Dietary supplements containing thermogenic ingredients are commonly used among fitness practitioners and those seeking rapid body weight loss in an attempt to increase resting energy expenditure and to facilitate body fat loss by increasing fat oxidation (1). Thermogenic supplements typically contain a combination of active ingredients, but caffeine and p-synephrine are recurrently present in these type of dietary supplements (1,2). p-Synephrine (4-[1-hydroxy-2-(methylamino)ethyl]phenol) is a phenylethylamine derivative naturally present in bitter orange (Citrus aurantium) and other Citrus species. The acute ingestion of p-synephrine (~0.5 mg·kg−1) has been found effective to increase energy expenditure and lipolysis at rest (3,4), likely due to its high binding affinity to β-3 adrenoceptors (5). The ingestion of p-synephrine (3 mg·kg−1) also has the capability of increasing fat oxidation rate during exercise without significantly affecting exercise energy expenditure or heart rate (6). Recently, it has been found that the effects of this substance to raise fat oxidation during exercise are maximized at 2 mg·kg−1, at least in healthy and active individuals (7).
Caffeine (1,3,7-trimethyl-xanthine) is a naturally occurring alkaloid found in varying quantities in the beans, leaves, and fruits of more than 60 plants. Some common sources of caffeine are the kola nut, the cocoa bean, the yerba mate, and the guarana berry. However, roasted coffee beans and tea leaves are the world’s primary sources of dietary caffeine. The effectiveness of low-to-moderate doses of caffeine to increase physical performance has been well established in a numerous of exercise situations (8,9). Caffeine can exert peripheral metabolic effects at rest and during submaximal exercise via increased release of epinephrine and mobilization of fatty acids from adipose tissue (9,10), but there is a growing consensus indicating that the main mechanism behind caffeine ergogenicity during exercise is the ability of this stimulant to act as an adenosine A1, A2A, and A2B receptor antagonist in the central nervous system (11,12).
Apart from the ergogenic effects of caffeine, there is evidence to suggest that the acute administration of caffeine can increase metabolic rate at rest (13–15) and after exercise (14,16). However, the effectiveness of caffeine to modify substrate oxidation during exercise is unclear. In the literature, several investigations have shown no change in the oxidation of substrates during prolonged submaximal exercise after the acute administration of 3–9 mg·kg−1 of caffeine (9,17–20), whereas an increase in the rate of fat oxidation has also been repeatedly reported with similar dosages of caffeine (10,21–25). The differences in the exercise protocols (freely chosen or fixed wattage), the dosages and forms of caffeine administration, and the coingestion of caffeine with other substances have likely affected the consistency of the results (26). In this regard, determining the effects of caffeine ingestion on fat oxidation rate during an exercise protocol of increasing intensity could help to clarify the effects of caffeine on substrate oxidation, as this protocol has been repeatedly used to determine the highest rate of fat oxidation during exercise (27,28).
The coingestion of p-synephrine and caffeine could have additive effects on substrate oxidation during exercise because each substance acts through a different physiological pathway (5,9,10). However, to our knowledge, only three investigations have determined the effects of the coingestion of p-synephrine and caffeine during or after exercise when compared with a placebo (2,29) and to the isolated ingestion p-synephrine (30,31), but the results are inconclusive. Sale et al. (29) found that a commercially available supplement containing bitter orange, green tea, and guarana (with 0.1 mg·kg−1 of p-synephrine and 1.7 mg·kg−1 of caffeine) increased the oxidation of carbohydrate, but it reduced the use of nonesterified fatty acids during 60 min of moderate-intensity exercise on a treadmill. Haller et al. (2) determined that the combined ingestion of p-synephrine (0.3 mg·kg−1) and caffeine (4.2 mg·kg−1) produced a lower perception of effort during 30 min of moderate exercise, but these authors did not measure substrate use during exercise. Ratamess et al. (30,31) found that the isolated ingestion of p-synephrine (1.2 mg·kg−1) increased the number of repetitions performed during a resistance exercise protocol (31) and produced higher postexercise energy expenditure and fat oxidation rates (30), whereas the addition of caffeine (1.2 mg·kg−1) to p-synephrine did not further affect these variables. With this scientific background, studying the isolated and combined outcomes of p-synephrine and caffeine on substrate oxidation during exercise could help to identify the effectiveness of these thermogenic substances to increase fat use during exercise. We hypothesized that both p-synephrine and caffeine would increase the highest rate of fat oxidation during exercise, but the coingestion of these substances would not produce further benefits.
