Bitter Orange: Synephrine, Weight-Loss Claims and Heart Safety

Table of Contents

1. One Tree, Three Traditions
2. Bitter Orange and Chen Pi Are Different Materials
3. Synephrine and Its Chemical Relatives
4. How p-Synephrine Differs From Ephedrine, as the Sources State It
5. Weight-Loss and Metabolic Trials
6. Blood Pressure and Heart Rate Studies
7. Case Reports of Heart and Brain Events
8. What Product Testing Has Found
9. Regulators and Sports Bodies
10. Interaction Concerns Reported in the Literature
11. What Is Not Known
12. Key Research Papers
13. Connections
14. Featured Videos

One Tree, Three Traditions

Bitter orange is also called sour orange, Seville orange or bigarade. A 2021 review describes it as an evergreen tree up to about 5 metres tall, known for its scented white flowers and grown in Spain, Italy and the United States; the review gives eastern Africa and Syria as its believed origin, while the U.S. National Center for Complementary and Integrative Health (NCCIH) fact sheet calls it native to Southeast Asia. The sources disagree, and this page does not settle it. The Oranges: History and Origins page covers its genetic ancestry.

The marmalade orange

The fruit is too sour to eat raw. A Spanish study of trees in Seville describes the fruit as used mainly to make marmalade, and found metal levels in fruit and marmalade below provisional tolerable intake values. The NCCIH fact sheet adds that the fruit, peel and oils flavour foods, beers and spirits.

Neroli and orange-flower water

The flowers are distilled for neroli essential oil and orange-flower water. In the 2021 review, distillation of the blossoms gives about 99.9% hydrosol (orange-flower water) and only about 0.1% neroli oil, whose main compounds include linalool, linalyl acetate, geranyl acetate, farnesol and nerolidol. Many small clinical trials of neroli inhalation for anxiety, pain and sleep exist; they test the scent of the flower oil rather than the fruit extracts discussed below, and they are outside this page.

Zhi shi and zhi qiao in Chinese medicine (tradition)

Chinese medicine uses two dried-fruit drugs from this tree. Zhi shi (枳实, Aurantii Fructus Immaturus) is the young immature fruit; zhi qiao (枳壳, also romanised zhi ke; Aurantii Fructus) is the fruit picked at a later stage. A 2024 chemistry study notes that the Chinese Pharmacopoeia lists them as distinct herbs from the same plant, harvested at different times, and that practitioners keep them apart. In the traditional description quoted in a 2026 study, zhi shi is a “qi-regulating” herb with a bitter, slightly sour taste that “breaks stagnant qi, promotes digestion, resolves phlegm, and treats constipation,” and frying it with bran is said to moderate its strength. Zhi qiao is likewise described as a qi-regulating herb, and traditional texts say of it “the older, the better”. A 2026 aging study found that stored zhi qiao lost volatile compounds such as D-limonene while small flavonoids rose. These are statements of tradition and of chemistry. The rat and mouse constipation experiments published on zhi shi are not human evidence.

The same 2026 study notes that zhi shi on the market comes from sour orange and also from sweet orange, and that the bitter flavonoids naringin and neohesperidin were higher in the sour-orange material. A traditional decoction of zhi shi and a capsule of extract standardised to p-synephrine are therefore different things, even when both come from the same tree.

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Bitter Orange and Chen Pi Are Different Materials

Chen pi is the aged peel of the ripe mandarin, Citrus reticulata. Zhi shi and zhi qiao are the whole dried fruits of Citrus aurantium. A 2022 comparison of four related citrus drugs (zhi shi, zhi qiao, green mandarin peel and chen pi) describes all four as traditionally used to “regulate qi” and aid gut movement, and found that species and ripeness stage separated them chemically, with flavonoid levels falling as the fruit ripens.

The Chen Pi page notes that mandarin peel contains only trace synephrine and does not belong in the same category as bitter-orange extracts. This page agrees. The weight-loss ingredient discussed below is an extract of Citrus aurantium fruit, concentrated and standardised for p-synephrine. Ordinary use of chen pi in food or decoction is not the same exposure.

