Home Ingredients Bitter Orange (Citrus aurantium)

Bitter Orange (Citrus aurantium)

Citrus aurantium
Evidence Level
Preliminary
16 Clinical Trials
4 Documented Benefits
1/5 Evidence Score

Bitter orange (Citrus aurantium) is a citrus tree whose peel and unripe fruit are rich in p-synephrine, a stimulant-like amine chemically related to ephedrine. Extracts concentrating it became popular in weight-loss and sports products after the FDA banned ephedrine alkaloids in supplements in 2004. Food and extracts differ: Germany's BfR estimates that average consumers get up to about 6.7 mg of synephrine a day from foods, while supplements can supply much more. An independent meta-analysis of 18 placebo-controlled trials found no significant weight loss or change in body composition, while blood pressure rose with prolonged use (systolic +6.4 mmHg, diastolic +4.3 mmHg). France's ANSES advises against combining it with caffeine or using it during physical activity, and it is on the NCAA banned list. The p-synephrine page covers the isolated compound.

Studied Dose About 49 mg p-synephrine twice daily for 60 days; 20 mg/day for 8 weeks in a pre-workout; single doses of 50 mg, a 900 mg extract (6 percent synephrine), or 1 to 3 mg/kg before exercise. ANSES advises under 20 mg/day from supplements; BfR, no more than 6.7 mg/day.
Active Compound p-Synephrine, the main protoalkaloid of the peel and unripe fruit, with smaller amounts of related amines such as octopamine and tyramine. A commercial extract tested in a blood pressure trial was standardized to 6 percent synephrine. Seville (bitter) orange juice also carries furanocoumarins (bergamottin, 6',7'-dihydroxybergamottin and bergapten) that act on gut CYP3A4.

Benefits

Body Weight and Body Composition

This is what bitter orange extract is sold for, and it has been tested. Pooled analysis of 18 placebo-controlled human trials found no significant weight loss after prolonged use and no change in body composition. An earlier literature review found one eligible randomized trial, 20 people for 6 weeks, with no significant weight loss, and adding 20 mg of synephrine to a pre-workout for 8 weeks did not change body composition.

Supported by Trial 1

Resting Metabolic Rate After a Single Dose

In one small trial run by researchers tied to a bitter orange extract maker, with 10 people per group and one measurement 75 minutes after dosing, 50 mg of p-synephrine alone gave a resting metabolic rate 65 kcal above placebo, a difference not reported as significant. Only the arm adding 600 mg naringin and 100 mg hesperidin was significantly above placebo (183 kcal).

Supported by Trial 3, Trial 5

Fat Use During Exercise

In crossover trials from one research group, mostly in men, single doses of 1 to 3 mg/kg (about 70 to 210 mg at 70 kg) raised peak fat burning during cycling, for example from 0.35 to 0.55 g/min, without changing energy expenditure. The same group's two trials in active women (18 and 16 women) found no effect. This fuel shift has not translated into fat loss in placebo-controlled trials.

Supported by Trial 10, Trial 11

Sprint, Strength and Anaerobic Performance

Results differ by test. In 13 experienced sprinters, 3 mg/kg did not change jump height or 60 m and 100 m sprint speed, and in 80 resistance-trained men, adding 20 mg to a caffeinated pre-workout for 8 weeks gave no extra gain in strength or anaerobic capacity. In 12 men, 100 mg taken for 3 days and before testing raised squat repetitions over placebo in a trial funded by an extract maker.

Supported by Trial 9, Trial 7

Mechanism of action

1

Adrenergic Activity: Beta-3 Selectivity Not Shown in Humans

p-Synephrine is often called a selective beta-3 agonist. In fat cells from five species it only partly stimulated fat breakdown, and blockers of beta-1 and beta-2 receptors also inhibited it, so it did not act as beta-3 selective. In human fat cells it had no effect up to 10 micrograms per mL and was only partly active at higher concentrations.

2

Blood Pressure and Heart Rate

Single-dose results differ. In 15 healthy adults, one 900 mg extract standardized to 6 percent synephrine raised systolic pressure by up to 7.3 mmHg over placebo, diastolic by up to 2.6 mmHg and heart rate by up to 4.2 beats per minute, while maker-linked trials of 50 mg once and about 98 mg a day for 60 days found no significant blood pressure change. Pooling 18 placebo-controlled trials, systolic pressure rose 6.4 mmHg and diastolic 4.3 mmHg with prolonged use.

3

Synephrine in Food Compared With Concentrated Extracts

Seville orange juice contained about 57 micrograms of synephrine per mL, and 8 ounces did not change blood pressure or heart rate in normotensive adults. Germany's BfR estimates intake from foods for average consumers at up to about 6.7 mg a day, and France's ANSES puts heavy citrus consumers near 20 mg. Supplements named in French adverse-event reports supplied 1 to 72 mg a day, all with caffeine.

4

Juice Furanocoumarins and Gut CYP3A4

Seville orange juice contains furanocoumarins that inactivate CYP3A4 in the gut: it raised felodipine exposure 76 percent in a 10-person crossover and raised dextromethorphan bioavailability, with an effect still present after a three-day washout. In a 28-day trial, one bitter orange supplement lacked the marker 6',7'-dihydroxybergamottin and did not change CYP3A4 activity, so content varies by product.