Thirteen young, healthy, and active participants volunteered to participate in this investigation (age = 25.0 ± 7.0 yr, body mass = 67.7 ± 11.9 kg, body height = 176 ± 8 cm, body mass index = 21.5 ± 2.7 kg·m−2, body fat = 13.8% ± 5.11%, maximal oxygen uptake [V˙O2max] = 50.8 ± 5.0 mL·kg−1·min−1). The study sample included two women who were always tested in their luteal phase. All participants were nonsmokers, had no previous history of cardiopulmonary diseases, and had suffered no musculoskeletal injuries in the previous 3 months. All participants were classified as low caffeine consumers (<50 mg·d−1) by using a food frequency questionnaire to assess habitual caffeine intake (32). They were encouraged to avoid medications, nutritional supplements, and sympathetic stimulants for the duration of the study, and compliance was examined with dietary questionnaires. One week before the onset of the investigation, the subjects were fully informed of the experimental procedures and the risks associated with the research protocols before they signed an informed written consent to participate in the investigation. The study was approved by the Camilo José Cela University Research Ethics Committee, in accordance with the latest version of the Declaration of Helsinki.
A double-blind, placebo-controlled experimental design was used, whereby each participant completed four identical trials separated by 3–5 d to allow complete physical recovery and substance washout. In a randomized order, participants ingested a capsule 60 min before the onset of the trial that contained 3 mg·kg−1 of a placebo (100% purity, cellulose, Guinama, Spain), 3 mg·kg−1 of caffeine (100% purity, Bulk Powders, United Kingdom), 3 mg·kg−1 of p-synephrine (99% purity; Synephrine HCL, Nutrition Power, Spain), or a combination of these same doses of p-synephrine and caffeine. The use of 3 mg·kg−1 of both caffeine and p-synephrine was based on previous publications, which have found this dosage to be effective to produce a positive physical effect (e.g., increased physical performance or increased fat oxidation during exercise) with a low prevalence of side effects (7,33).
Two days before the first experimental trial, participants underwent a preparticipation medical examination (including medical history and other routine physical exams) conducted by a licensed physician to ensure the suitability of all participants to take part in the research protocols. The participants then performed a standardized warm-up that included 10 min at 50 W on a cycle ergometer (SNT Medical, Cardgirus, Spain) and completed an incremental exercise test (25 W each 1 min) until volitional fatigue to determine V˙O2max (7). During the test, oxygen uptake (V˙O2) was continuously measured by means of a breath-by-breath analyzer (Metalyzer 3B, Cortex, Germany), and the data were averaged each 15 s. V˙O2max was defined as the highest V˙O2 value obtained during the test. The V˙O2max was considered valid when participants rated their perceived exertion higher than 19 on the Borg scale, the V˙O2 difference between the last two consecutive loads was less than 0.15 L min−1, the respiratory exchange ratio was higher than 1.10, and the heart rate was great than 80% of the age-adjusted estimate of maximal heart rate (34). To normalize exercise intensity in the experimental trials (increases of 10% of V˙O2max) among all individuals, a regression analysis was performed for each subject for the relationship between W and V˙O2 obtained in this test.