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Synephrine and Its Chemical Relatives

Synephrine is a small amine, related in shape to adrenaline and ephedrine. A 2011 review explains that it exists in three positional isomers (para, meta and ortho), and that only p-synephrine and m-synephrine have been described in weight-loss products. The names matter:

• p-Synephrine (para-synephrine) is the main amine in bitter orange. A 2021 Russian review reports that the R-(−) form of p-synephrine makes up about 90% or more of the fruit's amines, and that commercial dry extracts are standardised to anywhere from 4% to 98% synephrine. The 2022 meta-analysis gives 3% to 6% as the usual range for dried fruit extracts.
• m-Synephrine (meta-synephrine) is the medicine phenylephrine, a decongestant and blood-pressure drug. It is not the main amine of the fruit, but it appears when products are spiked with synthetic amines.
• p-Octopamine is a close relative found in smaller amounts. One perfused-liver study describes bitter-orange extracts as containing large amounts of p-synephrine and much smaller amounts of p-octopamine. A 2001 study of Seville orange juice did not detect octopamine at all.
• Other amines found in bitter-orange products include tyramine, N-methyltyramine and hordenine.

p-Synephrine is not unique to supplements. The 2001 juice study measured 56.9 micrograms of synephrine per millilitre of Seville orange juice; by simple arithmetic, an 8-ounce glass holds roughly 13 to 14 mg. A German risk-assessment team at the Federal Institute for Risk Assessment (BfR) put the median dietary intake of synephrine from ordinary foods in Germany at 6.7 mg a day.

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How p-Synephrine Differs From Ephedrine, as the Sources State It

Every paper on bitter orange compares it with ephedrine. They disagree about what the comparison means.

The case for a weaker drug

A group of reviews led by the same pharmacologist argues that small structural differences change how these molecules act on the body. According to the 2011 and 2020 reviews, p-synephrine and p-octopamine bind only weakly to the alpha-1, alpha-2, beta-1 and beta-2 adrenergic receptors that raise blood pressure and heart rate. At commonly used doses they are not known to release the body's own noradrenaline and adrenaline indirectly, which ephedrine does. On this account, the heart and blood-vessel effects of ephedrine and m-synephrine (phenylephrine) cannot be carried over to p-synephrine. The 2017 review adds that p-synephrine binds adrenergic receptors more strongly in rodents than in humans, so animal results do not transfer directly. The Russian review describes synephrine as a weak adrenergic agonist acting mainly through beta-3 receptors, which drive fat breakdown.

The case for real vascular activity

A 2011 toxicology review states that synephrine acts on several adrenergic and serotonergic receptors, and that its action on trace-amine-associated receptors has long been debated. Laboratory studies since then have found measurable activity. In isolated pig arteries, p-synephrine, p-octopamine and tyramine all made coronary and mesenteric arteries contract. The mesenteric response was abolished by the alpha-1 blocker prazosin and partly depended on the release of stored noradrenaline (2019). In cell lines carrying human receptors, many phenethylamines from supplements activated adrenergic receptors and almost all activated trace amine-associated receptor 1 (2024). In isolated rat arteries, p-synephrine and p-octopamine were the only two of the substances tested that contracted mesenteric artery segments, an effect largely blocked by prazosin (2026). The authors of the rat study suggest the risk may be greatest in people exercising or with existing heart disease. That is their interpretation of tissue experiments, not a measured outcome in people.

Both camps rely partly on laboratory evidence. Neither the receptor-binding argument nor the artery experiments, on their own, show what a capsule does to a person's heart.