Clinical trials

1
Meta-Analysis of 18 Placebo-Controlled Trials: Weight and Blood Pressure
PubMed

Systematic review and meta-analysis of placebo-controlled human trials of synephrine or bitter orange extract; the authors declare no commercial or financial conflicts. (Koncz et al. 2022, Nutrients)

Participants in 18 placebo-controlled human trials of synephrine or bitter orange extract.

Weight loss with synephrine was not significant after prolonged treatment and body composition did not change. Systolic pressure rose 6.37 mmHg (95% CI 1.02 to 11.72, p = 0.02) and diastolic 4.33 mmHg (95% CI 0.48 to 8.18, p = 0.03) with prolonged use.

2
Systematic Review of Citrus aurantium for Weight
PubMed

Search of MEDLINE, EMBASE, BIOSIS and the Cochrane database for randomized placebo-controlled trials. (Bent et al. 2004, Am J Cardiol)

One eligible trial: 20 patients followed for 6 weeks.

No statistically significant benefit for weight was shown, and the trial gave limited safety information.

3
50 mg p-Synephrine and Resting Energy Use: Single-Dose RCT
PubMed

Double-blind, randomized, placebo-controlled trial measuring resting energy use, blood pressure, heart rate and self-rated symptoms 75 minutes after one dose taken in vegetable juice. One author is a Nutratech employee and two have consulted for Nutratech, which markets bitter orange extract. (Stohs et al. 2011, Int J Med Sci)

Healthy adults, 10 per treatment group (placebo, p-synephrine alone, and p-synephrine with naringin, with or without hesperidin).

50 mg p-synephrine alone gave a reading 65 kcal above placebo, not reported as significant. Only 50 mg p-synephrine plus 600 mg naringin and 100 mg hesperidin was significantly above placebo (183 kcal, p < 0.02). No group differed from placebo in heart rate, blood pressure or self-rated symptoms.

4
Single 900 mg Bitter Orange Dose: Blood Pressure Crossover RCT
PubMed

Randomized, double-blind, placebo-controlled crossover trial of one dose of a commercial bitter orange extract standardized to 6% synephrine, with hourly readings for 6 hours and a one-week washout. (Bui et al. 2006, Ann Pharmacother)

15 young, healthy adults.

Systolic pressure was higher than placebo at hours 1 to 5 (peak difference 7.3 mmHg), diastolic at hours 4 and 5 (peak 2.6 mmHg) and heart rate at hours 2 to 5 (peak 4.2 beats per minute).

5
About 49 mg Twice Daily for 60 Days: Placebo-Controlled Safety Trial
PubMed

Double-blind, placebo-controlled safety trial of bitter orange extract alone or with naringin and hesperidin; the author group includes a Nutratech employee and Nutratech consultants (as disclosed in their 2011 trial). (Kaats et al. 2013, Food Chem Toxicol)

Healthy adults, 25 per group in three groups.

No significant changes in systolic or diastolic blood pressure, blood chemistries or blood cell counts; small heart rate differences between groups that the authors called clinically insignificant; no adverse effects reported.

6
Synephrine and Caffeine Product Before Cycling: Crossover
PubMed

Three-arm, double-blind, placebo-controlled crossover study of one dose of a commercial multi-ingredient product (21 mg synephrine and 304 mg caffeine by analysis) at rest and before 30 minutes of cycling; supported by US Public Health Service and NIH grants. (Haller et al. 2008, Br J Clin Pharmacol)

10 healthy adults aged 20 to 31 (three women).

Post-exercise diastolic pressure was higher than placebo (71.7 vs 63.0 mmHg, p = 0.007) and plasma glucose rose (121.0 vs 103.7 mg/dl, p = 0.004); no significant adverse events; exercise was rated less difficult. Effects cannot be assigned to synephrine alone.

7
3 mg/kg in Competitive Sprinters: Jumps and 60 m and 100 m Sprints
PubMed

Randomized, counterbalanced trial of one dose of p-synephrine or placebo taken 45 minutes before testing, with side-effect questionnaires afterward. (Gutiérrez-Hellín et al. 2016, Appl Physiol Nutr Metab)

13 experienced sprinters.

No change in countermovement jump (P = 0.52), squat jump (P = 0.34), 15-second repeated jumps (P = 0.18), or peak speed in the 60 m (P = 0.55) and 100 m (P = 0.92) sprints. Headache, stomach discomfort, muscle pain and insomnia were not more common after p-synephrine.

8
100 mg p-Synephrine Before Squats: Resistance Exercise Crossover RCT
PubMed

Double-blind, randomized crossover trial of p-synephrine (100 mg), p-synephrine plus 100 mg caffeine, or placebo, each taken for 3 days and on the test morning before 6 sets of squats at 80% of 1RM. Funded by a grant from Nutratech, which supplied the test chews; one author has consulted for Nutratech. (Ratamess et al. 2015, J Int Soc Sports Nutr)

12 healthy, college-aged men.

p-Synephrine alone and with caffeine raised total repetitions over the control protocol (by 11.0%) and placebo (by 6.0%) and raised volume load by 10.6%; only the caffeine combination raised mean power and velocity. Blood lactate and perceived exertion did not change, and no adverse effects were reported.

9
Pre-Workout With or Without 20 mg Synephrine: 8-Week Training RCT
PubMed

Double-blind trial comparing placebo, a caffeinated multi-ingredient pre-workout, and the same pre-workout plus Citrus aurantium extract (20 mg synephrine) once daily during 8 weeks of training. Funded by an unrestricted grant from Nutrabolt, maker of the pre-workout base, whose clinical science director helped design and analyze the study; two authors work for or advise Nutrabolt, and the synephrine extract came from Nutratech. (Jung et al. 2017, J Int Soc Sports Nutr)

80 resistance-trained men.

