Bitter orange

What it is

Bitter orange is a citrus tree whose fruit is too sour to eat raw: "Its fruit is too sour to eat raw, but the fruit, peel, and essential oils are used in cooking, as flavorings in beer and spirits, and to add aromas to perfumes." Supplements use an extract of the unripe fruit standardised for p-synephrine, a compound structurally related to ephedrine and adrenaline. Since ephedra was removed from US supplements, p-synephrine has been widely used in weight-loss and pre-workout products, usually combined with caffeine.

What the research says

It is sold to raise metabolic rate, help weight loss and boost exercise performance. An independent 2022 meta-analysis of 18 placebo-controlled studies found no weight loss and a significant rise in blood pressure with prolonged use. Reviews written by authors who consult for a bitter orange supplier reach the opposite conclusion on both effectiveness and cardiovascular safety. Thirty published case reports describe 35 people with cardiovascular events after using synephrine-containing pre-workout supplements, though most of those products also contained caffeine.

Evidence grade: Disputed.

What goes wrong

In the same meta-analysis, prolonged synephrine use raised systolic blood pressure by 6.37 mmHg and diastolic by 4.33 mmHg compared with placebo. (Source 1)

• Meta-analysis, Low certainty.
• Size: 18 articles included in the meta-analysis.
• Who: participants in placebo-controlled trials, mostly healthy adults.
• How long: "prolonged use"
• Result: "6.37 mmHg, 95% CI: 1.02–11.72, p = 0.02 and 4.33 mmHg, 95% CI: 0.48–8.18, p = 0.03, respectively"
• Funding: independent (Hungarian state funding; no commercial conflict declared)

Both systolic and diastolic blood pressure (DBP) increased significantly after prolonged use (6.37 mmHg, 95% CI: 1.02–11.72, p = 0.02 and 4.33 mmHg, 95% CI: 0.48–8.18, p = 0.03, respectively).

A review of published case reports found 30 reports describing 35 patients with adverse events, mostly cardiovascular, after using synephrine-containing pre-workout supplements; five were left disabled or still on medication at last follow-up. (Source 2)

• Case series, Low certainty.
• Size: 30 case reports describing a total of 35 patients.
• Who: users of synephrine-containing pre-workout supplements, "ages ranging from 16 to 57 years with a mean age of 32 ± 12 years"
• How long: single or repeated exposures; synephrine doses across a "wide range (12 to 100 mg)"
• Result: "The patients most often presented with chest pain, palpitations, syncope and dizziness. Commonly raised diagnoses were ischaemic heart disease, cardiac arrhythmias and cerebrovascular disease. Five patients were left disabled or remained on medication at last follow-up."
• Funding: not stated.

We obtained 30 case reports describing a total of 35 patients who suffered from medical complaints following use of synephrine-containing supplements.

The authors of that case-report review state they cannot exclude caffeine as a confounder, since most affected patients used products combining synephrine with caffeine. (Source 2)

• Case series, Low certainty.
• Size: 30 case reports describing a total of 35 patients; the review's own caution is that caffeine taken in the same products cannot be excluded as a contributor.
• Who: pre-workout supplement users with cardiovascular diagnoses.
• How long: not applicable.
• Result: association reported without a denominator; confounding acknowledged.
• Funding: not stated.

However, we cannot exclude a role of possible confounding factors such as caffeine.

A published case report attributed an acute lateral-wall myocardial infarction in a 55-year-old woman to a multi-ingredient weight-loss supplement containing 300 mg of bitter orange, rating the association as possible. (Source 3)

• Case report, Very low certainty.
• Size: 1 patient.
• Who: a 55-year-old woman taking a multicomponent weight-loss supplement for a year.
• How long: "for the past year"
• Result: acute lateral-wall myocardial infarction with a left main coronary artery lesion; Naranjo scale rating of "possibly associated"
• Funding: not stated.