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Weight-Loss and Metabolic Trials

Systematic reviews

• 2004, one usable trial. A systematic review searching four databases found only one eligible randomised placebo-controlled trial of bitter orange for weight loss. It followed 20 people for 6 weeks and showed no statistically significant benefit.
• 2006 update. A review in Obesity Reviews covering animal studies, weight-loss trials, short physiology studies and case reports concluded that “some evidence is promising” but that larger, more rigorous trials were needed before any conclusion on safety or efficacy.
• 2012 review of about 360 people. A review of more than 20 published and unpublished studies (about 360 participants, over half overweight) reported that roughly two-thirds of the overweight participants took caffeine (132 to 528 mg a day) along with p-synephrine (10 to 53 mg a day), for up to 12 weeks, and that about 56% took multi-ingredient products. The authors reported modest increases in weight loss over 6 to 12 weeks and increases in resting metabolic rate, and called for longer studies.
• 2022 meta-analysis. A systematic review and meta-analysis restricted to placebo-controlled human trials included 18 studies with 341 participants. Only three trials reported weight, lasting 42 to 56 days at 54, 20 and 10 mg of synephrine a day. The pooled difference in weight change versus placebo was 0.60 kg, with a confidence interval running from −5.62 to 6.83 kg (p = 0.85), meaning no detectable effect. Body fat fell by 1.87 percentage points (p = 0.07) and fat mass by 0.32 kg (p = 0.85), neither significant. The authors concluded that “there is no evidence that synephrine can facilitate weight loss.”

Short metabolic studies

• Resting metabolism. In a 2011 trial with 10 people per group, 50 mg of p-synephrine raised resting metabolic rate 75 minutes later by 65 kcal more than placebo. Adding the flavonoids naringin (600 mg) and hesperidin (100 mg) gave a 183 kcal rise, the only statistically significant result. A higher hesperidin dose gave only 79 kcal. Heart rate and blood pressure did not change.
• Fat burning during exercise. In a 2018 crossover trial in 13 people, 3 mg per kilogram of body weight of p-synephrine raised the peak rate of fat oxidation during cycling from 0.30 to 0.43 grams per minute, similar to caffeine. Neither raised total energy expenditure or heart rate, and combining them gave no extra effect. A 2021 narrative review by the same research group found the same pattern across studies at 2 to 3 mg per kg. It noted that nobody knows whether the effect lasts with daily use or leads to fat loss.
• Sports performance. In 13 competitive sprinters, 3 mg per kg did not change jump height or 60-metre and 100-metre sprint speed.

Who ran the studies matters when reading them. The 2011 metabolic trial and the 2020 mechanism review list employment or consulting ties to ingredient suppliers in their conflict-of-interest statements. The 2022 meta-analysis declares no such ties.

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Blood Pressure and Heart Rate Studies

The cardiovascular trials are small, mostly in healthy young adults, and they point in different directions.

Studies that found rises

• Single 900 mg dose, 2006. Fifteen healthy young adults took a commercial extract standardised to 6% synephrine (about 54 mg). Systolic pressure was higher than after placebo for hours 1 to 5 (peak difference 7.3 mmHg), diastolic pressure at hours 4 and 5 (peak 2.6 mmHg), and heart rate for hours 2 to 5 (peak 4.2 beats per minute).
• Single-ingredient versus multi-ingredient product, 2005. Ten healthy adults took a bitter-orange extract with 46.9 mg of synephrine, a multi-ingredient “ephedra-free” product with 5.5 mg of synephrine plus caffeine and other stimulants, and placebo. The multi-ingredient product raised systolic pressure by 9.6 mmHg and diastolic by 9.1 mmHg at 2 hours. The single extract did not raise blood pressure but raised heart rate by 11.4 beats per minute at 6 hours, against 16.7 for the combination. The authors attributed the pressure rise mostly to caffeine and the other stimulants, because an eightfold higher synephrine dose alone had no effect on blood pressure.
• Pooled long-term effect, 2022. In the meta-analysis, longer use (up to about 8 weeks) raised systolic pressure by 6.37 mmHg (95% confidence interval 1.02 to 11.72) and diastolic pressure by 4.33 mmHg (0.48 to 8.18), both statistically significant. Single doses did not significantly raise systolic pressure. Heart rate rose after single doses but not significantly; the largest change, at 3 hours, had p = 0.07 (full text).