No significant group interactions for body composition, resting heart rate and blood pressure, 1RM strength, anaerobic sprint capacity or blood chemistry. Adding synephrine gave no additive benefit over the pre-workout alone.

10
3 mg/kg Before a Cycling Ramp Test: Fat Oxidation Crossover
PubMed

Double-blind, randomized, counterbalanced trial with energy expenditure and fuel use measured by indirect calorimetry at rest and during an incremental cycling test; the study received no funding and the authors declare no competing interests. (Gutiérrez-Hellín et al. 2016, Br J Clin Pharmacol)

18 healthy adults.

Peak fat oxidation during exercise rose from 0.29 to 0.40 g/min (P = 0.01) without a change in energy expenditure; resting energy use (P = 0.69) and resting fat oxidation (P = 0.15) did not change.

11
1, 2 or 3 mg/kg Before a Cycling Test: Dose-Response Crossover
PubMed

Double-blind, randomized trial with four identical trials 72 hours apart (placebo or 1, 2 or 3 mg/kg p-synephrine), each followed by a cycling test of increasing intensity with gas exchange measured. (Gutiérrez-Hellín et al. 2018, Phytother Res)

17 healthy adults.

Peak fat oxidation rose from 0.35 g/min with placebo to 0.47 g/min with 1 mg/kg (p = 0.01) and 0.55 g/min with 2 and 3 mg/kg (p < 0.01); no dose changed energy expenditure or heart rate during the test.

12
3 mg/kg Before a Cycling Ramp Test in Active Women: Fuel Use
PubMed

Double-blind, randomized trial of p-synephrine or placebo before a ramp cycling test from 30 to 80% of maximal oxygen uptake, with fuel use measured by indirect calorimetry; the authors declare no conflicts. (Gutiérrez-Hellín et al. 2022, Nutrients)

18 healthy, recreationally active women.

No significant effect on fat oxidation rate (p = 0.484), carbohydrate oxidation or energy expenditure during exercise; peak fat oxidation was 0.26 g/min with placebo and 0.28 g/min with p-synephrine (p = 0.449). Resting ear temperature rose slightly; resting heart rate and blood pressure did not change.

13
3 mg/kg in Active Women, Morning and Evening: Fat Oxidation Crossover
PubMed

Randomized, double-blind, placebo-controlled crossover trial with p-synephrine or placebo taken 60 minutes before a cycling test from 30 to 80% of maximal oxygen uptake, once in the morning and once in the evening; the authors declare no conflicts. (Gutiérrez-Hellín et al. 2022, Nutrients)

16 healthy, active women.

Peak fat oxidation did not differ from placebo at either time of day (no main effect of substance, p = 0.349), and the exercise intensity at which it occurred did not change.

14
8 Ounces of Seville Orange Juice: Blood Pressure Crossover
PubMed

Crossover study of Seville (sour) orange juice versus water, each taken twice 8 hours apart, with hemodynamic readings and juice synephrine measured by HPLC. (Penzak et al. 2001, J Clin Pharmacol)

Normotensive adults.

Heart rate and systolic, diastolic and mean arterial pressure did not differ between juice and water. The juice held a mean 56.9 micrograms of synephrine per mL; octopamine was not detected.

15
Seville Orange Juice and Felodipine: Three-Way Crossover
PubMed

Randomized three-way crossover of a felodipine 10 mg extended-release tablet taken with 240 mL of Seville orange juice, dilute grapefruit juice or common orange juice. (Malhotra et al. 2001, Clin Pharmacol Ther)

10 volunteers.

Felodipine exposure (AUC) rose 76% with Seville orange juice and 93% with dilute grapefruit juice compared with common orange juice, probably through inactivation of intestinal CYP3A4.

16
Citrus aurantium Supplement for 28 Days: Drug-Metabolism Probe Study
PubMed

Randomized study with probe drugs (midazolam, caffeine, chlorzoxazone and debrisoquine) given before and after 28 days of each botanical, with a 30-day washout between phases. (Gurley et al. 2004, Clin Pharmacol Ther)

12 healthy volunteers (6 women, 6 men).

The Citrus aurantium supplement had no significant effect on CYP3A4, CYP1A2, CYP2E1 or CYP2D6 activity, and analysis found it lacked 6',7'-dihydroxybergamottin.

Side effects and drug interactions

Common Potential side effects

Blood pressure rose in pooled placebo-controlled trials of prolonged use (systolic +6.4 mmHg, diastolic +4.3 mmHg), and one 900 mg extract dose raised systolic pressure and heart rate for up to 5 hours. Germany's BfR warns that synephrine and caffeine reinforce each other's effects on heart rate and blood pressure.
France's ANSES received 18 well-documented adverse-event reports linked to supplements with Citrus-derived p-synephrine; the 13 cases judged possibly, likely or very likely related included cardiovascular effects, liver injury, high blood phosphate and a neurological effect. All the products named in cardiovascular reports also contained caffeine.
NCCIH notes reports of abnormal heart rhythms, heart attacks and strokes in people taking bitter orange products, though most contained several ingredients, so the role of bitter orange is unclear. Published single case reports describe a heart attack in a 55-year-old woman, a heart attack in a previously healthy 24-year-old man and a stroke in a 38-year-old man after synephrine-containing products; none establishes causation.
The authors of a Seville orange juice study advise people with severe hypertension, fast heart rhythms or narrow-angle glaucoma to avoid the juice.
ANSES strongly advises against use by people under treatment, in particular for high blood pressure, heart disease or depression, by pregnant or breastfeeding women, and by children and adolescents. NCCIH also says it may not be safe during pregnancy or breastfeeding.
On the NCAA banned stimulant list (2026-27); WADA's 2026 Monitoring Program tracks synephrine in competition but does not prohibit it.