A 55-year-old white woman presented to the emergency department with symptoms of dull aching shoulder and chest pain

The 2022 meta-analysis lists the cardiac events most often reported with synephrine, including cardiac arrest and sudden death, and concludes it may not be a safe substitute for ephedrine in people with predisposing conditions. (Source 4)

• Systematic review, Low certainty.
• Size: not applicable to this statement (narrative safety section of the review)
• Who: reported cases in the literature reviewed.
• How long: not applicable.
• Result: no rates given; a list of reported event types.
• Funding: independent (Hungarian state funding; no commercial conflict declared)

Cardiac adverse events, including hypertension, tachyarrhythmia, variant angina, cardiac arrest, QT prolongation, ventricular fibrillation, myocardial infarction, and sudden death, have been the most common adverse effects associated with synephrine intake.

Health Canada's January 2010 notice adopted a 30 mg per day cap on synephrine plus octopamine in natural health products and barred added caffeine in synephrine products without human clinical evidence. (Source 5)

• Official position, Certainty not rated.
• Size: not applicable.
• Who: Canadian natural health product market.
• How long: not applicable.
• Result: "A limit of 30 mg/day has been adopted as the maximum allowable dose for total synephrine and octopamine"
• Funding: government regulator.

Based on the potential for cardiovascular toxicity, the NHPD has adopted the following guidelines for the use of synephrine in Natural Health Products.

NCCIH's position, updated November 2024, is that serious cardiovascular events have been reported with bitter orange products but that most of those products contained multiple ingredients. (Source 6)

• Official position, Certainty not rated.
• Size: not applicable.
• Who: US consumers.
• How long: not applicable.
• Result: no rates given.
• Funding: US government agency.

Cases of serious medical events, including abnormal heart rhythms, heart attacks, and strokes, have been reported in people who had taken bitter orange products, but most of the products contained multiple ingredients rather than bitter orange alone.

What the evidence supports

A review whose authors all consult for a bitter orange supplier concluded that bitter orange extract and p-synephrine increase metabolism and energy expenditure without significant adverse cardiovascular effects; the review counts its own evidence base inconsistently, as 23 studies in about 450 subjects in its Discussion and over 20 studies in about 360 subjects in its Abstract. (Source 7)

• Expert review, not systematic, Very low certainty.
• Size: the paper's Discussion states "A total of 23 published and unpublished studies involving a total of approximately 450 total human subjects were reviewed.", while its Abstract instead describes over 20 studies in approximately 360 subjects.
• Who: human subjects in studies of bitter orange extract and p-synephrine, alone and with caffeine.
• How long: mostly short-term; the review calls for long-term studies.
• Result: no pooled numbers; a qualitative conclusion, plus "Five published studies and two unpublished studies reported no cardiovascular effects when using p-synephrine (bitter orange) only containing products."
• Funding: industry-funded: "All authors have served as consultants for Nutratech, Inc., a company that markets bitter orange extracts. Nutratech Inc. provided some of the unpublished research reports."

Limit of this finding: This paper counts its own evidence base two different ways. Its Discussion says 23 published and unpublished studies in a total of about 450 human subjects; its Abstract says over 20 studies in approximately 360 subjects. The figures recorded here are the Discussion's, not the Abstract's, and the paper does not explain the gap, so how much evidence it actually reviewed is uncertain. The count also includes unpublished reports supplied by a company that markets bitter orange extracts and for which all of the authors consulted, so it is not a count of independently published trials.

The results indicate that bitter orange extract and p-synephrine increase metabolism and energy expenditure

What the evidence does not support

An independent 2022 meta-analysis of 18 placebo-controlled human trials found no weight loss with synephrine and no effect on body composition. (Source 1)

• Meta-analysis, Low certainty.
• Size: Altogether, 18 articles were included in the meta-analysis.
• Who: participants in placebo-controlled human clinical trials of synephrine.
• How long: acute studies plus trials of "prolonged" treatment.
• Result: weight MD 0.60 kg (95% CI −5.62 to 6.83, p = 0.85); body fat −1.87% (p = 0.07); fat mass −0.32 kg (p = 0.85); fat-free mass −0.47 kg (p = 0.84)
• Funding: independent: Hungarian Ministry of Innovation and Technology, TKP2021-EGA-32; authors declare no commercial conflict.

