Synephrine (P-synephrine) is a phenylethylamine derivative naturally present in bitter orange (Citrus aurantium) and many other citrus fruits such as Seville oranges, Nova tangerines, and sweet Marra oranges [1, 2].
Moreover, P-synephrine can be synthesized in the human body through the same pathways involved in the synthesis of catecholamines , although it is considered a trace amine due to its low plasma levels.
R-synephrine became popular as an alternative to ephedra after the Food and Drug Administration (FDA) banned foods containing ephedrine in 2004. This substance, like synephrine or bitter orange-orange extract, has been included in a variety of foods and dietary supplements used for weight loss because of its purported thermogenic effects .
Previous studies have shown that acute  and chronic  use of supplements containing P-synephrine, among other sympathomimetic substances such as caffeine and octopamine, can cause increased resting energy expenditure and lipolysis.
Although it has been suggested that the thermogenic effect of orange may be related to the activation of β3 adrenergic receptors induced by P-synephrine , it is impossible to determine whether these effects are caused by P-synephrine contained in the orange or as a result of co-administration with other active substances, which are usually included in thermogenic additives.
Acute intake of P-synephrine (21 mg of orange or ~ 0.3 mg of P-synephrine per kg of body weight) together with caffeine caused a lower perceived load during 30 minutes of moderate-intensity exercise, that is, increased exercise tolerance .
In addition, supplementation with P-synephrine (~ 1.2 mg/kg for 3 days) alone or with caffeine was effective in increasing repetitions during the squat strength test .
On the other hand, oral P-synephrine (3 mg/kg) was ineffective in increasing jump height or running speed in elite sprinters during their maximum running speed tests .
The Effect of Acute Synephrine Intake on Fat Oxidation During Exercise
In a double blind, randomized experiment, 13 healthy subjects participated in four experimental trials after taking a capsule containing a placebo, 3 mg/kg caffeine, 3 mg/kg P-synephrine, or a combination of these doses of caffeine and P-synephrine.
Energy consumption and the rate of substrate oxidation were measured by indirect calorimetry during a test on a bicycle ergometer with aerobic power increasing from 30% to 90% VO2max.
Compared to placebo, caffeine, P-synephrine, or P-synephrine + caffeine did not alter total energy expenditure or heart rate throughout the exercise test.
At the same time, caffeine, P-synephrine, and P-synephrine + caffeine equally increased the maximum rate of fat oxidation during exercise compared with placebo, without changing energy expenditure or heart rate.
An increase in fat oxidation without an increase in energy expenditure means that fat expenditure by working muscle cells has increased due to a decrease in the oxidation of carbohydrates (blood glucose and muscle glycogen).
At the same time, the combined use of P-synephrine and caffeine did not have an additive effect for further increasing fat oxidation during exercise. That is, the action of P-synephrine was not enhanced by caffeine.
The intensity of the exercise that caused maximum fat oxidation was the same across all trials (~ 46.2% ± 10.2% VO2max) .
In an earlier study of 18 healthy, physically active men, similar results were obtained. Compared with placebo, intake of P-synephrine (3 mg/kg) did not change energy expenditure (1.6 ± 0.3 versus 1.6 ± 0.3 kcal/min), and the rate of fat oxidation at rest changed upwards only slightly (0.08 ± 0.02 versus 0.10 ± 0.04 g / min).
However, P-synephrine intake pushed the fat oxidation rate upward during the test aerobic exercise. In addition, p-synephrine increased the maximum rate of fat oxidation (from 0.29 ± 0.15 to 0.40 ± 0.18 g / min) during exercise at low to moderate intensity, while it decreased the rate of oxidation carbohydrates .
In last year’s double blind and randomized experiment, 14 healthy subjects conducted two acute experimental studies after taking either P-synephrine (3 mg/kg) or placebo (cellulose). Energy expenditure and the rate of fat oxidation were continuously measured by indirect calorimetry over a 1-hour continuous cycle at an intensity that induces the maximum rate of fat oxidation.