Important Drug interactions

Health Canada's 2010 synephrine notice lists antihypertensives, thyroid hormones, MAO inhibitors and tricyclic antidepressants as prescription drugs to discuss with a health care practitioner before use; a Seville orange juice study also advises people taking MAO inhibitors to avoid the juice.
Do not combine with caffeine: ANSES advises against combining p-synephrine with caffeine, caffeine-containing preparations or any substance with similar effects on the heart and circulation, and BfR states the two reinforce each other's cardiovascular effects.
May work against blood pressure medication: pooled placebo-controlled trials show systolic and diastolic pressure rising with prolonged use.
Health Canada's 2010 notice says not to use synephrine products with phenylephrine or pseudoephedrine decongestants, ephedra or ephedrine products, or other drugs that raise blood pressure.
CYP3A4 substrates: Seville orange juice raised felodipine exposure 76 percent and raised dextromethorphan bioavailability by blocking gut CYP3A4, much as grapefruit juice does. One 28-day supplement study found no CYP3A4 effect and no 6',7'-dihydroxybergamottin in that product, so content varies; if you take a CYP3A4-metabolized drug, ask a pharmacist before using bitter orange juice or extract.

Explore Other Ingredients

Weight Management
MitoBurn® (L-BAIBA)
MitoBurn® is NNB Nutrition's patented stabilized form of L-β-aminoisobutyric acid (L-BAIBA…
CaloriBurn GP® (Grains of Paradise — NNB Nutrition)
CaloriBurn GP is NNB Nutrition's grains of paradise (Aframomum melegueta) seed extract, ma…
Athletic Performance
L-Carnitine
L-carnitine is a nutrient the body uses to carry long-chain fats into mitochondria, the ce…

Frequently asked questions about Bitter Orange (Citrus aurantium)

What is bitter orange used for?

The peel and unripe fruit are made into extracts rich in p-synephrine, sold in weight-loss and pre-workout products. Bitter orange products became more popular after the FDA banned ephedrine alkaloids in supplements in 2004. Placebo-controlled trials have not shown that it produces weight loss.

Does bitter orange help with weight loss?

It has been tested, and the pooled evidence says no. A 2022 meta-analysis of 18 placebo-controlled trials found no significant weight loss and no change in body composition, while blood pressure rose with prolonged use. Single doses raised fat use during cycling in trials from one group, mostly in men, but not in two trials in women, and a fuel shift during exercise is not fat loss.

Is bitter orange juice the same as a bitter orange extract?

No. Seville orange juice held about 57 micrograms of synephrine per mL, and 8 ounces did not change blood pressure in normotensive adults; NCCIH says amounts commonly found in foods are likely safe. Extracts concentrate p-synephrine, often alongside caffeine. The juice, however, carries furanocoumarins that can raise levels of some drugs, which one tested extract lacked.

What is the recommended dosage of bitter orange?

No dose has been shown to help with weight. Trials used about 49 mg p-synephrine twice daily for 60 days, 20 mg/day for 8 weeks, or single doses of 50 mg, a 900 mg extract with 6 percent synephrine, or 1 to 3 mg/kg before exercise. France's ANSES says supplement intake should stay below 20 mg/day, Germany's BfR says no more than about 6.7 mg/day, and Health Canada's 2010 notice set 30 mg/day for synephrine and octopamine combined.

Is bitter orange safe, and does it have side effects?

Pooled trials show blood pressure rising with prolonged use, and NCCIH notes reports of abnormal heart rhythms, heart attacks and strokes in people taking bitter orange products, although most contained several ingredients. ANSES advises against combining it with caffeine or using it during exercise, and strongly advises against use by people treated for high blood pressure, heart disease or depression, pregnant or breastfeeding women, children and adolescents.

Can competitive athletes use bitter orange?

Synephrine (bitter orange) is on the NCAA banned stimulant list for 2026-27. WADA does not prohibit it but includes it in its 2026 Monitoring Program, in competition only, to track patterns of use in sport. A sprint trial found no performance gain at 3 mg/kg.

What is Bitter Orange?

Bitter orange (Citrus aurantium) is a citrus tree whose peel and unripe fruit are rich in p-synephrine, a stimulant-like amine chemically related to ephedrine. Extracts concentrating it became popular in weight-loss and sports products after the FDA banned ephedrine alkaloids in supplements in 2004.

Does Bitter Orange interact with any medications?

Possible interactions include: Health Canada's 2010 synephrine notice lists antihypertensives, thyroid hormones, MAO inhibitors and tricyclic antidepressants as prescription drugs to discuss with a health care practitioner before use; a Seville orange juice study also advises people taking MAO inhibitors to av… If you take prescription medication, check with a pharmacist or doctor before using it.

How strong is the scientific evidence for Bitter Orange?