Twenty-four hours before each experimental trial, participants refrained from strenuous exercise and adopted a similar diet and fluid intake regimen. Subjects were also required to refrain from consuming alcohol, caffeine, and foods that contained C. aurantium (e.g., bitter orange, sweet orange, and tangerine) for 24 h before each trial. To standardize these routines, subjects were requested to complete a 24-h dietary record on the day before the first trial and to follow the same dietary pattern before the subsequent visits. Participants arrived at the laboratory (11.00 am) at least 4 h after their last meal. The preexercise meals were analyzed with a nutritional software (PCN, Cesnid, Spain), and the ranges for the proportions of macronutrients were as follows: carbohydrate = 53%–62%, protein = 7%–19%, and fat = 25%–39%. Upon arrival, the capsule with the assigned experimental treatment was provided in an unidentifiable bag. The capsule was ingested with 150 mL of tap water. Participants then dressed in a T-shirt and a pair of shorts, and a heart rate belt (Wearlink, Polar, Finland) was attached to their chest. After that, they rested supine for 60 min to allow for substance absorption. Resting heart rate and systolic and diastolic blood pressure (M6 Comfort, Omron, Japan; by triplicate) were measured during the last 5 min of the resting period. An average of three blood pressure measurements was used for analysis.
After the resting measurements, participants performed a 10-min standardized warm-up at a workload equivalent to 30% of V˙O2max on the cycle ergometer, and then the exercise intensity was increased by 10% of V˙O2max every 3 min until they completed the workload equivalent to 90% of V˙O2max. During this incremental exercise intensity test, breath-by-breath gas exchange data were collected continuously and used to calculate V˙O2 and carbon dioxide production (V˙CO2). During the last minute of each stage, the gas exchange data and heart rate were averaged every 15 s to achieve representative values for each intensity level. Certified calibration gases (16.0% O2; 5.0% CO2, Cortex, Germany) and a 3-L syringe were used to calibrate the gas analyzer and the flowmeter before each trial. An individually chosen cadence (between 70 and 90 rpm for all participants) was replicated on all days. The environmental temperature was, on average for all experimental trials, 20.8°C ± 0.6°C, whereas the relative humidity was 40% ± 12%.
At the end of the test, participants were required to fill out a brief questionnaire to rate their feelings of muscle power, endurance, and exertion during the test (by using a 1- to 10-point scale to assess each item). In addition, participants were provided with a survey to be filled out the following morning about sleep quality, nervousness, and gastrointestinal discomfort that included a yes/no scale to assess the frequency of these symptoms. These same questionnaires have been previously used to evaluate perceived physical performance during exercise and side effects derived from acute caffeine and p-synephrine ingestion (35,36). To evaluate the success of the blinding process during the experiment, participants were asked to guess the order of the experimental trials at the end of the last trial.
The rates of energy expenditure and substrate oxidation (fat and carbohydrate) were calculated using the nonprotein respiratory quotient proposed by Brouwer (37). Energy expenditure (kcal·min−1) during exercise was calculated as (3.869 V˙O2) + (1.195 V˙CO2), where V˙O2 and V˙CO2 are in liters per minute. Fat oxidation rate (g·min−1) was calculated as (1.67 V˙O2) − (1.67 V˙CO2), and carbohydrate oxidation rate (g·min−1) was calculated as (4.55 V˙CO2) − (3.21 V˙O2). Fat oxidation rate was equaled to 0.0 g·min−1 in the exercise workloads with a respiratory exchange ratio ≥1.0. The rate of maximal fat oxidation was individually calculated for each participant as the highest value of fat oxidation rate obtained during the incremental exercise intensity test. The exercise in which maximal fat oxidation was achieved (Fatmax) was also registered for each individual.
The results of each test were blindly introduced into the statistical package SPSS version 20.0 and analyzed afterward. The normality of each quantitative variable was initially tested with the Shapiro–Wilk test. All the quantitative variables included in this investigation presented a normal distribution, and parametric statistics were used to determine differences among trials. A one-way ANOVA was used to compare heart rate and blood pressure at rest. A two-way ANOVA (treatment × workload) was used to compare energy expenditure, fat, and carbohydrate oxidation rates and heart rates during exercise. In the case of a significant F-test (Geisser–Greenhouse correction for the assumption of sphericity), the Bonferroni post hoc analysis was used to identify differences among trials. The significance level was set at P < 0.05. The data are presented as mean ± SD.
