Polygala root

Polygala Root (Polygala tenuifolia Willd.): A Comprehensive Reference

1. Identity and Botanical Description

Taxonomy and Nomenclature

Polygalae Radix — the dried root of Polygala tenuifolia Willd. or Polygala sibirica L. — is mainly distributed in China, South Korea, Mongolia, and Russia. The plant belongs to the family Polygalaceae. With almost 50% of the family's species, Polygala is the most representative genus in the Polygalaceae family, containing more than 600 species with recognized Latin names, including trees, shrubs, and herbs. There are more than 500 species of Polygala plants worldwide, with 39 species and 8 varieties in China; 17 species and 2 varieties are available for medicinal use.

The root is known by multiple names across cultures. It is widely used in Japanese Kampo medicine, traditional Korean medicine, traditional Chinese medicine (TCM), and Mongolian medicine as a tonic, expectorant, sedative, and antasthmatic. It is known as "Onji" in Japan and "Wonji" in South Korea — terms that refer only to the root or root bark of Polygala tenuifolia Willd. In China, Polygalae Radix (PR) is called "Yuanzhi" and ranks as the third most frequently used single herb in the clinical application of cognitive enhancement prescriptions.

P. tenuifolia is one of the 50 fundamental herbs used in traditional Chinese medicine, where it is called yuǎn zhì (Chinese: 遠志) and believed to have neuropsychiatric effects. It has been studied as a potential drug source in depression and Alzheimer's disease.

Botanical Description

Polygala tenuifolia is a perennial medicinal plant that has been widely used in traditional Chinese medicine for treating mental diseases. The plant is a perennial herb that can reach a height of 18 inches, with oval-shaped green leaves and pale red, yellow, or lavender flowers, depending on the species. The plant's root varies in color from yellowish-gray to brownish-gray, and is usually twisted or spiraled, with a thick, gnarled crown. The root is used medicinally.

Pharmacopeial Status

The roots of Polygala tenuifolia Willd. (Polygalae Radix) are included in several standardized documents, including the European (Ph. Eur.), Korean, Chinese, and Japanese Pharmacopoeias, as well as WHO monographs. Polygalae Radix, also known as "Onji" or "Yuanzhi" in East Asia, is one of the most important ingredients in traditional Oriental medicine. Since 1963, PR has been officially listed in the Chinese Pharmacopoeia.

Common Forms and Preparations

According to the 2020 Chinese Pharmacopoeia, PR is usually harvested in spring and autumn; the fibrous root and silt are removed, and the product is dried directly or after the wood heart is removed. Yuanzhi, Radix Polygalae, is the dry root of Polygala tenuifolia Willd. or P. sibirica L. (Polygalaceae) collected in the spring and fall. It is officially listed in the Chinese Pharmacopoeia and is used in traditional Chinese medicine as a mucolytic for the treatment of cough; it is further used as a sedative and for anti-swelling purposes. Two galenic preparations are also listed in the Chinese Pharmacopoeia: Yuanzhi Liujingao, Extractum Polygalae liquidum; and Yuanzhi Ding, Tinctura Polygalae — used only as mucolytics.

Modern commercial preparations include standardized capsules and powders. Polygala tenuifolia is available as a powder or as capsules. Traditional decoctions (water-based teas from dried root) represent the classical form of preparation used historically in East Asia.

In China, the main producing areas are Shanxi and Shaanxi provinces, which have the largest production and are traditionally considered to have the best quality of PR.

2. Traditional and Historical Use

China

The roots of Polygala tenuifolia Willd. (Polygalaceae), which is among the most important components of traditional Chinese herbal medicine, have been widely used for over 1,000 years to treat a variety of diseases. Since more than 2,000 years ago, Polygala tenuifolia Willd.'s roots — also known as Polygala Radix or "Yuan-Zhi" in Chinese — have been widely used.

Yuan zhi (Polygala tenuifolia) was the most frequently cited herb for forgetfulness in classical Chinese herbal literature in total, in Section 3, and for aging. It first appeared in Shen Nong Ben Cao Jing (ca. 188 CE) and is included in the Zhong Yao Da Ci Dian (ZYDCD). The early text Shennong Bencao Jing highlights the importance of Yuan Zhi, underscoring its role in clearing the mind and harmonizing the spirit, a view that aligns with subsequent texts such as the Shang Han Za Bing Lun and Bencao Gangmu.

Historically, Yuan Zhi has been valued for settling the heart and opening its orifice, dispersing phlegm, and reconnecting communication between heart and kidney. In TCM, the concept of opening the orifices represents a therapeutic principle aimed at removing obstructions in the heart's ability to integrate sensory information, to restore mental clarity and cognitive function. This approach is based on the understanding that mental disturbances are often linked to blockages resulting from qi and blood stagnation, qi deficiency, phlegm, and cold. Polygala root (Yuan Zhi) is recognized in this context as an agent capable of clearing these obstructions, thereby enhancing mental and emotional well-being.

In China, Polygalae Radix has been widely used in the treatment of insomnia, forgetfulness, depression, cough, palpitation, and other diseases. It has also been widely used as a nootropic, anti-inflammatory, and antipsychotic medicine to cure insomnia, forgetfulness, neurasthenia, coughing, and soreness caused by heart and kidney disharmony. Classical TCM formulas incorporating Yuan Zhi include Kai-Xin-San (KXS), Buwang San, and Cong-Ming-Tang. Polygala radix is one of three medicinal plants used in the preparation of Cong-Ming-Tang, a Chinese herbal formula in TCM used for the treatment of amnesia.