NutraSmarts rates the evidence for Bitter Orange as Preliminary (1 out of 5). It is backed by 16 study summaries and 29 cited references summarized on this page. A higher rating reflects more, larger, and better-designed human studies.

References(29 citations)

Evidence ratings on NutraSmarts are based on the totality of human clinical research, with emphasis on randomized controlled trials, meta-analyses, and systematic reviews. The references below directly support claims made throughout this page.

  1. Koncz D, Tóth B, Bahar MA, Roza O, Csupor D. The Safety and Efficacy of Citrus aurantium (Bitter Orange) Extracts and p-Synephrine: A Systematic Review and Meta-Analysis. Nutrients. 2022;14(19):4019. doi: 10.3390/nu14194019.PubMedUsed to support: Systematic review and meta-analysis of 18 placebo-controlled human trials of synephrine or bitter orange extract. Weight loss in the synephrine groups was not significant after prolonged treatment and body-composition measures did not change, while systolic blood pressure rose 6.37 mmHg (95% CI 1.02 to 11.72, p = 0.02) and diastolic 4.33 mmHg (95% CI 0.48 to 8.18, p = 0.03). The authors conclude there is no evidence that synephrine can facilitate weight loss and that it tends to raise blood pressure and heart rate. They declare no commercial or financial conflicts.
  2. Bent S, Padula A, Neuhaus J. Safety and efficacy of citrus aurantium for weight loss. Am J Cardiol. 2004;94(10):1359-61. doi: 10.1016/j.amjcard.2004.07.137.PubMedUsed to support: Systematic review of MEDLINE, EMBASE, BIOSIS and the Cochrane database that found only one eligible randomized placebo-controlled trial of Citrus aurantium for weight loss: 20 patients followed for 6 weeks, with no statistically significant weight-loss benefit and limited safety information.
  3. Stohs SJ, Preuss HG, Keith SC, Keith PL, Miller H, Kaats GR. Effects of p-synephrine alone and in combination with selected bioflavonoids on resting metabolism, blood pressure, heart rate and self-reported mood changes. Int J Med Sci. 2011;8(4):295-301. doi: 10.7150/ijms.8.295.PubMedUsed to support: Double-blind, randomized, placebo-controlled trial with 10 subjects per group, measured once 75 minutes after a single dose in vegetable juice. 50 mg p-synephrine alone gave a resting metabolic rate 65 kcal above placebo; adding 600 mg naringin gave 129 kcal; adding 600 mg naringin and 100 mg hesperidin gave 183 kcal, the only increase reported as significant (p<0.02); adding 1000 mg hesperidin instead gave 79 kcal. No group changed heart rate, blood pressure or self-rated symptoms versus placebo. One author is a Nutratech employee and two have consulted for Nutratech, which markets bitter orange extract.
  4. Bui LT, Nguyen DT, Ambrose PJ. Blood pressure and heart rate effects following a single dose of bitter orange. Ann Pharmacother. 2006;40(1):53-7. doi: 10.1345/aph.1G488.PubMedUsed to support: Randomized, double-blind, placebo-controlled crossover trial in 15 young healthy adults given one dose of a commercial 900 mg bitter orange extract standardized to 6% synephrine, with a one-week washout. Systolic pressure was significantly higher than placebo at hours 1 to 5 (peak difference 7.3 mmHg), diastolic at hours 4 and 5 (peak 2.6 mmHg), and heart rate at hours 2 to 5 (peak 4.2 beats per minute).
  5. Kaats GR, Miller H, Preuss HG, Stohs SJ. A 60day double-blind, placebo-controlled safety study involving Citrus aurantium (bitter orange) extract. Food Chem Toxicol. 2013;55:358-62. doi: 10.1016/j.fct.2013.01.013.PubMedUsed to support: Double-blind, placebo-controlled safety trial giving bitter orange extract (about 49 mg p-synephrine) twice daily, alone or with naringin and hesperidin, to 25 healthy subjects per group for 60 days. No significant changes occurred in systolic or diastolic blood pressure, blood chemistries or blood cell counts; heart rate differences between groups were small and called clinically insignificant; no adverse effects were reported. Coauthors H Miller (a Nutratech employee) and SJ Stohs and HG Preuss (Nutratech consultants) disclosed those ties in their 2011 trial.
  6. 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(6):833-40. doi: 10.1111/j.1365-2125.2008.03144.x.PubMedUsed to support: Three-arm, double-blind, placebo-controlled crossover study in 10 healthy adults given one dose of a commercial multi-ingredient product (Ripped Fuel Extreme Cut, 21 mg synephrine and 304 mg caffeine by analysis) at rest and before 30 minutes of cycling. Post-exercise diastolic pressure was higher than placebo (71.7 vs 63.0 mmHg, p = 0.007) and plasma glucose rose (121.0 vs 103.7 mg/dl, p = 0.004); no significant adverse events occurred and exercise was rated less difficult. Effects cannot be assigned to synephrine alone. Supported by US Public Health Service and NIH grants.
  7. Gutiérrez-Hellín J, Salinero JJ, Abían-Vicen J, Areces F, Lara B, Gallo C, Puente C, Del Coso J. Acute consumption of p-synephrine does not enhance performance in sprint athletes. Appl Physiol Nutr Metab. 2016;41(1):63-9. doi: 10.1139/apnm-2015-0299.PubMedUsed to support: Randomized, counterbalanced trial in 13 experienced sprinters given 3 mg/kg p-synephrine or placebo 45 minutes before testing. Countermovement jump (37.4 vs 36.7 cm, P = 0.52), squat jump (P = 0.34), 15-second repeated jumps (P = 0.18) and peak speed in the 60 m (P = 0.55) and 100 m (P = 0.92) sprints did not change, and headache, gastrointestinal discomfort, muscle pain and insomnia were not more frequent. The paper notes that p-synephrine is in the World Anti-Doping Agency monitoring program.