Compared with placebo, energy expenditure during 1 hour of cycling remained unchanged with P-synephrine (698 ± 129 versus 686 ± 123 kcal).
However, P-synephrine increased whole-body fat oxidation (placebo 33.6 ± 10.4 versus synephrine 37.3 ± 9.8 g) and also decreased carbohydrate oxidation (placebo 99.5 ± 30.4 versus synephrine 85.0 ± 28.4 g) However, the magnitude of the shift in substrate oxidation induced by P-synephrine was not so small.
Another recent study aimed to determine the effect of different doses of synephrine on maximum fat oxidation during exercise. Seventeen healthy subjects volunteered to participate in a double-blind and randomized experiment consisting of four identical experimental studies.
In four trials, spaced 72 hours apart, participants took placebo or supplementation at 1, 2, or 3 mg/kg P-synephrine. Sixty minutes after ingestion, to ensure absorption of the substance, the participants performed an exercise intensity increase test on a bicycle ergometer while their gas exchange was continuously measured, which can characterize the intensity of energy expenditure and the type of substrate used as an energy source.
None of the doses of P-synephrine affected energy expenditure or heart rate during the test. The highest rate of fat oxidation with placebo (0.35 ± 0.05 g / min) was achieved with an aerobic capacity of 38.0 ± 1.9% of maximum oxygen consumption (VO2max).
Ingestion of 1 mg/kg increased the maximum fat oxidation to 0.47 ± 0.11 g / min but did not change the intensity at which it was obtained (42.0 ± 9.4% of VO2max).
Oral ingestion of 2 and 3 mg/kg of P-synephrine increased the maximum fat oxidation to 0.55 ± 0.14 g / min, although only 3 mg/kg slightly changed the intensity at which it was obtained (43.0 ± 9.5 % of VO 2max).
In conclusion, the study authors note that although all doses of P-synephrine increased the maximum rate of fat oxidation during exercise, the greatest effects were found with 2 and 3 mg/kg .
Overall, the researchers agree on the results of the experiments that the metabolic effects found after taking synephrine may be beneficial for those people who seek to increase fat oxidation during exercise.
Synephrine vs Obesity
One study looked at the use of orange extract and its constituent p-synephrine for the treatment of obesity in 360 patients. More than 50% of the subjects in these clinical trials were overweight, and about two-thirds of them consumed caffeine (132-528 mg/day) and P-synephrine (10-53 mg/day).
Approximately 44% of the subjects consumed a product containing only orange extract or synephrine, while the rest consumed a combination product containing several ingredients, including synephrine.
The results showed that the orange extract alone or in combination with other ingredients did not cause significant side effects, including an increase in heart rate or blood pressure, or changes in electrocardiographic data, serum chemistry, blood cell count, or urinalysis.
Synephrine, alone or in combination with other foods, has been shown to increase metabolic rate and energy expenditure, and promote weight loss when taken for 6-12 weeks .
A study by Verpeut et al.  studied the effect of a combination of orange extract (standardized for 6% synephrine content) and Rhodiola Rosea extract (standardized to 3% rosavin and 1% salidroside) on the diet of induced obesity in rats.
Acute administration of an extract of orange (1-10 mg/kg) or Rhodiola Rosea (2-20 mg/kg) did not independently reduce food intake in animals with normal weight, but the combination of orange (5.6 mg/kg) and Rhodiola Rosea (20 mg/kg) provided suppression of food intake by 10.5%.
On the other hand, 10 days of treatment with orange (5.6 mg/kg) or Rhodiola Rosea (20 mg/kg) alone or in combination resulted in a 30% reduction in visceral fat mass compared to other treatments, in animals fed a high-fat diet (60% fat) for a 13 week period.
The combined use of orange and Rhodiola also led to increased levels of hypothalamic norepinephrine and dopamine in the frontal cortex, indicating a beneficial role in the treatment of obesity .