None of the participants correctly guessed the order of the trials (only 31%, 31%, 31%, and 23% of the participants guessed the ingestion of placebo, p-synephrine, caffeine, and p-synephrine + caffeine, respectively), which indicated the adequacy of the blinding protocol. In comparison with the placebo, the ingestion of p-synephrine did not modify any cardiovascular variable at rest (Table 1). However, the ingestion of caffeine increased systolic, diastolic, and mean arterial blood pressures. The combination of p-synephrine and caffeine increased all the cardiovascular variables measured at rest (all P < 0.05).
During exercise, heart rate progressively increased with increases in exercise intensity in the placebo trial (P < 0.05), but the ingestion of p-synephrine, caffeine, and p-synephrine + caffeine did not modify heart rate at any workload. Similarly, the rate of energy expenditure progressively increased with the workload (Fig. 1, upper panel; P < 0.05). This pattern was similar in the remaining trials, whereby the ingestion of p-synephrine, caffeine, and p-synephrine + caffeine did not modify energy expenditure rate at any workload. Carbohydrate oxidation rate increased with workload (Fig. 1, middle panel; P < 0.05). The carbohydrate oxidation rate–exercise workload relationship followed a similar pattern with the ingestion of p-synephrine, caffeine, and p-synephrine + caffeine. However, the carbohydrate oxidation rate in the placebo trial was higher when compared with p-synephrine at 60% of V˙O2max (P = 0.05) and compared with caffeine at 70% of V˙O2max (P < 0.05). With the placebo, fat oxidation rate increased from 30% to 40% of V˙O2max, and then it descended with further increases in exercise intensity, presenting an inverted U-shaped relationship between fat oxidation rate and exercise intensity (Fig. 1, lower panel; P < 0.05). In comparison with the placebo, the ingestion of p-synephrine increased the fat oxidation rate at 40% of V˙O2max (P < 0.05). The ingestion of caffeine increased fat oxidation rates at 30%, 40%, 50%, 60%, and 70% of V˙O2max (P < 0.05). The combination of p-synephrine and caffeine also increased fat oxidation rates at 40% and 70% of V˙O2max (P < 0.05), although the effect of the combination of these substances was no greater than with the isolated ingestion of p-synephrine or caffeine.
Figure 2 depicts individual responses with a box-and-whisker plot (whiskers represent the minimum and maximum values for the whole group) and mean ± SD for the highest rate of fat oxidation obtained during the exercise of increasing intensity. Maximal fat oxidation rate was 0.30 ± 0.12 g·min−1 obtained at 44.4% ± 8.8% of V˙O2max with the ingestion of the placebo. p-Synephrine increased maximal fat oxidation by 45.5% ± 29.5% to reach 0.43 ± 0.19 g·min−1 (P < 0.05), but it was obtained at a similar percentage of V˙O2max (46.3% ± 13.0% of V˙O2max). The ingestion of caffeine increased maximal fat oxidation by 48.5% ± 18.5% (0.44 ± 0.15 g·min−1; P < 0.05) without affecting the intensity at which it was obtained (47.0% ± 10.6% of V˙O2max). Finally, the combination of p-synephrine + caffeine increased maximal fat oxidation rate by 52.3% ± 17.2% (0.45 ± 0.15 g·min−1; P < 0.05) with no changes in the exercise intensity that elicited this maximum value (47.0% ± 8.2% of V˙O2max).
The ingestion of p-synephrine did not modify the perceived ratings of muscle power, endurance, or exertion during the exercise when compared with the ingestion of the placebo (Table 2). On the contrary, the ingestion of caffeine increased the ratings of perceived muscle power and endurance, but it reduced perceived exertion when compared with the placebo (all P < 0.05). The combination of p-synephrine + caffeine only increased the feelings of muscle power during exercise with respect to the ingestion of the placebo (P < 0.05). The frequency of abdominal discomfort in the hours after the exercise was low and was unaltered with the ingestion of the treatments.