  8. Ratamess NA, Bush JA, Kang J, Kraemer WJ, Stohs SJ, Nocera VG, Leise MD, Diamond KB, Faigenbaum AD. 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. doi: 10.1186/s12970-015-0096-5.PubMedUsed to support: Double-blind, randomized crossover trial in 12 healthy college-aged men given p-synephrine (100 mg), p-synephrine plus 100 mg caffeine, or placebo for 3 days and on the test morning before 6 sets of squats at 80% of 1RM. Both synephrine treatments raised total repetitions over control (11.0%) and placebo (6.0%) and volume load (10.6%); only the caffeine combination raised mean power and velocity; blood lactate and perceived exertion did not change and no adverse effects were reported. Funded by a Nutratech grant, with Nutratech supplying the chews; SJ Stohs has consulted for Nutratech.
  9. Jung YP, Earnest CP, Koozehchian M, Cho M, Barringer N, Walker D, Rasmussen C, Greenwood M, Murano PS, Kreider RB. Effects of ingesting a pre-workout dietary supplement with and without synephrine for 8 weeks on training adaptations in resistance-trained males. J Int Soc Sports Nutr. 2017;14:1. doi: 10.1186/s12970-016-0158-3.PubMedUsed to support: Double-blind trial in 80 resistance-trained men over 8 weeks of training comparing placebo, a caffeinated (284 mg) multi-ingredient pre-workout, and the same pre-workout plus Citrus aurantium extract with 20 mg synephrine. There were no significant group interactions for body composition (DXA), resting heart rate and blood pressure, 1RM strength, anaerobic capacity or blood chemistry, and synephrine gave no additive benefit over the pre-workout alone. Funded by an unrestricted grant from Nutrabolt, maker of the pre-workout base, whose clinical science director helped design and analyze the study; CP Earnest works for and RB Kreider advises Nutrabolt; the synephrine extract (30 percent synephrine) came from Nutratech.
  10. Gutiérrez-Hellín J, Del Coso J. Acute p-synephrine ingestion increases fat oxidation rate during exercise. Br J Clin Pharmacol. 2016;82(2):362-8. doi: 10.1111/bcp.12952.PubMedUsed to support: Double-blind, randomized, counterbalanced trial in 18 healthy adults given 3 mg/kg p-synephrine or placebo. Peak fat oxidation during a cycling ramp test rose from 0.29 to 0.40 g/min (P = 0.01) without a change in energy expenditure; resting energy use (P = 0.69) and resting fat oxidation (P = 0.15) did not change. The study received no funding and the authors declare no competing interests.
  11. Gutiérrez-Hellín J, Del Coso J. Dose-Response Effects of p-Synephrine on Fat Oxidation Rate During Exercise of Increasing Intensity. Phytother Res. 2018;32(2):370-374. doi: 10.1002/ptr.5937.PubMedUsed to support: Double-blind, randomized trial in 17 healthy subjects given placebo or 1, 2 or 3 mg/kg p-synephrine in four trials 72 hours apart before a cycling test of increasing intensity. Peak fat oxidation rose from 0.35 g/min with placebo to 0.47 g/min with 1 mg/kg (p = 0.01) and 0.55 g/min with 2 and 3 mg/kg (p < 0.01); no dose changed energy expenditure or heart rate during the test.
  12. Gutiérrez-Hellín J, Aguilar-Navarro M, Ruiz-Moreno C, Muñoz A, Amaro-Gahete FJ, Posada-Ayala M, López-Samanes Á, Del Coso J, Varillas-Delgado D. Effect of p-Synephrine on Fat Oxidation Rate during Exercise of Increasing Intensity in Healthy Active Women. Nutrients. 2022;14(20):4352. doi: 10.3390/nu14204352.PubMedUsed to support: Double-blind, randomized trial in 18 healthy, recreationally active women given 3 mg/kg p-synephrine or placebo before a ramp cycling test. There was no significant effect on fat oxidation (p = 0.484), carbohydrate oxidation or energy expenditure; peak fat oxidation was 0.26 g/min with placebo and 0.28 g/min with p-synephrine (p = 0.449). Resting ear temperature rose slightly, with no change in resting heart rate or blood pressure. The authors declare no conflicts.
  13. Gutiérrez-Hellín J, Del Coso J, Aguilar-Navarro M, Varillas-Delgado D, Ruiz-Moreno C, López-Samanés Á, Amaro-Gahete FJ, Muñoz A. Does the Time of Day Play a Role in the Acute Effect of p-Synephrine on Fat Oxidation Rate during Exercise in Women? A Randomized, Crossover and Double-Blind Study. Nutrients. 2022;14(23):5030. doi: 10.3390/nu14235030.PubMedUsed to support: Randomized, double-blind, placebo-controlled crossover trial in 16 healthy active women given 3 mg/kg p-synephrine or placebo 60 minutes before a cycling test, in the morning and in the evening. Peak fat oxidation did not differ from placebo (no main effect of substance, p = 0.349) at either time of day, nor did the intensity at which it occurred. The authors declare no conflicts.
  14. Carpéné C, Galitzky J, Fontana E, Atgié C, Lafontan M, Berlan M. Selective activation of beta3-adrenoceptors by octopamine: comparative studies in mammalian fat cells. Naunyn Schmiedebergs Arch Pharmacol. 1999;359(4):310-21. doi: 10.1007/pl00005357.PubMedUsed to support: In vitro study of fat cells from five mammalian species. Synephrine was only partly active at stimulating lipolysis in all species, and its effect was blocked by every beta-blocker tested, including beta-1-selective and beta-2-selective ones, so it did not behave as a beta-3-selective agonist. Octopamine was the most beta-3-selective amine and was fully active in rat, hamster and dog fat cells but inactive in guinea-pig and human fat cells. Cited only for mechanism, not benefit.