It should be added that the human equivalent of the doses of substances used in experiments on animals is, on average, 10 times less.
A review of human clinical studies involving orange extract and synephrine noted nine studies involving the administration of orange extract alone or in combination with other ingredients that demonstrated an increase in metabolic rate without an increase in heart rate or blood pressure.
Thus, according to the results of one experiment, in the group receiving only synephrine (50 mg), there was an increase in resting metabolic parameters (RMP) by 65 kcal compared with the placebo group.
Consumption of 600 mg of naringin with 50 mg of synephrine resulted in an increase in RMP by 129 kcal compared to the placebo group.
In the group receiving 100 mg of hesperidin in addition to 50 mg of synephrine plus 600 mg of naringin, the RMP increased by 183 kcal, which was statistically significant compared to the placebo control .
However, since many studies do not confirm the effect of supplements containing synephrine (or orange extract) alone on resting metabolic changes, such as those listed in the previous chapter, this cannot be argued.
Therefore, when the main purpose of taking synephrine is to affect metabolism outside of training time, it is better to combine it with other supplements, a similar effect of which has more reliable evidence.
These include caffeine (100-300 mg at a time), yohimbine (4-8 mg at a time), green tea extract (a single dose contains 50 mg of caffeine and 90 mg of epigallocatechin gallate).
Safety and Dosage
Several interventional studies investigating the acute effects of synephrine on blood pressure and heart rate in healthy normotensive subjects indicate that synephrine may induce cardiovascular effects in humans.
Several published reports of adverse cardiovascular effects (hypertension, cardiac arrhythmia) have been associated with the consumption of dietary supplements containing both synephrine and caffeine .
Nevertheless, a large systematic review that focused on current human, animal, in vitro, and mechanistic studies regarding the safety, efficacy, and mechanisms of action of orange and P-synephrine extracts showed a rather favorable situation.
About 30 human studies have shown that R-synephrine and bitter orange extracts do not produce cardiovascular effects and do not act as stimulants at commonly used doses. Mechanistic studies suggest that P-synephrine acts through multiple mechanisms that are being studied.
Since synephrine exhibits greater adrenergic receptor binding in rodents than in humans, data from animals cannot be directly extrapolated to humans.
This review, as well as several other evaluations published in recent years, concluded that bitter orange extract and synephrine are safe to use in dietary supplements and foods at generally accepted doses .
As with any stimulant, synephrine should be started at the lowest dose. Similarly, when synephrine is combined with other tonic substances (caffeine, yohimbine, adaptogens) since the latter enhance its effects.
The recommended dosage range for synephrine is 0.3 to 3 mg/kg body weight.
It should be taken before meals in the morning or daytime (1-2 times a day) or the entire daily dose 1 time per day one hour before exercise (preferably aerobic).
The substance is not banned by the World Anti-Doping Agency (WADA), which deals with Olympic athletes.
- Pellati F, Benvenuti S. Fast high‐performance liquid chromatography analysis of phenethylamine alkaloids in citrus natural products on a pentafluorophenylpropyl stationary phase. J Chromatogr A 2007; 1165: 58–66.
- Dragull K, Breksa AP 3rd, Cain B. Synephrine content of juice from Satsuma mandarins (Citrus unshiu Marcovitch). J Agric Food Chem 2008; 56: 8874–8.
- Rossato LG, Costa VM, Limberger RP, Bastos Mde L, Remiao F. Synephrine: from trace concentrations to massive consumption in weight‐loss. Food Chem Toxicol 2011; 49: 8–16.
- Stohs SJ, Preuss HG, Shara M. A review of the human clinical studies involving Citrus aurantium (bitter orange) extract and its primary protoalkaloid p‐synephrine. Int J Med Sci 2012; 9: 527–38.