Studies that found no rise

• 60 days, 2013. Twenty-five healthy people per group took about 49 mg of p-synephrine twice daily (up to 98 mg a day), alone or with naringin and hesperidin, or placebo. Blood pressure, blood chemistry and blood counts did not change significantly; heart-rate differences were small and judged clinically insignificant.
• Single 49 mg dose, 2016. In 18 healthy adults followed for 8 hours, heart rate, systolic pressure and electrocardiograms did not change. Diastolic pressure fell by 4.5 mmHg at 60 minutes.
• 15 days, 2018. In 16 healthy adults taking 49 mg a day, heart rate, blood pressure and electrocardiograms showed no significant change.
• With and without caffeine, 2018. Sixteen people sat quietly for 3 hours after 103 mg of p-synephrine, caffeine alone (240 or 325 mg), the two combined, or placebo. Only the higher caffeine dose, alone or with synephrine, raised systolic pressure. Synephrine alone lowered diastolic and mean arterial pressure, and adding it to caffeine did not raise pressure or heart rate further.
• Before exercise, 2022. Twelve healthy men took 600 mg of extract containing 180 mg of p-synephrine before 60 minutes of recovery monitoring after moderate exercise. Systolic pressure fell faster after exercise, and no unfavourable change in heart rate or other pressures was seen.
• Seville orange juice, 2001. Two 8-ounce glasses taken 8 hours apart produced no significant change in heart rate or blood pressure in adults with normal blood pressure.

All of these trials enrolled healthy volunteers. None studied people with high blood pressure, heart-rhythm disorders or coronary disease.

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Case Reports of Heart and Brain Events

Case reports describe single patients. They cannot prove that a supplement caused an event, and most involve products with several stimulants. They are listed here as case reports, with combinations noted where the authors noted them.

• Stroke, 2005. A 38-year-old man with no major risk factors developed memory loss and an unsteady gait after one week of an “ephedra-free” product containing synephrine and caffeine. Brain imaging showed infarcts in the thalamus and cerebellum; the doctors considered blood-vessel spasm the most likely cause. He recovered almost completely.
• Heart attack, 2004. A 55-year-old woman who smoked had taken a multi-ingredient weight-loss product containing 300 mg of bitter orange for a year. She had a lateral-wall heart attack, and an angiogram showed a lesion in the left main coronary artery. On a standard causality scale the authors rated bitter orange as “possibly” associated.
• Variant angina, 2006. Described by its authors as the first report of coronary-spasm angina associated with bitter orange in a supplement.
• Heart attack in a 24-year-old, 2009. A previously healthy man had an ST-elevation heart attack within hours of taking a synephrine-containing “ephedra-free” product. He had a large clot in the left anterior descending artery and no clotting disorder, drug use or coronary risk factors.
• Ventricular fibrillation, 2009. A 27-year-old woman in active military service had ventricular fibrillation, a cardiac-arrest rhythm, while using a synephrine-containing supplement.
• Heart attack with two products, 2014. A healthy 22-year-old man had taken a 1,3-dimethylamylamine (DMAA) pre-workout product and a bitter-orange product daily for 3 weeks before exercise. He had a heart attack with a clot in the left anterior descending artery. The authors note there is no safety data on taking the two together.
• Ischemic colitis, 2006. Loss of blood supply to the colon developed one week after a woman began a bitter-orange weight-loss supplement; she had no other predisposing factors and recovered after stopping it.
• Anorexia nervosa, 2005. In a 16-year-old with an eating disorder, the authors suggest the supplement's adrenergic action may have masked a slow heart rate and low blood pressure while adding to her weight loss.
• Tachycardia and heart-muscle injury, 2026. A 38-year-old woman without cardiovascular risk factors developed supraventricular tachycardia, chest pain and vomiting after one week of a weight-loss supplement containing bitter orange. Troponin rose from 17.9 to 1,395.7 ng/L, the coronary arteries were not blocked, and cardiac MRI showed nonspecific late gadolinium enhancement, an abnormal contrast pattern in the heart muscle. The authors call it a possible association.

