is affected through several intrinsic and extrinsic factors; however, the influence of the combination of CA + C on resting HR is relatively unknown. The limited amount of information available pertains to the isolated components CA and C, with only one known study to have examined the combination of both [2]. For instance, Min et al., [10] examined only p-synephrine, the active component of CA, and found no changes in resting HR at one-hour, three-hours, six-hours, or eight-hours following consumption. Furthermore, recent studies have shown little no changes in resting HR with caffeine consumption alone in habitual caffeine consumers [27, 28]. When combining a 100 mg of CA, and 100 mg of C, Ratamess et al. [2] observed no significant changes in resting HR following a three-week washout period from caffeine when compared to controls. In contrast, the findings of the current study demonstrated a time-dependent increase in HR following the consumption of the CA + C complex. No time-dependent changes were observed during the ingestion phase for the PLA trial. This discrepancy may be due to differences in the experimental design. For instance, the participants in the Ratamess et al. [2] study underwent a three day exposure to the CA + C complex prior to testing, while in the current study participants were not given the CA + C complex prior to the experimental trials, which may account for the difference in the response.

Overall, the evaluation of CA or CA + C on markers of ANS activity is currently understudied, but information regarding other stimulants (e.g. caffeine) is replete [35, 29, 30]. For instance, Rauh et al. [31] found that the consumption of either 100 mg or 200 mg of caffeine in habitual users failed to alter any examined marker of HRV. Zimmerman et al. [28] examined caffeine consumption in both habitual and non-habitual consumers and found no effect on SNS related activity (LF and LF/HF), but enhanced PNS activity (RMSSD and HF) in habitual users was observed. Conversely, Yoshinaga et al., observed significant increases in the power spectral density in both LF and HF following the ingestion of 4 mg•kg of bodyweight [32]. The findings of the current study provide equivocal results to the literature, where the consumption of CA + C increased HR, lnLF, LFnu, E, and NE; indicating an increase in SNS activity while showing no changes in PNS markers (lnRMSSD and lnHF) during the ingestion period. Interestingly, a nonsignificant rise of lnLF and reduction of lnHF was observed following the PLA trial. However, when evaluating LFnu and HFnu a similar yet significant changed was observed, demonstrating a relative change in the ratios rather than the absolute values of the power spectral density. This may in part be due to the anticipation of the upcoming exhaustive protocol and pre-performance anxiety, resulting in minor shifts of ANS activity. Future studies should evaluate and account for pre trial emotional stress.

When evaluating plasma markers of SNS activity, it has been proposed that circulating sympathetic biomarkers E and NE increase following consumption of caffeine [33, 34]; however, a recent study demonstrated caffeine to have little to no influence over resting values [35]. The observed changes in E and NE within the current study support the previous notion that caffeine influences resting plasma levels and reflect the changes observed in SNS related HRV markers following the CA + C ingestion. The lack of change in the lnRMSSD and lnHF in the presence of increased SNS activity acts against the traditional interplay between PNS and SNS balance. Generally, with increases in SNS activity a withdrawal of vagal tone occurs. However, this was not observed and could be the result of a decreased sensitivity to caffeine or the rested state of the participant, which resulted in the attenuation of vagal activity.

Regardless of the mechanisms involved, the overall cardiac autonomic response observed during the ingestion phase is suggestive of a “priming” of the SNS response to the CA + C supplementation. Traditionally, it is believed that ANS activity is balanced between the PNS and SNS branches, exhibiting an inverse relationship [12]. However, the PNS/SNS interplay appears to be more complex, and likely exhibits their influences upon each other on a spectrum, rather than direct counter balance. The findings of this study are indicative of this type of relationship between the SNS and PNS branches, specifically the lack of change in resting PNS activity when compared to the time-based increases in SNS drive observed in the CA + C trial. Specifically, there was an increase in lnSDNN and lnLF without the presence of altered vagal activity. This is important because these markers are believed to have influences stemming from both the SNS and PNS [36]. Therefore, with no discernable changes within markers of vagal activity, it can be inferred that the increases of lnLF and lnSDNN are the result of changes seen in SNS activity. This response adds to the understanding of the level of complexity within ANS control and should be further investigated to determine thresholds between the various markers.

Recovery period

Following the exhaustive protocols, HR was significantly elevated in both trials and recovered in a similar time-dependent fashion (Table 2A and B). This is consistent with the findings of Haller et al. [37] who did not observe any differences in post-exercise recovery of HR when comparing a commercially available supplement (21 mg of synephrine, 303.8 mg of caffeine, and various additives) to a placebo during the 30-min to 12-h following a moderate exercise bout [37]. Additionally, markers of HRV following the exhaustive protocol demonstrated nearly identical physiological responses, with a decrease in activity post exercise and a gradual increase toward baseline values, which is a commonly observed post exercise response [11, 38]. A similar yet inverse response was observed in circulating plasma E and NE, with substantial increases post exercise and a return to baseline values within 45-min post (R2). It is important to note that though increased SNS activity was observed following the ingestion of CA + C, the effect was lost following the exhaustive protocol. Therefore, the findings are suggestive that the influence of CA + C occurs only in a resting environment and does not influence the recovery of the system.

Though it was outside the scope of the current study to establish mechanisms involved with CA + C consumption, we will postulate on potential factors involved in the observed findings. The ingestion phase (I1 – I2) at rest was the only period in which CA + C appeared to have an effect on SNS activity. As previously mentioned, recent studies have demonstrated that C provides little cardiovascular stimulation and more so acts to improve PNS activity rather than inhibit in habitual users [28]. However, it should not be overlooked that the research is conflicting in habitual consumers and that C has been shown to alter SNS activity through increased sensitivity to circulating E and NE [29]. Within the current study, plasma E and NE significantly increased following CA + C ingestion in our habitual C population (209 ± 95.5 mg/day). There was no withdrawal of PNS activity despite a significant increase in resting HR, which could be explained by the combined effects of circulating E and NE as well as improved sensitivity related to C. The acting ingredient of CA, p-synephrine, works primarily on the ß-3 receptors on adipose tissue and therefore is unlikely to have any direct impact on autonomic function [7]. Indirectly, the increased activity of lipolysis, and thermogenesis caused by p-synephrine could have elevated SNS activity, which was demonstrated by Reimann et al. [39] who found that acute hyperlipidemia increased both HR and sympathetic drive. Though we did not measure changes in plasma lipids we can postulate that the known action of p-synephrine could have elevated plasma levels and consequently influenced sympathetic activity.