Zhi Shi
Also known as: Zhi Shi, Immature Bitter Orange, Citrus aurantium immature fruit, Citrus aurantium L.
Overview
Zhi Shi refers to the dried immature fruit of Citrus aurantium L., commonly known as bitter orange. It is a significant ingredient in Traditional Chinese Medicine (TCM), primarily utilized for its digestive and cardiovascular benefits. This herbal supplement contains active compounds such as flavonoids, alkaloids (notably synephrine), and essential oils, which contribute to its therapeutic effects. Traditionally, Zhi Shi is incorporated into multi-herb decoctions like Zhishi Xiebai Guizhi Decoction (ZXGD) and Zhi Shi Xiao Pi Wan (ZSXPW) to address conditions such as dyspepsia, delayed gastric emptying, and coronary heart disease (CHD). Research indicates its potential to influence gastrointestinal motility, lipid metabolism, and vascular function. While promising, the evidence base, largely from Chinese clinical studies, is considered moderate, with ongoing research needed to solidify its efficacy and safety profile.
Benefits
Zhi Shi, primarily used in multi-herb TCM formulas, shows promising benefits for both cardiovascular and digestive health. For Coronary Heart Disease (CHD), a 2024 systematic review and meta-analysis of 8 RCTs demonstrated that Zhishi Xiebai Guizhi Decoction (ZXGD) combined with Western medicine significantly improved lipid profiles. Specifically, LDL-C was reduced by a mean difference of −0.93 mmol/L, and HDL-C increased by 0.31 mmol/L compared to Western medicine alone, indicating clinically relevant improvements. For digestive disorders like diabetic gastroparesis (DGP), a meta-analysis of RCTs found that the Zhi Shi-containing formula Zhi Shi Xiao Pi Wan (ZSXPW) showed a relative risk of 1.24 for clinical effectiveness in improving gastric emptying and symptoms compared to pharmacotherapy. Secondary effects, though requiring further validation, include improvements in vascular endothelial function, reduction of inflammatory markers, and modulation of gastrointestinal hormones. These benefits are most relevant for adults with CHD and diabetic gastroparesis, with treatment durations in studies ranging from weeks to several months.
How it works
Zhi Shi exerts its therapeutic effects primarily through its active compounds, including flavonoids and alkaloids like synephrine. These compounds are believed to enhance gastrointestinal motility by stimulating smooth muscle contraction and modulating neurotransmitters within the digestive system. Synephrine, a sympathomimetic alkaloid, may contribute to its effects on lipid metabolism and vasodilation. The herb interacts with the digestive system by influencing motility and secretion, and with the cardiovascular system by affecting lipid metabolism and endothelial function. It also appears to modulate inflammatory pathways. Known molecular targets likely include adrenergic receptors (via synephrine), smooth muscle receptors in the GI tract, and enzymes involved in lipid metabolism. The active compounds are absorbed orally, though bioavailability can vary depending on the specific compound and formulation.
Side effects
Zhi Shi is generally considered safe when used in traditional doses within multi-herb formulas under clinical supervision. Common side effects, reported in some studies, include mild gastrointestinal discomfort. Less common side effects (1-5% incidence) have been noted, such as dry mouth, hypersomnia, and breast tenderness, with the latter reported in one specific RCT on ZSXPW. Serious adverse events are rare, with no such occurrences reported in the reviewed randomized controlled trials. Due to its synephrine content, Zhi Shi has potential interactions with sympathomimetic drugs, and caution is advised when co-administering with cardiovascular medications. Patients with pre-existing hypertension or cardiovascular disease should use Zhi Shi with caution, and more data is needed to fully assess risks in these populations. Limited safety data is available for special populations, including pregnant or lactating women, children, and the elderly.
Dosage
The dosage of Zhi Shi is not standardized and varies significantly depending on the specific multi-herb formulation and traditional Chinese medicine (TCM) practice. It is typically administered as part of decoctions or pills, such as Zhishi Xiebai Guizhi Decoction (ZXGD) or Zhi Shi Xiao Pi Wan (ZSXPW). Doses are adjusted by TCM practitioners based on individual patient needs and conditions. There is no well-established maximum safe dose, but traditional use suggests safety within prescribed ranges. Zhi Shi is usually taken orally one to two times daily, often with meals. It can be found in various forms, including decoctions, pills, or extracts, which may be standardized to specific active components. While no specific cofactors are identified as required, its efficacy is often enhanced when used within the context of a complete herbal formula, as its bioavailability may be improved by other co-administered herbs.
FAQs
Is Zhi Shi safe for cardiovascular patients?
Evidence suggests benefit in coronary heart disease when combined with conventional treatment, but caution is warranted due to synephrine’s sympathomimetic effects. Consult a healthcare professional.
How quickly does it work?
Symptom improvement has been observed within 4 weeks to several months, depending on the specific condition being treated and the individual's response.
Can it be used alone?
Most scientific evidence supports the use of Zhi Shi in combination with other herbs or conventional medicine, rather than as a standalone treatment.
Does it cause stimulant side effects?
Mild stimulant effects are possible due to its synephrine content, but serious adverse events are rare when used within studied traditional doses.
Research Sources
- https://pmc.ncbi.nlm.nih.gov/articles/PMC10798696/ – This systematic review and meta-analysis of 8 RCTs (Li et al., 2024) investigated the efficacy and safety of Zhishi Xiebai Guizhi Decoction (ZXGD) for coronary heart disease. It found that ZXGD combined with Western medicine significantly improved lipid profiles (reduced LDL-C, increased HDL-C) and symptom improvement rates compared to Western medicine alone, with a moderate quality of evidence.
- https://pubmed.ncbi.nlm.nih.gov/38241594/ – This PubMed entry corresponds to the Li et al., 2024 systematic review and meta-analysis. It highlights the findings that ZXGD, containing Zhi Shi, effectively improved lipid parameters and clinical symptoms in patients with coronary heart disease when used as an adjunct to conventional therapy.
- https://f1000research.com/articles/11-861 – This systematic review and meta-analysis by Yang et al., 2020, evaluated the efficacy and safety of Zhi Shi Xiao Pi Wan (ZSXPW) for diabetic gastroparesis. The study concluded that ZSXPW significantly improved gastric emptying and clinical symptoms compared to pharmacotherapy, with mild and infrequent side effects.
- https://f1000research.com/articles/11-861/v1/pdf – This PDF version of the Yang et al., 2020 meta-analysis provides detailed methodology and results regarding ZSXPW for diabetic gastroparesis. It reinforces the finding of improved clinical effectiveness and symptom relief, noting the overall moderate quality of included RCTs and some heterogeneity.
- https://www.springermedizin.de/chinese-herbal-medicine-for-functional-dyspepsia-a-network-meta-/19970062 – This network meta-analysis by Li et al., 2021, explored the efficacy of Chinese herbal medicine, including formulas containing Zhi Shi, for functional dyspepsia. It suggested that these herbal interventions provided symptom relief comparable to or superior to prokinetics, though direct evidence on Zhi Shi alone was limited.