When compared with the placebo/control trial, the substances investigated in this study produced the following main outcomes: (a) The isolated ingestion of p-synephrine did not modify blood pressure or heart rate at rest nor energy expenditure or heart rate during the exercise protocol. However, p-synephrine was effective to increase the rate of fat oxidation at 40% of V˙O2max and the maximal rate of fat oxidation during exercise. (b) The isolated ingestion of caffeine increased systolic and diastolic blood pressure at rest, although it did not modify heart rate or energy expenditure at any workload during exercise. Caffeine increased the rate of fat oxidation at 30%–70% of V˙O2max and the maximal rate of fat oxidation during exercise. (c) The coingestion of p-synephrine and caffeine increased heart rate and blood pressure at rest with no effects on energy expenditure or heart rate during exercise. p-Synephrine + caffeine increased the rate of fat oxidation at 40% and 70% of V˙O2max and the maximal rate of fat oxidation during exercise.
The current data present p-synephrine as an effective substance to increase fat oxidation rate at 40% of V˙O2max and the maximal rate of fat oxidation during an incremental exercise test, but with minimal effects on heart rate both at rest and during exercise. Previous investigations have found that p-synephrine (1–3 mg·kg−1) might augment lipid use during exercise at 30%–80% of V˙O2max (6,7) or after exercise (30), suggesting the usefulness of this substance for athletes or fitness practitioners to modify substrate use during exercise. However, its effectiveness to increase fat oxidation at rest is less clear (3,4,6). Several investigations have reported that the acute ingestion of p-synephrine does not modify heart rate or blood pressure at rest (6,30) nor produce electrocardiographic abnormalities (38). This selective capacity of p-synephrine to modify substrate oxidation during exercise without modifying cardiovascular response is likely related to its high binding affinity to β-3 adrenoceptors, whereas the properties of p-synephrine to bind β-1 and β-2 are less evident, at least when compared with other substances such as norepinephrine (5). The frequency of side effects such as abdominal discomfort, muscle soreness, and insomnia derived from p-synephrine were not different compared with the ingestion of the placebo, as has been previously found with similar dosages (36). Thus, the data of this study agree with previous investigations (6,7) that suggest p-synephrine as a safe substance to be used for increasing fat oxidation during exercise of low-to-moderate intensity, at least when ingested acutely and with a dose of 3 mg·kg−1. Still, it is necessary to investigate the effects of chronic ingestions of p-synephrine on metabolic and cardiovascular variables.
The results of this investigation also present caffeine as a substance with the capacity of raising fat oxidation during exercise of increasing intensity and supports previous evidence that had found the efficacy of caffeine to alter substrate oxidation during prolonged exercise (10,21–25). In fact, caffeine, in comparison with placebo, significantly increased fat oxidation rates in all exercise workloads between 30% and 70% of V˙O2max. Although fat oxidation rates were not higher with the acute intake of caffeine compared with the isolated ingestion of p-synephrine, the capacity of caffeine to increase fat oxidation at exercise intensities ≥50% of V˙O2max might indicate a certain advantage of caffeine over p-synephrine to augment lipid oxidation during exercise of moderate-to-high intensity. The metabolic effects of the acute ingestion of caffeine were accompanied by increased systolic, diastolic, and mean blood pressure at rest, as well increased perceived muscle power and endurance, and reduced perceived exertion, during exercise. Caffeine is a substance with strong evidence in favor of an ergogenic effect mediated through central nervous system mechanisms, at least in part by blocking adenosine in A1, A2A, and A2B adrenoreceptors (11,12), but there is no evidence supporting that the blockage of adenosine receptors in the central nervous system influences substrate oxidation during exercise. However, caffeine also increases adrenaline and noradrenaline release at rest and during exercise (9,10), which in turn might stimulate the action of β adrenoreceptors responsible for its metabolic effects (20). Although the increases in blood pressure variables at rest cannot be considered clinically relevant in our sample of active and healthy individuals, this effect should be considered when using caffeine to stimulate fat oxidation in individuals with known or presumable cardiovascular abnormalities. In addition, the use of a similar dose of caffeine has been related to increased frequency of insomnia in athletes (35), although the same effect was not produced in the current investigation, likely because the caffeine was administrated in the morning. In any case, this drawback should be taken into account for those using caffeine to increase fat use during exercise. Lastly, all the participants in this investigation were classified as light caffeine consumers (32), and they could be more prone to respond to the acute ingestion of caffeine than individuals habituated to this substance, as it has been found for the ergogenic properties of caffeine (39). In the future, the presence of a progressive habituation to the effects of caffeine on fat oxidation during exercise should be investigated when this substance is ingested on a day-to-day basis.