Limit of this finding: The paper reports its fat-free mass result in two incompatible ways. Its Discussion prints it as −0.47 kg (n = 78, p = 0.84), a small loss, while its Results print the same outcome as MD 0.47 kg, 95% CI: −4.19–5.13, p = 0.84, a small gain. The size matches but the sign is reversed, and the article never explains the difference. Both versions give p = 0.84, which means no difference was detected either way: the fair reading is that synephrine had no measurable effect on fat-free mass. The −0.47 kg figure is not settled and should not be read as evidence that synephrine causes loss of lean tissue.

The weight loss in the synephrine group was non-significant after prolonged treatment, and it did not influence body composition parameters.

The same meta-analysis concluded there is no evidence that synephrine facilitates weight loss and that it tends to raise blood pressure and heart rate. (Source 1)

• Meta-analysis, Low certainty.
• Size: 18 articles.
• Who: participants in placebo-controlled synephrine trials.
• How long: acute and prolonged use.
• Result: "Synephrine was ineffective in influencing body fat (−1.87%, n = 94, p = 0.07), fat mass (−0.32 kg, n = 69, p = 0.85), and fat-free mass (−0.47 kg, n = 78, p = 0.84)."
• Funding: independent (Hungarian state funding; no commercial conflict declared)

Limit of this finding: The paper reports its fat-free mass result in two incompatible ways. Its Discussion prints it as −0.47 kg (n = 78, p = 0.84), a small loss, while its Results print the same outcome as MD 0.47 kg, 95% CI: −4.19–5.13, p = 0.84, a small gain. The size matches but the sign is reversed, and the article never explains the difference. Both versions give p = 0.84, which means no difference was detected either way: the fair reading is that synephrine had no measurable effect on fat-free mass. The −0.47 kg figure is not settled and should not be read as evidence that synephrine causes loss of lean tissue.

synephrine tends to raise blood pressure and heart rate, and there is no evidence that synephrine can facilitate weight loss

NCCIH also states that most studies of bitter orange for athletic performance did not show a benefit and that body-weight effects are unclear. (Source 8)

• Official position, Certainty not rated.
• Size: not applicable.
• Who: US consumers; studies summarised without numbers.
• How long: not applicable.
• Result: no numbers given.
• Funding: US government agency.

The effects of bitter orange on body weight are unclear. Studies on this topic involved small numbers of people, usually evaluated combination products rather than bitter orange alone, and had conflicting results.

Where the evidence is mixed

A 2024 laboratory study in human stem-cell-derived heart cells concluded that the proarrhythmia risk of p-synephrine at conventional doses is low, while noting the conflicting clinical reports. (Source 9)

• Lab study in cells, Very low certainty.
• Size: human induced pluripotent stem cell-derived cardiomyocytes (no human participants)
• Who: cultured human cardiomyocytes, not people.
• How long: not applicable.
• Result: qualitative conclusion of low proarrhythmic risk at conventional doses; no clinical endpoints.
• Funding: not stated.

the proarrhythmia risk of SYN at conventional doses is low.

Where the research disagrees

Whether p-synephrine has clinically meaningful cardiovascular effects

• Koncz and colleagues, Nutrients 2022 (independent, Hungarian state funded), systematic review and meta-analysis of 18 placebo-controlled human trials: "the use of synephrine does not lack cardiovascular side effects; therefore, it may not be a safe alternative to ephedrine for those with predisposing comorbidities." (Source 10)
• Stohs and colleagues, International Journal of Medical Sciences 2012 (all authors consultants to a bitter orange supplier), narrative review of human studies, counted as 23 studies in the paper's Discussion and over 20 in its Abstract: "p-synephrine alone or in combination with caffeine does not appear to produce significant adverse cardiovascular effects" (Source 11)
• Frontiers in Cardiovascular Medicine 2024 laboratory study, in-vitro study in human stem-cell-derived cardiomyocytes: "the proarrhythmia risk of SYN at conventional doses is low." (Source 9)

Whether the reported cardiovascular events can be blamed on synephrine rather than on caffeine and other ingredients