Two reviews of the same reports

A 2023 review collected 30 case reports describing 35 patients who became ill after synephrine-containing supplements. The most common complaints were chest pain, palpitations, fainting and dizziness, and the most common diagnoses were ischaemic heart disease, arrhythmias and stroke. Five patients were left disabled or still on medication at last follow-up. The authors found an association but could not exclude caffeine or other confounders.

A 2020 review by authors who consider p-synephrine safe argues the opposite: in no case was p-synephrine measured in the product or the patient, most reports did not give the product's composition, and none showed a direct link. A 2025 clinical-toxicology review lists synephrine with ephedra and yohimbine among supplement stimulants linked to fast heart rate, high blood pressure, heart attack and cardiac arrest, and describes serious cardiovascular toxicity from supplements overall as “a fortunately rare phenomenon.” The NCCIH fact sheet summarises the position: serious events have been reported, but most products contained several ingredients, so the role of bitter orange is unclear.

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What Product Testing Has Found

The amount of synephrine on a label is often not what is in the product. Researchers bought 59 U.S. products labelled as containing bitter orange peel, extract or its amines (2020; the study is published as U.S. Government work). Of the 23 that stated a synephrine amount, only 5 (22%) were within 80 to 120% of the label. Several contained more amines than a normal bitter-orange extract would supply. Six contained the synthetic amine methylsynephrine (up to 240 mg per daily serving) and one contained isopropyloctopamine (up to 76 mg per daily serving). The authors note that neither is permitted in dietary supplements and that their effects in humans are unknown. A 2018 survey of 32 U.S. sports supplements found eight phenethylamines, including synephrine, octopamine, oxilofrine and deterenol. The Russian review lists undeclared bitter-orange extract, added synthetic synephrine and its isomers or analogues among the kinds of adulteration found in weight-loss and sports products.

This matters for the case reports above. Most of the products involved were never chemically tested, so a label reading “bitter orange” does not show what a patient actually took.

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Regulators and Sports Bodies

• United States. The NCCIH fact sheet (last updated November 2024) records the FDA's 2004 ban on ephedrine alkaloids in dietary supplements and says bitter orange products became more popular afterwards as ephedra alternatives. The 2020 product study states that methylsynephrine and isopropyloctopamine are not permitted in dietary supplements, and that hordenine, N-methyltyramine and octopamine are on the FDA's Dietary Supplement Ingredient Advisory List.
• European Union. According to the 2022 meta-analysis (full text), no EU-wide law limits synephrine in food supplements; under Directive 2002/46/EC each country is expected to set its own maximum, and products exceeding national limits have been reported through the Rapid Alert System for Food and Feed (RASFF).
• France. The same full text reports that the French food-safety agency (ANSES) concluded synephrine intake from supplements must stay below 20 mg a day, advised against combining it with caffeine or using it during exercise, and advised against its use by people taking certain medicines, pregnant or breastfeeding women, children and adolescents.
• Germany. The BfR team considered up to 6.7 mg of synephrine a day from supplements, equal to median intake from ordinary food, a safe intake, and reported evidence of cardiovascular effects at high doses, especially with caffeine and physical exertion.
• Russia. The 2021 Russian review gives the upper permissible intake there as 30 mg a day.
• Sport. A 2016 trial and the 2022 meta-analysis report that synephrine was added to the World Anti-Doping Agency (WADA) monitoring program, and the meta-analysis states it was not a prohibited substance as of 2022. This page could not open WADA's own current list to confirm its status today. The NCCIH fact sheet states that the National Collegiate Athletic Association (NCAA) lists “synephrine (bitter orange)” as a banned stimulant.