The coingestion of p-synephrine and caffeine increased heart rate and blood pressure variables when compared with the placebo, but to a similar extent as with the ingestion of caffeine alone. The ingestion of p-synpehrine + caffeine increased fat oxidation rate and the maximal rate of fat oxidation in comparison with placebo, but again, the magnitude of these effects was not greater than the isolated ingestion of p-synephrine or caffeine alone. These outcomes suggest that the combination of p-synephrine and caffeine had no additive or synergistic effect on substrate oxidation during incremental exercise. This is consistent with previous investigations in which the addition of caffeine to p-synephrine did not produce further increases in resistance exercise performance (31) or substrate oxidation after resistance exercise (30). However, the current data contradict the reduced fat use during exercise found by Sale et al. (29) after the administration of a supplement that contained p-synephrine and caffeine. Perhaps, the use of higher doses for p-synephrine (0.1 vs 3 mg·kg−1) and caffeine (1.7 vs 3 mg·kg−1) and the absence of other coingredients, such as vitamins and catechin polyphenols, are accountable for the higher fat oxidation rate found in the current investigation using these substances.
The experimental design used in the present investigation had several limitations. First, we used an exercise protocol of increasing intensity that helps to identify the maximal rate of fat oxidation and the intensity that elicits maximized lipid use during exercise. However, the increasing exercise intensity protocol might produce a slightly lower value for maximal fat oxidation rate than continuous and constant-load exercise protocols (40). In addition, the exercise of increasing intensity is not a typical training routine for exercise practitioners who seek body mass/body fat loss as they usually perform prolonged continuous or intermittent activities. Thus, the isolated effects of p-synephrine and caffeine should be confirmed by using prolonged and constant-load exercise protocols or by using more ecological exercise training situations. A second limitation is that we did not obtain blood and tissue samples and are thus unable to determine whether the increased fat oxidation induced by p-synephrine and caffeine were due to increased oxidation of adipose tissue versus intramuscular triacylglycerols. We are also unable to establish the effects of these substances to deliver released fatty acids to active skeletal muscle. Finally, the foods of the last meal ingested 4 h before the onset of the experimental trials were standardized for each individual, but there were small differences in the macronutrient contents among participants. It should be investigated whether the proportions of macronutrients in the preexercise meal can modify the effects of caffeine and p-synephrine on fat oxidation during exercise.
In summary, the acute and isolated ingestion of p-syneprhine (3 mg·kg−1) or caffeine (3 mg·kg−1) was effective to increase the maximal rate of fat oxidation during exercise without affecting the intensity at which lipid use by the muscle was maximized (Fatmax). p-Synephrine produced this “metabolic” effect without affecting cardiovascular variables at rest, whereas caffeine increased blood pressure at rest and perceived physical performance and exertion during exercise. In addition, the isolated intake of caffeine increased fat oxidation rate over a wider range of exercise intensities (from 40% to 70% of V˙O2max) compared with the isolated ingestion of p-synephrine (40% of V˙O2max only). The selection of one of these substances with the aim of increasing fat oxidation during exercise might depend on the exercise intensity and the objective population, but the absence of cardiovascular effects at rest might indicate a superiority of p-synephrine over caffeine in terms of safety for some populations. Finally, the combination of p-synephrine and caffeine did not produce a synergistic effect on substrate oxidation during exercise, when compared with the acute and isolated ingestion of these substances. Thus, the use of only one of these two substances seems sufficient to increase lipid use during exercise. Nevertheless, it is necessary to investigate whether there is a progressive tolerance to the effects of both caffeine and p-synephrine on fat oxidation during exercise when these substances are ingested on a day-to-day basis.
This investigation did not receive any funding. The authors thank the subjects for their invaluable contribution to the study.
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 endorsement by the American College of Sports Medicine.
The authors declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 yr, and no other relationships or activities that could seem to have influenced the submitted work.
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