  15. Mercader J, Wanecq E, Chen J, Carpéné C. Isopropylnorsynephrine is a stronger lipolytic agent in human adipocytes than synephrine and other amines present in Citrus aurantium. J Physiol Biochem. 2011;67(3):443-52. doi: 10.1007/s13105-011-0078-2.PubMedUsed to support: In vitro study comparing rat and human fat cells. In human fat cells, synephrine, octopamine, tyramine and N-methyltyramine did not stimulate lipolysis up to 10 micrograms per mL, and synephrine and octopamine were only partly stimulatory at high concentrations. The abstract describes the amines as abundant in the unripe fruit. Cited only for mechanism, not benefit.
  16. Penzak SR, Jann MW, Cold JA, Hon YY, Desai HD, Gurley BJ. Seville (sour) orange juice: synephrine content and cardiovascular effects in normotensive adults. J Clin Pharmacol. 2001;41(10):1059-63. doi: 10.1177/00912700122012652.PubMedUsed to support: Crossover study in normotensive adults: 8 ounces of Seville (sour) orange juice, repeated 8 hours later, did not change heart rate or blood pressure compared with water. The juice contained a mean 56.9 micrograms of synephrine per mL and no detectable octopamine. The authors advise people with severe hypertension, tachyarrhythmias or narrow-angle glaucoma, people taking monoamine oxidase inhibitors, and people taking decongestant cold preparations to avoid the juice. The paper describes the extract's synephrine as m-synephrine; it is cited here only for juice content and blood pressure, not chemical identity.
  17. Malhotra S, Bailey DG, Paine MF, Watkins PB. Seville orange juice-felodipine interaction: comparison with dilute grapefruit juice and involvement of furocoumarins. Clin Pharmacol Ther. 2001;69(1):14-23. doi: 10.1067/mcp.2001.113185.PubMedUsed to support: Randomized three-way crossover in 10 volunteers: felodipine exposure (AUC) rose 76% with Seville orange juice and 93% with dilute grapefruit juice compared with common orange juice. The juice contained bergamottin, 6',7'-dihydroxybergamottin and bergapten, and the authors conclude the interaction probably works by inactivating intestinal CYP3A4. Seville orange juice did not interact with cyclosporine. This is juice, not a peel extract.
  18. Di Marco MP, Edwards DJ, Wainer IW, Ducharme MP. The effect of grapefruit juice and seville orange juice on the pharmacokinetics of dextromethorphan: the role of gut CYP3A and P-glycoprotein. Life Sci. 2002;71(10):1149-60. doi: 10.1016/s0024-3205(02)01799-x.PubMedUsed to support: Study in 11 healthy volunteers: dextromethorphan bioavailability rose significantly with grapefruit juice and with Seville orange juice and had returned only to half the baseline value after a three-day washout, consistent with long-lasting inhibition of gut CYP3A and P-glycoprotein. This is juice, not a peel extract.
  19. Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Carrier J, Khan IA, Edwards DJ, Shah A. In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes: Citrus aurantium, Echinacea purpurea, milk thistle, and saw palmetto. Clin Pharmacol Ther. 2004;76(5):428-40. doi: 10.1016/j.clpt.2004.07.007.PubMedUsed to support: Randomized study in 12 healthy volunteers taking a Citrus aurantium supplement for 28 days with probe drugs: no significant effect on CYP3A4, CYP1A2, CYP2E1 or CYP2D6 activity, and the supplement was devoid of the CYP3A4 inhibitor 6',7'-dihydroxybergamottin. One product only, so it shows that furanocoumarin content varies by preparation.
  20. Nykamp DL, Fackih MN, Compton AL. Possible association of acute lateral-wall myocardial infarction and bitter orange supplement. Ann Pharmacother. 2004;38(5):812-6. doi: 10.1345/aph.1D473.PubMedUsed to support: Case report of acute lateral-wall myocardial infarction in a 55-year-old woman who had taken a multicomponent weight-loss supplement containing 300 mg of bitter orange for a year; she had a smoking history and an arteriogram showed a left main coronary lesion. Rated possibly associated on the Naranjo scale; the authors say more studies or reports are needed.
  21. Thomas JE, Munir JA, McIntyre PZ, Ferguson MA. STEMI in a 24-year-old man after use of a synephrine-containing dietary supplement: a case report and review of the literature. Tex Heart Inst J. 2009;36(6):586-90.PubMedUsed to support: Case report of ST-segment-elevation myocardial infarction with extensive thrombus in the left anterior descending artery in a previously healthy 24-year-old man within hours of taking a synephrine-containing ephedra-free product, with no coronary risk factors, no hypercoagulable state and no illicit drug use. A single case; it does not establish causation.
  22. Bouchard NC, Howland MA, Greller HA, Hoffman RS, Nelson LS. Ischemic stroke associated with use of an ephedra-free dietary supplement containing synephrine. Mayo Clin Proc. 2005;80(4):541-5. doi: 10.4065/80.4.541.PubMedUsed to support: Case report of thalamic and cerebellar infarction in a 38-year-old man with no major atherosclerotic risk factors after one week of an ephedra-free supplement containing synephrine and caffeine; a vasospastic origin was considered most likely. A single case of a combination product; it does not establish causation.