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Interaction Concerns Reported in the Literature

• Caffeine and other stimulants. In the 2005 crossover study, a multi-ingredient product with caffeine raised blood pressure when a larger dose of synephrine alone did not. The BfR assessment names caffeine and exertion as the conditions under which cardiovascular effects were seen. The 2012 review found that most overweight trial participants took caffeine with synephrine, so most of the weight-loss evidence concerns the combination. Several case reports involved products combining synephrine with caffeine or with DMAA. In the 2018 seated study, adding up to 104 mg of p-synephrine to caffeine did not raise blood pressure or heart rate further. Studies of a single ingredient therefore do not settle the question for multi-ingredient products.
• Monoamine oxidase inhibitors. The authors of the 2001 Seville orange juice study advised that people taking a monoamine oxidase inhibitor (MAOI), and people with severe high blood pressure, fast heart rhythms or narrow-angle glaucoma, avoid Seville orange juice, and that people using decongestant cold remedies refrain from it. The stimulants page explains why monoamine oxidase inhibitors and adrenaline-like stimulants are a dangerous combination.
• Drugs affected by grapefruit. Separate from synephrine, Seville orange juice contains furanocoumarins. In 10 volunteers it raised blood levels of the blood-pressure drug felodipine by 76%, against 93% for diluted grapefruit juice, probably by switching off the gut enzyme CYP3A4. In laboratory tests, slices of processed bitter orange inhibited CYP3A about as strongly as 100% grapefruit juice. The grapefruit interactions page lists the drugs involved.
• Pregnancy and breastfeeding. The NCCIH fact sheet states that bitter orange may not be safe in pregnancy or breastfeeding and that animal data suggest it might reduce milk production.

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What Is Not Known

• The weight-loss studies reviewed lasted at most 12 weeks, and the pooled data on weight rest on three small trials.
• The blood-pressure trials enrolled healthy volunteers; none tested people with high blood pressure, arrhythmia or coronary disease.
• Whether the pooled rise in blood pressure with longer use is real and lasting, or reflects a few small studies, is not settled. The single-dose and 60-day trials found no rise.
• The faster fat burning seen during exercise has not been shown to lead to fat loss with daily use.
• Most case reports involved untested multi-ingredient products, so the share of harm due to synephrine, caffeine, other stimulants or undeclared synthetic amines is unknown. How often such events happen in people who take bitter orange is also unknown.
• Much of the human safety research comes from one research network, part of which declares ties to ingredient suppliers. The independent meta-analysis reached a different conclusion on blood pressure.
• Traditional uses of zhi shi and zhi qiao for digestion have been studied mainly in rats and mice and in chemistry studies, not in controlled human trials of the single herb.

