Zhi Ke
StarCitrus aurantium L.
Traditionally used for
- Cough & breathing
- Digestion
Cautions & contraindications
- Pregnancy
- Heart conditions
☯ TCM Properties
Regulates Qi and Broadens the Middle Burner; Moves Qi and Resolves Stagnation; Transforms Phlegm and Dissipates Nodules; Lifts Sunken Qi
Traditional Chinese Uses
Zhi Ke (bitter orange fruit) is the ripe form of the same fruit that yields Zhi Shi. Compared to Zhi Shi, its action is gentler and more oriented toward moving Qi in the chest and upper digestive tract, making it better suited for mild to moderate Qi stagnation with bloating, belching, and chest discomfort. It is a common ingredient in formulas addressing post-meal fullness and tension in the epigastrium without the harsh force of Zhi Shi.
Western Herbalism Properties
Pharmacological Effects
- General: Stated to have chemistry and pharmacology similar to Zhi Shi (Fructus Aurantii Immaturus).
Source: Zhu YP. Chinese Materia Medica: Chemistry, Pharmacology and Applications. Harwood Academic, 1998, p. 375.
Used In Formulas (57)
Relationships
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Botanical Description
Citrus aurantium, the bitter or Seville orange, is an evergreen tree in the Rutaceae family, originally native to Southeast Asia and now widely cultivated in subtropical regions including the Mediterranean and southern China. It typically grows 4-10 meters tall with a rounded crown, smooth grey-green bark, and sharp axillary spines on younger branches. The alternate leaves are ovate to elliptic, 7-10 cm long, dark glossy green, with finely crenate margins and broadly winged petioles. Fragrant white flowers, 2-3 cm across with five petals, are borne singly or in small clusters; they are intensely aromatic. The fruit is a globose hesperidium, 7-8 cm across, with a thick, rough, orange-red rind and acidic, bitter pulp. In TCM, the nearly ripe or just-ripe fruit, dried and sliced (Zhi Ke), is used as a bitter, acrid, slightly cold herb that regulates qi, eases the chest, and disperses focal distention.
Active Constituents
p-Synephrine
Phenylethylamine protoalkaloidConcentration: about 1.25 mg/g (0.13%) of the dried mature fruit drug Zhi Ke, roughly one tenth of the 11.8 mg/g measured in the immature drug Zhi Shi
The sympathomimetic amine that makes bitter orange a cardiovascular question. It acts principally at β-3 adrenoceptors with low affinity for α-1, α-2, β-1 and β-2, which is why it is far weaker than the m-synephrine (phenylephrine) isomer it is often confused with. The near tenfold difference between the mature and immature fruit is the pharmacological reason Zhi Ke and Zhi Shi are dispensed as separate drugs and are not interchangeable.
Stachydrine
Pyrrolidine alkaloid (proline betaine)Concentration: about 3.04 mg/g in Zhi Ke, where it exceeds synephrine; about 5.16 mg/g in Zhi Shi
Zhi Ke is the one Citrus drug of the four studied in which stachydrine content exceeds synephrine content, the reverse of Zhi Shi, Qing Pi and Chen Pi. The authors propose stachydrine as a bioactive counterweight to synephrine's adrenergic effect, which would help explain the gentler clinical character attributed to the mature fruit; the counterbalancing role is a hypothesis, not a demonstrated clinical fact.
Naringin
Flavanone-7-O-neohesperidosideConcentration: a Chinese Pharmacopoeia assay marker for Aurantii Fructus, required at not less than 4.0%; measured at 80.4-106.8 mg/g in sampled material
The dominant flavonoid and the source of the drug's bitterness. Its aglycone naringenin is an in vitro inhibitor of CYP3A4, though the intestinal CYP3A4 interaction documented for bitter orange juice is attributed to furanocoumarins rather than to flavanones.
Neohesperidin
Flavanone glycosideConcentration: second Pharmacopoeia assay marker, required at not less than 3.0%; measured at 27.0-102.3 mg/g
Co-marker with naringin for identity and potency of Aurantii Fructus. The wide measured range between samples means flavonoid dose per gram of Zhi Ke varies severalfold across commercial batches.
Hesperidin
Flavanone glycosideConcentration: 5.10-38.14 mg/g in sampled Aurantii Fructus
A widely distributed citrus flavanone with vascular and anti-inflammatory activity in preclinical work; present in Zhi Ke but not used as an identity marker.
Narirutin, poncirin and neoeriocitrin
Flavanone glycosidesConcentration: 2.87-9.15, 1.80-9.40 and 1.27-6.48 mg/g respectively
Minor flavanone glycosides that contribute to the chromatographic fingerprint used to distinguish authentic Aurantii Fructus from substituted Citrus material.
6',7'-Dihydroxybergamottin and bergamottin
FuranocoumarinsThe mechanism-based inactivators of intestinal CYP3A4 that give Seville orange the same drug-interaction behaviour as grapefruit. They are the single most clinically important class in this drug. The human interaction studies used the fresh fruit juice; whether a water decoction of the dried mature fruit delivers a comparable furanocoumarin dose has not been established either way.
Octopamine
PhenylethylamineA trace biogenic amine of Citrus aurantium. It matters out of proportion to its amount because octopamine is a stimulant prohibited in competition on the World Anti-Doping Agency list, while synephrine itself sits only on the 2026 Monitoring Program.
N-Methyltyramine
PhenylethylamineA further sympathomimetic amine of the fruit, present with synephrine and octopamine and contributing to the drug's overall adrenergic character.
Auraptene
PrenyloxycoumarinReported to increase when Fructus Aurantii is stir-baked with bran, the processed form (chao Zhi Ke) usually dispensed for middle-burner distension. This is one of the concrete chemical differences between raw and bran-fried Zhi Ke.
Limonene
MonoterpeneThe principal volatile of the fruit peel, responsible for the aromatic character on which the qi-moving action is traditionally explained.
⚠ Drug Interactions
Felodipine and other CYP3A4-substrate dihydropyridine calcium channel blockers
In a randomised three-way crossover study in ten volunteers, 240 mL of Seville orange juice raised felodipine AUC by 76% compared with common orange juice, an effect comparable to dilute grapefruit juice. The mechanism is mechanism-based inactivation of intestinal CYP3A4 by the furanocoumarins 6',7'-dihydroxybergamottin and bergamottin, which Citrus aurantium contains and Citrus sinensis does not. The exposure studied was juice of the fruit; the dried mature fruit drug Zhi Ke has not been tested in this design.
Clinical note: Do not combine bitter orange juice or bitter orange extracts with felodipine, nifedipine or nisoldipine. For dispensed Zhi Ke in a decoction, separate dosing from a CYP3A4-substrate calcium channel blocker and monitor blood pressure, on the basis that the furanocoumarin content of the decoction is unquantified rather than known to be zero.
Dextromethorphan and other gut CYP3A4 / P-glycoprotein substrates
Di Marco and colleagues compared grapefruit juice and Seville orange juice on dextromethorphan pharmacokinetics specifically to separate the contributions of gut CYP3A and P-glycoprotein. Seville orange juice is used in this literature precisely because it carries furanocoumarins without the flavonoid profile of grapefruit, which makes Citrus aurantium a recognised probe of intestinal CYP3A4 rather than an incidental interactor.
Clinical note: Advise patients on chronic dextromethorphan or other gut-CYP3A-limited drugs to avoid bitter orange juice and concentrated bitter orange products; ask specifically about weight-loss and sports supplements, which is how most people meet this species.
Ciclosporin, tacrolimus, simvastatin, atorvastatin and other narrow-therapeutic-index CYP3A4 substrates
Extrapolated from the felodipine and dextromethorphan data by shared mechanism rather than demonstrated directly for these drugs. Because inactivation of intestinal CYP3A4 by furanocoumarins is irreversible and enzyme recovery takes days, separating doses within a day does not reliably abolish the effect.
Clinical note: Treat bitter orange as a grapefruit-equivalent for any drug whose label carries a grapefruit warning. Where a transplant or high-dose statin patient wants Zhi Ke, substitute another qi-regulating herb rather than trying to time the doses apart.
Monoamine oxidase inhibitors (phenelzine, tranylcypromine, selegiline, linezolid)
Synephrine, octopamine and N-methyltyramine are monoamine oxidase substrates, and unopposed MAO inhibition allows sympathomimetic amines to accumulate. The classical warning against Seville orange juice with MAO inhibitors was framed on the mistaken assumption that the fruit contains m-synephrine; the isomer actually present is the weaker p-synephrine, so the risk is smaller than once stated but has not been shown to be absent, and no deliberate interaction study exists.
Clinical note: Avoid bitter orange in any form in patients taking an MAO inhibitor, including linezolid courses. The theoretical downgrade from m- to p-synephrine does not justify running the test on a patient.
Caffeine, ephedrine-type sympathomimetics and other stimulants
The evidence is genuinely divided. Around 30 human studies reviewed by Stohs found no significant change in heart rate, blood pressure or ECG from bitter orange extract or p-synephrine alone, and a randomised placebo-controlled crossover trial of 49 mg p-synephrine found no cardiovascular signal. Against that, a 2022 systematic review and meta-analysis of 18 trials found systolic pressure rose by 6.37 mmHg and diastolic by 4.33 mmHg after prolonged use, and concluded there is no evidence synephrine aids weight loss. Reported STEMI and stroke cases almost always involved products combining synephrine with caffeine and other stimulants, so causal attribution to bitter orange alone is not possible.
Clinical note: Do not stack Zhi Ke or bitter orange extracts with high-dose caffeine, pre-workout stimulants or decongestants. Avoid in uncontrolled hypertension, tachyarrhythmia, coronary disease and narrow-angle glaucoma, and take a blood pressure reading before and during any prolonged course.
Antihypertensive drugs
The 2022 meta-analysis of 18 clinical trials found statistically significant increases in both systolic and diastolic pressure after prolonged bitter orange use. This opposes the intended effect of antihypertensive therapy and is separate from the CYP3A4 mechanism, which pushes felodipine exposure the other way; a patient on a dihydropyridine can therefore meet both effects at once.
Clinical note: Monitor home blood pressure if a hypertensive patient uses Zhi Ke for more than a short course, and be alert that the same patient on felodipine may show erratic readings from two opposing mechanisms.
m-Synephrine (phenylephrine) and methylsynephrine as adulterants of bitter orange weight-loss products
Bitter orange took over the weight-loss market after ephedra was banned in the United States, and adulteration followed. m-Synephrine, a far stronger agonist at several α-receptor subtypes, has been found in supplements although it does not occur naturally in the fruit in meaningful amounts; methylsynephrine likewise is not a natural bitter orange constituent. p-Synephrine content in many weight-loss products is close to tenfold the amount present in the fruit itself.
Clinical note: A dispensed gram of Zhi Ke and a bitter orange slimming capsule are not the same exposure and should not be counselled as if they were. When a patient reports palpitations or a pressor event on bitter orange, ask what product they actually took and treat adulteration as a live possibility.
Anti-doping controls in competitive sport (World Anti-Doping Agency Prohibited List)
Synephrine is on the 2026 WADA Monitoring Program and is not prohibited. Octopamine, however, is a prohibited in-competition stimulant under S6, and Citrus aurantium contains it. The risk to an athlete therefore comes from a minor constituent rather than from the one everybody names.
Clinical note: Do not prescribe Zhi Ke or any bitter orange product to a tested athlete during competition season; direct them to a batch-tested alternative and document the discussion.
Dosage
| Form | Amount | Frequency | Duration | Population | Notes |
|---|---|---|---|---|---|
| decoction | 3–10 g | Daily | — | — | 中国药典 2020 【用法与用量】3～10g。 【注意】孕妇慎用。 【性味与归经】苦、辛、酸，微寒。归脾、胃经。 — Chinese Pharmacopoeia 2020, quoted verbatim; route and cautions preserved. Replaces a cleared category-filler value. |
Dui Yao — Herb Pairs
The classical two-herb combinations this herb appears in, each with an action neither herb has alone.
One raises and diffuses lung qi, the other descends and moves qi; together they restore the ascent and descent of qi in the chest, relieving fullness and oppression.
Named pairing — Lü Jingshan, Shi Jinmo Dui Yao
Evidence Tier
Strong evidence · 8 studiesRecorded studies by study design, strongest design at the top. This is a study-design tier only, not a GRADE rating: it does not weigh risk of bias, consistency or precision.
Systematic review / meta-analysis
1
1 verified · 0 unverified
Randomized controlled trial
2
2 verified · 0 unverified
Other clinical trial
1
1 verified · 0 unverified
Observational / case report
0
In vitro / animal
2
2 verified · 0 unverified
Other / unclassified
2
1 verified · 1 unverified
Verified: design read from PubMed for a DOI that resolves to the cited paper Unverified: taken from the study's recorded description
Clinical Studies
Seville orange juice-felodipine interaction: Comparison with dilute grapefruit juice and involvement of furocoumarins
Ten volunteers took felodipine with 240 mL of Seville orange juice, dilute grapefruit juice or common orange juice in a randomised three-way crossover. Felodipine AUC rose 76% after Seville orange juice versus common orange juice, matching dilute grapefruit juice, and the authors attribute the shared mechanism to inactivation of intestinal CYP3A4 by furanocoumarins present in Citrus aurantium but absent from Citrus sinensis.
The effect of grapefruit juice and seville orange juice on the pharmacokinetics of dextromethorphan: The role of gut CYP3A and P-glycoprotein
Seville orange juice was used alongside grapefruit juice in volunteers to dissect the separate contributions of intestinal CYP3A and P-glycoprotein to dextromethorphan disposition. The design rests on Citrus aurantium carrying furanocoumarins without grapefruit's flavonoid profile, which is why bitter orange functions as a selective probe of gut CYP3A4.
Cardiovascular Safety of Oral p-Synephrine (Bitter Orange) in Healthy Subjects: A Randomized Placebo-Controlled Cross-over Clinical Trial
A randomised placebo-controlled crossover trial of 49 mg oral p-synephrine in healthy adults found no significant change in electrocardiograms, heart rate, systolic blood pressure, blood chemistries or blood cell counts at any timepoint. This is the strongest single piece of reassurance for short-term, single-ingredient exposure, and it does not address prolonged use or stimulant-stacked products.
The Safety and Efficacy of Citrus aurantium (Bitter Orange) Extracts and p-Synephrine: A Systematic Review and Meta-Analysis
Pooling 18 clinical trials, systolic blood pressure rose by 6.37 mmHg and diastolic by 4.33 mmHg after prolonged use, and the authors concluded there is no evidence that synephrine facilitates weight loss. This is the counterweight to the manufacturer-aligned safety reviews and is the more conservative basis for advising patients on long courses.
A Review of the Human Clinical Studies Involving Citrus aurantium (Bitter Orange) Extract and its Primary Protoalkaloid p-Synephrine
Review of human studies concluding that bitter orange extract, alone or combined with other herbal ingredients, did not significantly raise heart rate or blood pressure or alter electrocardiographic data, serum chemistry, blood counts or urinalysis. The review also sets out the receptor-binding case that p-synephrine is not equivalent to m-synephrine. Readers should note the authors' long-standing association with the bitter orange supplement industry.
Stachydrine, a Bioactive Equilibrist for Synephrine, Identified from Four Citrus Chinese Herbs
Quantified synephrine and stachydrine across four Citrus drugs. Zhi Shi (immature fruit) averaged 11.82 mg/g synephrine and 5.16 mg/g stachydrine; Zhi Ke (mature fruit) averaged only 1.25 mg/g synephrine against 3.04 mg/g stachydrine; Qing Pi 5.76 and 1.98 mg/g; Chen Pi 2.50 and 1.68 mg/g. Zhi Ke is the only one of the four in which stachydrine exceeds synephrine, which is the clearest quantitative reason not to treat the mature and immature fruit as one drug.
Comparison of the chemical constituents of raw Fructus Aurantii and Fructus Aurantii stir-baked with bran, and the biological effects of auraptene
Directly compares raw Fructus Aurantii with the bran stir-baked form (chao Zhi Ke) that is usually dispensed, and identifies auraptene as a constituent whose behaviour differs between them. Confirms that raw and bran-fried Zhi Ke are chemically distinct preparations rather than interchangeable.
STEMI in a 24-year-old man after use of a synephrine-containing dietary supplement: a case report and review of the literature
Case report of ST-elevation myocardial infarction in a young man following use of a synephrine-containing dietary supplement, with a review of comparable cardiovascular events. As in most such reports the product was multi-ingredient, so this establishes an association with stimulant supplements containing bitter orange rather than causation by p-synephrine alone.
⚠ Safety & Contraindications
- Pregnancy
- Heart conditions
Contraindications
Its use is cautious in pregnant women or patients with weakness of the spleen and stomach, or qi and blood insufficiency.
Source: Xi S, Gong Y. Essentials of Chinese Materia Medica and Medical Formulas. Academic Press/Elsevier, 2017, pp. 171–182.
Historical Texts
Shen Nong Ben Cao Jing
Han dynastyKai Bao Ben Cao
Song dynasty, 973 CEReferences
- Gao T, Jiang M, Deng B, Zhang Z, Fu Q, Fu C. Aurantii Fructus: a systematic review of ethnopharmacology, phytochemistry and pharmacology . Phytochemistry Reviews (2020) [DOI]
- Stohs SJ. Safety, Efficacy, and Mechanistic Studies Regarding Citrus aurantium (Bitter Orange) Extract and p-Synephrine . Phytotherapy Research (2017) [DOI]
This information is for educational purposes only and is not intended to replace professional medical advice. Always consult a qualified healthcare provider before using any herbal remedy, especially if you are pregnant, nursing, or taking medications.
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