  23. Bakhyia N, Dusemund B, Richter K, Lindtner O, Hirsch-Ernst KI, Schäfer B, Lampen A. [Risk assessment of synephrine in dietary supplements]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2017;60(3):323-331. doi: 10.1007/s00103-016-2506-5.PubMedUsed to support: Risk assessment by Germany's Federal Institute for Risk Assessment (BfR), in German with an English abstract. In animals, oral synephrine raised blood pressure and caused ventricular arrhythmias, effects enhanced by caffeine and physical activity; some human studies show cardiovascular effects; case reports of hypertension, arrhythmia and myocardial infarction were linked to synephrine plus caffeine supplements. It concludes that daily synephrine intake from supplements should not exceed the median intake from conventional foods.
  24. ANSES (French Agency for Food, Environmental and Occupational Health and Safety). Compléments alimentaires minceurs à base de p-synéphrine : l’Anses publie aujourd’hui ses recommandations. ANSES. 2014;News release dated 5 May 2014 summarizing the ANSES opinion. Accessed 2026..SourceUsed to support: Not PubMed-indexed; French government risk assessment (in French). p-Synephrine is found in bitter orange peel. ANSES received 18 well-documented adverse-event reports linked to supplements with Citrus-derived p-synephrine; the 13 cases judged possibly, likely or very likely related included cardiovascular effects, liver injury, high blood phosphate and a neurological effect. Products named in cardiovascular reports supplied 1 to 72 mg/day and all contained caffeine. A balanced diet can supply up to 20 mg/day; ANSES treats 20 mg/day, the intake of heavy citrus consumers, as a reference value supplements should not exceed (not a strict safety limit), advises against combining p-synephrine with caffeine or substances with similar cardiovascular effects, strongly advises against use by people under treatment (in particular for hypertension, heart disease or depression), pregnant or breastfeeding women, children and adolescents, and advises against use during physical activity.
  25. Federal Institute for Risk Assessment (BfR). Health assessment of sports and weight loss products containing synephrine and caffeine. BfR Opinion No. 004/2013. Bundesinstitut für Risikobewertung. 2012;Opinion dated 16 November 2012 (English translation). Accessed 2026..SourceUsed to support: Not PubMed-indexed; German government risk assessment. States that synephrine and caffeine taken together can reinforce each other's effects on heart rate (possibly including arrhythmia) and blood pressure, and recommends that no more than 6.7 mg/day of synephrine be consumed from a food supplement, the intake from conventional foods for average consumers assuming maximum synephrine contents, so that total intake for frequent citrus consumers stays at or below 25.7 mg/day. Some high-dose combination products were judged unsafe.
  26. Health Canada, Natural Health Products Directorate. Notice: Guidelines for the Use of Synephrine in Natural Health Products (archived). Health Canada. 2010;Notice dated January 2010; archived and no longer updated. Accessed 2026..SourceUsed to support: Not PubMed-indexed; archived regulatory notice. Set 30 mg/day as the maximum for total synephrine plus octopamine, did not permit caffeine or caffeine sources in synephrine products without sufficient human clinical evidence, gave antihypertensives, thyroid hormones, MAO inhibitors and tricyclic antidepressants as examples of prescription drugs warranting practitioner advice, and said not to use the products with phenylephrine or pseudoephedrine decongestants, ephedra or ephedrine products, or other drugs that raise blood pressure.
  27. National Center for Complementary and Integrative Health. Bitter Orange. National Center for Complementary and Integrative Health. 2024;Fact sheet, last updated November 2024. Accessed 2026..SourceUsed to support: Not PubMed-indexed; NIH fact sheet. Notes the 2004 FDA ban on ephedrine alkaloids in supplements and that bitter orange products became more popular afterward; says effects on body weight are unclear and most athletic studies showed no benefit; says bitter orange is likely safe orally in amounts commonly found in foods; reports cases of abnormal heart rhythms, heart attacks and strokes in people taking bitter orange products, most of which contained several ingredients; and says it may not be safe during pregnancy or breastfeeding.
  28. National Collegiate Athletic Association. 2026-27 NCAA Banned Substances. National Collegiate Athletic Association. 2026;Banned drug class list for the 2026-27 academic year. Accessed 2026..SourceUsed to support: Not PubMed-indexed; official NCAA list. Under the Stimulants class, 'Synephrine (bitter orange)' is listed among the example banned substances, along with octopamine and hordenine.
  29. World Anti-Doping Agency. The 2026 Monitoring Program. World Anti-Doping Agency. 2025;Official WADA document, published September 2025. Accessed 2026..SourceUsed to support: Not PubMed-indexed; official WADA document. Lists synephrine under Stimulants, in-competition only. The Monitoring Program covers substances that are not on the Prohibited List but that WADA wishes to monitor in order to detect potential patterns of misuse in sport.