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Key Research Papers

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. PubMed PMID: 36235672
2. Bent S, Padula A, Neuhaus J. Safety and efficacy of citrus aurantium for weight loss. The American Journal of Cardiology. 2004;94(10):1359-61. PubMed PMID: 15541270
3. Haaz S, Fontaine KR, Cutter G, Limdi N, Perumean-Chaney S, Allison DB. Citrus aurantium and synephrine alkaloids in the treatment of overweight and obesity: an update. Obesity Reviews. 2006;7(1):79-88. PubMed PMID: 16436104
4. 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. International Journal of Medical Sciences. 2012;9(7):527-38. PubMed PMID: 22991491
5. Stohs SJ. Safety, Efficacy, and Mechanistic Studies Regarding Citrus aurantium (Bitter Orange) Extract and p-Synephrine. Phytotherapy Research. 2017;31(10):1463-1474. PubMed PMID: 28752649
6. Stohs SJ, Preuss HG, Shara M. A review of the receptor-binding properties of p-synephrine as related to its pharmacological effects. Oxidative Medicine and Cellular Longevity. 2011;2011:482973. PubMed PMID: 21904645
7. Stohs SJ, Shara M, Ray SD. p-Synephrine, ephedrine, p-octopamine and m-synephrine: Comparative mechanistic, physiological and pharmacological properties. Phytotherapy Research. 2020;34(8):1838-1846. PubMed PMID: 32101364
8. Rossato LG, Costa VM, Limberger RP, Bastos Mde L, Remião F. Synephrine: from trace concentrations to massive consumption in weight-loss. Food and Chemical Toxicology. 2011;49(1):8-16. PubMed PMID: 21075161
9. Perova IB, Eller KI, Musatov AV, Tymolskaya EV. [Synephrine in dietary supplements and specialized foodstuffs: biological activity, safety and methods of analysis]. Voprosy Pitaniia. 2021;90(6):101-113. PubMed PMID: 35032130
10. 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. International Journal of Medical Sciences. 2011;8(4):295-301. PubMed PMID: 21537493
11. Gutiérrez-Hellín J, Del Coso J. Effects of p-Synephrine and Caffeine Ingestion on Substrate Oxidation during Exercise. Medicine and Science in Sports and Exercise. 2018;50(9):1899-1906. PubMed PMID: 29727404
12. Ruiz-Moreno C, Del Coso J, Giráldez-Costas V, González-García J, Gutiérrez-Hellín J. Effects of p-Synephrine during Exercise: A Brief Narrative Review. Nutrients. 2021;13(1):233. PubMed PMID: 33467423
13. 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. Applied Physiology, Nutrition, and Metabolism. 2016;41(1):63-9. PubMed PMID: 26673246
14. Bui LT, Nguyen DT, Ambrose PJ. Blood pressure and heart rate effects following a single dose of bitter orange. The Annals of Pharmacotherapy. 2006;40(1):53-7. PubMed PMID: 16317106
15. Haller CA, Benowitz NL, Jacob P 3rd. Hemodynamic effects of ephedra-free weight-loss supplements in humans. The American Journal of Medicine. 2005;118(9):998-1003. PubMed PMID: 16164886
16. Kaats GR, Miller H, Preuss HG, Stohs SJ. A 60day double-blind, placebo-controlled safety study involving Citrus aurantium (bitter orange) extract. Food and Chemical Toxicology. 2013;55:358-62. PubMed PMID: 23354394
17. Shara M, Stohs SJ, Mukattash TL. Cardiovascular Safety of Oral p-Synephrine (Bitter Orange) in Healthy Subjects: A Randomized Placebo-Controlled Cross-over Clinical Trial. Phytotherapy Research. 2016;30(5):842-7. PubMed PMID: 26948284
18. Shara M, Stohs SJ, Smadi MM. Safety evaluation of p-synephrine following 15 days of oral administration to healthy subjects: A clinical study. Phytotherapy Research. 2018;32(1):125-131. PubMed PMID: 29130542
19. Ratamess NA, Bush JA, Stohs SJ, Ellis NL, Vought IT, O'Grady EA, Kuper JD, Hasan SB, Kang J, Faigenbaum AD. Acute cardiovascular effects of bitter orange extract (p-synephrine) consumed alone and in combination with caffeine in human subjects: A placebo-controlled, double-blind study. Phytotherapy Research. 2018;32(1):94-102. PubMed PMID: 29047215
20. Benjamim CJR, Júnior FWS, Porto AA, Rocha ÉMB, Santana MD, Garner DM, Valenti VE, Bueno Júnior CR. Bitter Orange (Citrus aurantium L.) Intake Before Submaximal Aerobic Exercise Is Safe for Cardiovascular and Autonomic Systems in Healthy Males: A Randomized Trial. Frontiers in Nutrition. 2022;9:890388. PubMed PMID: 35694173