- Gougeon R, Harrigan K, Tremblay JF, Hedrei P, Lamarche M, Morais JA. Increase in the thermic effect of food in women by adrenergic amines extracted from Citrus aurantium . Obes Res 2005; 13: 1187–94.
- Colker CM, Kaiman DS, Torina GC, Perlis T, Street C. Effects of Citrus aurantium extract, caffeine and St John’s wort on body fat loss, lipid levels and mood states in normal weight and obese individuals. Curr Ther Res 1999; 60: 145–53.
- Stohs SJ, Preuss HG, Shara M. A review of the receptor‐binding properties of p‐synephrine as related to its pharmacological effects. Oxid Med Cell Longev 2011; 2011: 482973.
- Haller CA, Duan M, Jacob P 3rd, Benowitz N. Human pharmacology of a performance‐enhancing dietary supplement under resting and exercise conditions. Br J Clin Pharmacol 2008; 65: 833–40.
- Ratamess NA, Bush JA, Kang J, Kraemer WJ, Stohs SJ, Nocera VG, et al. The effects of supplementation with p‐synephrine alone and in combination with caffeine on resistance exercise performance. J Int Soc Sports Nutr 2015; 12: 35.
- Gutiérrez‐Hellín J, Salinero JJ, Abían‐Vicen J, Areces F, Lara B, Gallo C, et al. Acute consumption of p‐synephrine does not enhance performance in sprint athletes. Appl Physiol Nutr Metab 2016; 41: 63–9.
- Effects of p-Synephrine and Caffeine Ingestion on Substrate Oxidation during Exercise. Gutiérrez-Hellín J, Del Coso J. Med Sci Sports Exerc. 2018 Sep;50(9):1899-1906.
- Acute p-synephrine ingestion increases fat oxidation rate during exercise. Gutiérrez-Hellín J, Del Coso J. Br J Clin Pharmacol. 2016 Aug;82(2):362-8.
- Acute p-synephrine ingestion increases whole-body fat oxidation during 1-h of cycling at Fatmax. Gutiérrez-Hellín J, Ruiz-Moreno C, Del Coso J. Eur J Nutr. 2019 Nov 5.
- Dose-Response Effects of p-Synephrine on Fat Oxidation Rate During Exercise of Increasing Intensity. Gutiérrez-Hellín J, Del Coso J. Phytother Res. 2018 Feb;32(2):370-374.
- A review of the human clinical studies involving Citrus aurantium (bitter orange) extract and its primary protoalkaloid p-synephrine. Stohs SJ, Preuss HG, Shara M. Int J Med Sci. 2012; 9(7):527-38.
- Citrus aurantium and Rhodiola rosea in combination reduce visceral white adipose tissue and increase hypothalamic norepinephrine in a rat model of diet-induced obesity. Verpeut JL, Walters AL, Bello NT. Nutr Res. 2013 Jun; 33(6):503-12.
- A review of the human clinical studies involving Citrus aurantium (bitter orange) extract and its primary protoalkaloid p-synephrine. Sidney J Stohs 1, Harry G Preuss, Mohd Shara. Int J Med Sci. 2012;9(7):527-38.
- Effects of p-synephrine alone and in combination with selected bioflavonoids on resting metabolism, blood pressure, heart rate and self-reported mood changes Sidney J Stohs 1, Harry G Preuss, Samuel C Keith, Patti L Keith, Howard Miller, Gilbert R Kaats.Int J Med Sci. 2011 Apr 28;8(4):295-301.
- Risk assessment of synephrine in dietary supplements. Bakhyia N, Dusemund B, Richter K, Lindtner O, Hirsch-Ernst KI, Schäfer B, Lampen A. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2017 Mar;60(3):323-331.
- Safety, Efficacy, and Mechanistic Studies Regarding Citrus aurantium (Bitter Orange) Extract and p-Synephrine. Stohs SJ. Phytother Res. 2017 Oct;31(10):1463-1474.
More about this topic: