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Traditional Chinese medicine

Bitter orangeCitrus aurantium

Two Chinese fruit drugs, one weight-loss ingredient: a 21-trial review of the zhi shi formula (OR 3.54) and, for synephrine, a 6.4 mmHg rise in systolic pressure.

Botanical name
Citrus aurantium
Part used
immature fruit (zhi shi) and nearly ripe fruit (zhi ke); supplements use a fruit extract standardized to p-synephrine
Also called
pinyin Zhi shi (immature fruit), Zhi ke or Zhi qiao (more mature fruit) (枳实 / 枳壳); Seville orange, Sour orange, Aurantii fructus immaturus, Aurantii fructus
Used in
Traditional Chinese medicine
Taken for
Bloating, Indigestion, Constipation
Sold as
dried fruit slices, pills in formulas, decoction, capsules, standardized extract

The plant

Bitter orange is Citrus aurantium, the sour orange tree whose fruit is too acid to eat out of hand. Two different drugs come from it in Chinese medicine. Zhi shi is the young, dried fruit, picked before it ripens; the pharmacopoeia accepts Citrus aurantium or Citrus sinensis as its source. Zhi ke, also written zhi qiao, is the fruit picked later and dried. Chemical work on the two finds the same compounds at falling levels as the fruit matures, with synephrine falling fastest, so zhi shi carries more than zhi ke.

That is not the form most Western readers meet. Bitter orange in a supplement is usually a fruit extract sold for weight loss or energy and standardized to p-synephrine, the compound at the center of its safety questions. Reviews of the human studies list daily p-synephrine intakes of 10 to 53 mg. For digestion, zhi shi is a member of classic formulas for fullness and distension, especially Zhi Shi Xiao Pi Wan, where it is the first and largest herb. The juice of the bitter (Seville) orange is a separate matter again: it has a documented effect on drug metabolism, covered below.

How the traditions use it

Traditional Chinese medicine (about TCM)

Zhi shi and zhi ke are classed in the Chinese materia medica as bitter, pungent and sour, and slightly cold, entering the spleen and stomach channels. The tradition says they break up stuck qi and food accumulation, and the texts use them for what they describe as fullness and distension in the chest and abdomen, a feeling of food stuck in the stomach, and constipation with distension. Zhi shi is the stronger, more downward-moving drug in these texts and zhi ke is the milder one. Zhi Shi Xiao Pi Wan, a formula of ten herbs that includes zhi shi, magnolia bark, coptis, pinellia, ginger, barley sprout, ginseng, atractylodes, poria and roasted licorice, is attributed to the Jin-dynasty author Li Dongyuan and is the formula the tradition uses for bloating and fullness, which the texts call pi man. These are the tradition’s own classifications and not findings about the body.

What is in it

Bitter orange fruit contains the protoalkaloid p-synephrine as its main amine, along with stachydrine and choline. The case literature describes synephrine as a sympathomimetic, meaning stimulant, amine. An analysis of four citrus herbs found synephrine highest in the immature fruit and falling with later harvest, with a second compound, stachydrine, falling more slowly. Seville orange juice also contains furanocoumarins, the grapefruit-type compounds that inactivate an intestinal enzyme, CYP3A4. One study quantified bergapten at 31 micromoles per liter in Seville orange juice, a compound not found in grapefruit juice.

What the human trials show

Two bodies of evidence apply and should not be mixed. The first is the Chinese zhi shi formula. A trial of 51 people with functional dyspepsia compared a Zhi Shi Xiao Pi decoction (100 mL three times a day before meals) with the prokinetic drug cisapride for 4 weeks: effective rates were 81.49% and 87.50% (not significantly different), and half-emptying time of the stomach fell from 51.63 to 45.62 minutes on the formula, a smaller change than cisapride produced. A meta-analysis of 21 trials of the formula found a higher total effective rate than Western medicines (odds ratio 3.54, 95% CI 2.49 to 5.05) without more adverse events, but no significant difference in motilin, gastrin, somatostatin or gastric emptying measures, and the trials were from mainland China.

The second is synephrine in supplements, which has little to do with digestion. A meta-analysis of 18 placebo-controlled trials found blood pressure rose after prolonged use, by 6.37 mmHg systolic (95% CI 1.02 to 11.72) and 4.33 mmHg diastolic (0.48 to 8.18), with no evidence of weight loss. An earlier review of over 20 studies in about 360 people (many also taking 132 to 528 mg of caffeine a day) reported no significant rise in heart rate or blood pressure and modest weight loss over 6 to 12 weeks. The two reviews disagree and the studies were small.

What has not been tested: zhi shi alone for the gut, and synephrine supplements in people with heart disease.

StudyDoseWhat it found
Randomized trial, 51 adults with functional dyspepsia: Zhi Shi Xiao Pi decoction (27) vs cisapride (24) PMID 11819367Decoction 100 mL three times a day before meals, 4 weeksEffective rate 81.49% vs 87.50% (P above 0.05); gastric half-emptying time 51.63 to 45.62 min; less change than cisapride
Meta-analysis of 21 trials of Zhi Shi Xiao Pi decoction in functional dyspepsia PMID 38809916Formula; 2 weeks to 2 monthsTotal effective rate OR 3.54 (95% CI 2.49 to 5.05) vs Western medicine; no significant difference in motilin or gastric emptying; adverse events not increased
Meta-analysis of 18 placebo-controlled trials of p-synephrine PMID 36235672Synephrine, prolonged useSystolic +6.37 mmHg (95% CI 1.02 to 11.72), diastolic +4.33 mmHg (0.48 to 8.18); no evidence of weight loss
Review of over 20 studies, about 360 people, bitter orange extract or p-synephrine PMID 2299149110 to 53 mg p-synephrine a day, up to 12 weeks; two-thirds also took 132 to 528 mg caffeineNo significant change in heart rate or blood pressure reported; modest weight loss over 6 to 12 weeks
Crossover study, 10 volunteers: Seville orange juice vs dilute grapefruit juice vs common orange juice with felodipine PMID 11180034240 mL juice with felodipine 10 mgFelodipine exposure (AUC) up 76% with Seville orange juice and 93% with grapefruit juice
Randomized study, 12 volunteers, 28 days of a Citrus aurantium supplement PMID 15536458Supplement extract, 28 daysNo significant effect on CYP3A4, CYP1A2, CYP2D6 or CYP2E1; extract lacked 6',7'-dihydroxybergamottin

How much the studies and the texts used

The 51-person trial gave a Zhi Shi Xiao Pi decoction, 100 mL three times a day before meals, for 4 weeks. In the 21-trial meta-analysis most trials gave the formula two or three times a day for 2 weeks to 2 months; specified forms included 6 g of pills or 10 g of powder three times a day. Zhi shi is the largest herb in the formula, 15 g in the prescription that review tabulates. The supplement studies used 10 to 53 mg of p-synephrine a day for up to 12 weeks, often with caffeine. There is no tested dose of zhi shi or zhi ke alone for the gut.

Doses here describe what studies and pharmacopoeias used. They are not a recommendation for any person; a clinician or pharmacist who knows your medicines and conditions is the right person to ask.

Side effects and cautions

Bitter orange as a stimulant supplement has produced case reports of cardiovascular events. A 55-year-old woman with undetected coronary disease, who had taken a multicomponent weight-loss product with 300 mg of bitter orange for a year, was diagnosed with an acute heart attack; a previously healthy 24-year-old man had an ST-elevation heart attack within hours of a synephrine-containing product; and the authors of the first report rated the link only as possible. A meta-analysis found that synephrine tends to raise blood pressure and heart rate. In the Chinese formula trials the meta-analysis authors reported no significant increase in adverse events against Western drugs. We found no pregnancy or breastfeeding data for synephrine supplements. A laboratory screen of 90 Chinese medicines bought in New York found Western drugs in 5 samples, 2 undeclared or mislabeled; that is a finding about that sample and not about every product.

Interactions

Two mechanisms are documented. First, Seville orange juice, not the extract, raised felodipine exposure by 76% in 10 volunteers, through furanocoumarins that inactivate intestinal CYP3A4; in another study it lowered colchicine absorption by about 20%. Second, in a 28-day trial in 12 volunteers a bitter orange supplement had no significant effect on tests of four drug-metabolizing enzymes, and the extract lacked the grapefruit furanocoumarin 6',7'-dihydroxybergamottin. Separately, synephrine raised blood pressure and heart rate in trials, so an additive effect with blood-pressure drugs, stimulants and caffeine-containing products is a pharmacological concern.

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Often paired or compared

TCM / Western Orange peel Citrus reticulata (chen pi); Citrus sinensis (sweet orange); Citrus aurantium (bitter orange) TCM Magnolia bark Magnolia officinalis TCM Atractylodes Atractylodes macrocephala (bai zhu); A. lancea (cang zhu) TCM Barley sprout (mai ya) Hordeum vulgare TCM Aucklandia (costus root) Aucklandia costus (syn. Aucklandia lappa, Saussurea costus)

What people want to know

What is the difference between zhi shi and zhi ke?

Zhi shi is the immature fruit and zhi ke the more mature one. Chemical work finds synephrine higher in the immature fruit and falling as the fruit ripens. The texts call zhi shi the stronger of the two.

Is bitter orange for digestion the same as bitter orange for weight loss?

They share a plant, not a use. The digestive drug is the fruit in Chinese formulas such as Zhi Shi Xiao Pi Wan; the weight-loss product is an extract standardized to p-synephrine, which raised blood pressure in an 18-trial meta-analysis.

Does bitter orange interact with medicines the way grapefruit does?

The juice of Seville orange did, raising felodipine exposure by 76% in 10 volunteers. A supplement extract in a 12-volunteer 28-day study did not change the enzymes tested, but that study tested one product.

What have formula trials found?

A 21-trial meta-analysis of the Zhi Shi Xiao Pi formula found a higher effective rate than Western drugs for functional dyspepsia (OR 3.54), though motilin and gastric emptying did not differ and the trials were small and from mainland China.

Sources