• Cardiovascular Toxicology 2023 review of case reports, review of 30 case reports covering 35 patients: "Thus, the use of pre-workout supplements containing synephrine may lead to serious adverse health events, and therefore, caution is needed." (Source 2)
• NCCIH, November 2024, agency position summarising case reports: "Cases of serious medical events, including abnormal heart rhythms, heart attacks, and strokes, have been reported in people who had taken bitter orange products, but most of the products contained multiple ingredients rather than bitter orange alone." (Source 6)

How much

• Reference intake: No dietary reference intake exists. Bitter orange is a culinary and flavouring plant, not an essential nutrient: NCCIH describes the fruit, peel and essential oils as "used in cooking, as flavorings in beer and spirits, and to add aromas to perfumes." No body has set an RDA or adequate intake for p-synephrine. (Source 12)
• Upper limit: No tolerable upper intake level has been set by a nutrition body. The nearest regulatory ceiling we could reach is Health Canada's archived January 2010 notice: "A limit of 30 mg/day has been adopted as the maximum allowable dose for total synephrine and octopamine". Trade reports indicate Health Canada later relaxed this figure, but we could not reach a primary Health Canada document confirming the revised number. (Source 13)
• Studied: The 2022 meta-analysis records that "First, the studied products were different and contained varying doses (6–214 mg) of synephrine with different isometric forms". (Source 14)
• Studied: The case-report review found the supplements involved spanned a "wide range (12 to 100 mg)" of synephrine, and one case report involved a product containing 300 mg of bitter orange extract. (Source 15)

A common belief, and what the research shows

The belief: Bitter orange is the safe, natural replacement for ephedra that burns fat without stimulant risks.

What the research shows: The independent meta-analysis of 18 placebo-controlled trials found that "synephrine tends to raise blood pressure and heart rate, and there is no evidence that synephrine can facilitate weight loss", and that "the use of synephrine does not lack cardiovascular side effects; therefore, it may not be a safe alternative to ephedrine for those with predisposing comorbidities." The reviews that report it as both effective and cardiovascularly neutral were written by authors who disclose that "All authors have served as consultants for Nutratech, Inc., a company that markets bitter orange extracts."

Questions and answers

What is it?

Bitter orange is a citrus tree, Citrus aurantium, grown in Southeast Asia and the Mediterranean. Its fruit is too sour to eat raw but the peel and oils flavour marmalade, liqueurs and perfumes. Supplements use an extract of the unripe fruit standardised for p-synephrine, a stimulant-like compound. (Source 12)

What does it do in the body?

p-Synephrine acts on adrenaline-type receptors, which is the basis for claims that it raises metabolic rate and helps fat loss. In pooled human trials that mechanism shows up mainly as a rise in blood pressure rather than as weight loss. Industry-linked reviews report increased energy expenditure; independent pooling does not find a weight effect. (Source 2)

Is it good or bad for you?

The independent evidence points to more risk than benefit. Pooling 18 placebo-controlled trials found no weight loss and a significant rise in blood pressure with prolonged use, and 30 published case reports describe cardiovascular events in 35 people using synephrine pre-workout products. Whether synephrine itself or the caffeine alongside it is responsible is genuinely contested. (Source 1)

How do you get more of it?

p-Synephrine occurs naturally in bitter orange fruit and peel, and supplements concentrate it. The products studied in trials contained between 6 and 214 mg of synephrine, in different isomeric forms, which is one reason the trials are hard to compare. That is what was given in studies, not a recommendation. (Source 14)

If it is harmful, what reduces it?

The literature we reached describes no treatment to clear synephrine; it is a short-acting stimulant and exposure ends when the product is stopped. The regulatory response has instead been to limit exposure: Health Canada capped total synephrine and octopamine at 30 mg a day and disallowed added caffeine in such products without human clinical evidence, citing cardiovascular toxicity. (Source 16)

Why might someone be low in it or missing it?

This does not apply. p-Synephrine is a plant compound, not a nutrient the body requires or stores, so there is no low or missing state to explain. Someone has none unless they eat bitter orange products or take a supplement containing the extract. (Source 12)

Which whole foods contain it or feed it?

The whole-food sources are bitter orange fruit and its peel, used in marmalade, in bitter liqueurs and as a flavouring, and the essential oils from the peel. Culinary amounts are far smaller than the concentrated extracts used in supplements, which contained 6 to 214 mg of synephrine in the trials reviewed. (Source 12)

What happens if you do not have it?