21. Penzak SR, Jann MW, Cold JA, Hon YY, Desai HD, Gurley BJ. Seville (sour) orange juice: synephrine content and cardiovascular effects in normotensive adults. Journal of Clinical Pharmacology. 2001;41(10):1059-63. PubMed PMID: 11583473
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 Clinic Proceedings. 2005;80(4):541-5. PubMed PMID: 15819293
23. Nykamp DL, Fackih MN, Compton AL. Possible association of acute lateral-wall myocardial infarction and bitter orange supplement. The Annals of Pharmacotherapy. 2004;38(5):812-6. PubMed PMID: 15026566
24. Gange CA, Madias C, Felix-Getzik EM, Weintraub AR, Estes NA 3rd. Variant angina associated with bitter orange in a dietary supplement. Mayo Clinic Proceedings. 2006;81(4):545-8. PubMed PMID: 16610576
25. 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. Texas Heart Institute Journal. 2009;36(6):586-90. PubMed PMID: 20069086
26. Stephensen TA, Sarlay R Jr. Ventricular fibrillation associated with use of synephrine containing dietary supplement. Military Medicine. 2009;174(12):1313-9. PubMed PMID: 20055074
27. Smith TB, Staub BA, Natarajan GM, Lasorda DM, Poornima IG. Acute myocardial infarction associated with dietary supplements containing 1,3-dimethylamylamine and Citrus aurantium. Texas Heart Institute Journal. 2014;41(1):70-2. PubMed PMID: 24512406
28. Sultan S, Spector J, Mitchell RM. Ischemic colitis associated with use of a bitter orange-containing dietary weight-loss supplement. Mayo Clinic Proceedings. 2006;81(12):1630-1. PubMed PMID: 17165643
29. Gray S, Woolf AD. Citrus aurantium used for weight loss by an adolescent with anorexia nervosa. The Journal of Adolescent Health. 2005;37(5):414-5. PubMed PMID: 16227131
30. Plaitis A, Grigoraki E, Karakosta M, Gardikioti V, Kalesi AE, Kalivi A, Giannakodimos A, Barmpagiannis D, Theodosis-Georgilas A, Patsourakos N. Unexplained Supraventricular Tachycardia and Myocardial Injury After Bitter Orange Supplement Use in a Young Woman. JACC: Case Reports. 2026;31(26):108361. PubMed PMID: 42132724
31. de Jonge MLL, Kieviet LC, Sierts M, Egberink LB, van der Heyden MAG. Review of Case Reports on Adverse Events Related to Pre-workout Supplements Containing Synephrine. Cardiovascular Toxicology. 2023;23(1):1-9. PubMed PMID: 36639595
32. Stohs SJ, Ray SD. Review of Published Bitter Orange Extract and p-Synephrine Adverse Event Clinical Study Case Reports. Journal of Dietary Supplements. 2020;17(3):355-363. PubMed PMID: 30835576
33. Corcoran J. Cardiovascular toxicity associated with supplement use. Clinical Toxicology. 2025;63(11):801-809. PubMed PMID: 40960841
34. Koh AHW, Chess-Williams R, Lohning AE. Differential mechanisms of action of the trace amines octopamine, synephrine and tyramine on the porcine coronary and mesenteric artery. Scientific Reports. 2019;9(1):10925. PubMed PMID: 31358768
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Also read: U.S. National Center for Complementary and Integrative Health. Bitter Orange (fact sheet, last updated November 2024). nccih.nih.gov/health/bitter-orange

PubMed Topic Searches

1. PubMed: synephrine and weight loss, randomised trials
2. PubMed: bitter orange, blood pressure and heart rate
3. PubMed: synephrine case reports
4. PubMed: Aurantii Fructus Immaturus (zhi shi)

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Connections

• Heart, Liver and Metabolic Herbs — the category this page belongs to
• Stimulants in Weight-Loss and Energy Products — emergency-room data, proprietary blends and stimulant interactions
• Sida Cordifolia for Weight Loss — another “ephedra-free” botanical, compared with bitter orange
• Chen Pi (Aged Tangerine Peel) — the mandarin-peel herb often confused with bitter orange
• Dangerous Supplements — the section on supplement risk patterns
• Oranges: History and Origins — how the sour orange reached the Mediterranean and became marmalade
• Grapefruit and Drug Interactions — the furanocoumarin effect Seville orange shares
• Garcinia Cambogia — another popular weight-loss botanical
• Brown Fat: How You Burn Calories as Heat — the thermogenesis these products claim to boost

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