Nothing described in the literature happens if you never take it. There is no requirement, no reference intake and no deficiency syndrome for p-synephrine; the research question is whether adding it does anything, and the independent meta-analysis found no weight-loss benefit to forgo. (Source 1)

We searched: We searched the 2022 Nutrients systematic review and meta-analysis, the NCCIH bitter orange page and Health Canada's synephrine notice for any requirement, reference intake or deficiency state; none is described.

How can you test for it?

There is no validated clinical test for p-synephrine status in a person. Analytical laboratories can measure synephrine content in a product, and the trial literature shows why that matters: products differed in both dose and isomeric form, so the same label can mean different chemistry. Blood pressure and heart rate are what studies measured as the effect. (Source 14)

References

1. Nutrients. The Safety and Efficacy of Citrus aurantium (Bitter Orange) Extracts and p-Synephrine: A Systematic Review and Meta-Analysis. 2022. PMID 36235672, DOI 10.3390/nu14194019. Read the source
2. Cardiovascular Toxicology. Review of Case Reports on Adverse Events Related to Pre-workout Supplements Containing Synephrine. 2023. DOI 10.1007/s12012-022-09777-z. Read the source
3. Annals of Pharmacotherapy. Possible Association of Acute Lateral-Wall Myocardial Infarction and Bitter Orange Supplement. 2004. PMID 15026566, DOI 10.1345/aph.1D473. Read the source
4. Nutrients. The Safety and Efficacy of Citrus aurantium (Bitter Orange) Extracts and p-Synephrine: A Systematic Review and Meta-Analysis. 2022. PMID 36235672, DOI 10.3390/nu14194019. Read the source
5. Health Canada, Natural Health Products Directorate. ARCHIVED - Notice - Guidelines for the Use of Synephrine in Natural Health Products. 2010. Read the source
6. National Center for Complementary and Integrative Health (NCCIH), NIH. Bitter Orange: Usefulness and Safety. 2024. Read the source
7. International Journal of Medical Sciences. A Review of the Human Clinical Studies Involving Citrus aurantium (Bitter Orange) Extract and its Primary Protoalkaloid p-Synephrine. 2012. PMID 22991491, DOI 10.7150/ijms.4446. Read the source
8. National Center for Complementary and Integrative Health (NCCIH), NIH. Bitter Orange: Usefulness and Safety. 2024. Read the source
9. Frontiers in Cardiovascular Medicine. Non-invasive assessment of proarrhythmic risks associated with isoprenaline and the dietary supplement ingredient synephrine using human induced pluripotent stem cell-derived cardiomyocytes. 2024. DOI 10.3389/fcvm.2024.1407138. Read the source
10. Nutrients. The Safety and Efficacy of Citrus aurantium (Bitter Orange) Extracts and p-Synephrine: A Systematic Review and Meta-Analysis. 2022. PMID 36235672, DOI 10.3390/nu14194019. Read the source
11. International Journal of Medical Sciences. A Review of the Human Clinical Studies Involving Citrus aurantium (Bitter Orange) Extract and its Primary Protoalkaloid p-Synephrine. 2012. PMID 22991491, DOI 10.7150/ijms.4446. Read the source
12. National Center for Complementary and Integrative Health (NCCIH), NIH. Bitter Orange: Usefulness and Safety. 2024. Read the source
13. Health Canada, Natural Health Products Directorate. ARCHIVED - Notice - Guidelines for the Use of Synephrine in Natural Health Products. 2010. Read the source
14. Nutrients. The Safety and Efficacy of Citrus aurantium (Bitter Orange) Extracts and p-Synephrine: A Systematic Review and Meta-Analysis. 2022. PMID 36235672, DOI 10.3390/nu14194019. Read the source
15. Cardiovascular Toxicology. Review of Case Reports on Adverse Events Related to Pre-workout Supplements Containing Synephrine. 2023. DOI 10.1007/s12012-022-09777-z. Read the source
16. Health Canada, Natural Health Products Directorate. ARCHIVED - Notice - Guidelines for the Use of Synephrine in Natural Health Products. 2010. Read the source