Japan

In the Japanese Pharmacopoeia, P. radix (Onji) is recorded as one of the main ingredients of Kampo Medicine, for its anti-neurotic, tonic, and sedative effects. The formulations used in Kampo include Kami-kihi-to, Kami-untan-to, Ninjin-yoei-to, and Kai Xin San. It is also prescribed to treat amnesia, insomnia, and anxiety in Kampo Medicine, in addition to its uses as an expectorant and stimulant to treat bronchial asthma, chronic bronchitis, and whooping cough.

Korea

P. tenuifolia is a herb in the Polygalaceae family, which is widely distributed in Asia. In traditional folk medicine, it has been used for thousands of years as an expectorant and stimulant to treat bronchial asthma, chronic bronchitis, and whooping cough. Known as "Wonji" in Korea, it has been employed similarly to its Chinese counterpart, primarily for memory support and respiratory conditions.

Traditional Preparations

Root bark preparations have been predominant across traditions. The roots are dug in spring or autumn. After the fibrous roots have been removed, the roots are cleaned in water and dried in the sun. In TCM practice, the root bark (without the xylem core) is the preferred medicinal part. Processing with other herbs has long been employed to mitigate gastrointestinal irritation; for instance, Polygalae Radix should be processed or used in combination with other Chinese herbal medicines to reduce the irritation to the throat and reduce gastrointestinal irritation. One classical compatibility is preparation with Gan Cao (licorice), which is reported in TCM sources to mitigate adverse gastrointestinal effects. In China, pharmacy workers always process Radix Polygalae to reduce gastrointestinal irritation, such as honey-stir-baking, because in the course of processing drugs, the glycosyl link at C28 of polygala triterpene saponins breaks easily and then produces more tenuifolin.

3. Key Constituents and Active Compounds

Overall Phytochemistry

More than 320 metabolites have been isolated from PR; saponins, xanthones, and oligosaccharide esters are the main functional metabolites. More than 140 compounds have been isolated from Polygalae Radix, including saponins, xanthones, oligosaccharide esters, and so on.

The major components of P. tenuifolia include triterpenoid saponins, xanthone glycosides, phenolic glycosides, and oligosaccharide ester derivatives.

Triterpenoid Saponins

The saponin compounds of P. tenuifolia represent some of the most significant active ingredients in PT, all categorized as triterpenoid saponins with a fundamental structure of pentacyclic triterpenes, specifically of the oleanane-type. To date, numerous PT saponins have been identified, including Sibiricasaponins A–E, onjisaponins (A, B, E, F, etc.), and tenuifoliside A–C. Although extensive, pharmacological research has primarily concentrated on tenuigenin (senegenin), polygalasaponins XXXII, tenuifolin, and onjisaponin B.

As the main pharmacologically active components of P. tenuifolia, polygalasaponins — including polygalasaponin XXXII (PGS 32), tenuifolin, polygalacic acid, and senegenin (tenuigenin) — have been shown to possess multiplex neuroprotective potential.

• Tenuifolin (TEN): Tenuifolin is a natural neuroprotective compound isolated from the dried roots of Polygala tenuifolia Willd., which can treat forgetfulness, insomnia, and depression, and has pharmacological effects such as inhibiting Aβ secretion and anti-apoptosis. Tenuifolin is a metabolite of onjisaponin B, and it has been demonstrated that oral administration of tenuifolin markedly improved the cognitive function of Alzheimer's disease animals.
• Tenuigenin / Senegenin: Senegenin, which is also called tenuigenin, is an effective component of Polygala tenuifolia root extract. Its chemical structure is (2β,3β,4α,12α)-12-(Chloromethyl)-2,3-dihydroxy-27-norolean-13-ene-23,28-dioic acid (molecular formula: C₃₀H₄₅ClO₆; molecular mass: 537; lipophilic and hydrosoluble).
• Onjisaponin B (OB): Onjisaponin B could mitigate cognitive impairments by elimination of neuroinflammation, oxidative stress, and Aβ pathology in AD animals. Onjisaponin B has a high molecular mass; therefore, it cannot cross the blood–brain barrier. The administration of its metabolite, tenuifolin, was found to enter the mice's brains and provide a therapeutic effect.
• 3,6′-Disinapoyl sucrose (DISS): DISS could protect SH-SY5Y cells from apoptosis induced by glutamate. DISS was reported to activate the CREB/BDNF pathway in vitro and in vivo, with ERK1/2 and CaMKII involved upstream. DISS also reduced serum CORT, ACTH, and CRH levels induced by chronic mild stress in rats and increased the expression of glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) mRNA in the hippocampus, thereby influencing stress-induced HPA axis changes.

Xanthones

One of the key elements of Polygala Radix is xanthones. Xanthones have been found to have antifungal, analgesic, anti-cancer, and other properties, according to recent pharmacological studies. Xanthones have antitumor, analgesic, antimycotic, and other effects. Xanthone constituents from P. tenuifolia were found to inhibit neuraminidases from influenza A viruses. Identified xanthone compounds include polygalaxanthone III, polygalaxanthone IV, 7-O-methylmangiferin, and sibiricaxanthone B, among others.

Oligosaccharide Esters

Oligosaccharide esters have remarkable antidementia, antidepressant, and brain-protective activities. Key phenylpropanoid sucrose esters identified include tenuifoliside A, tenuifoliside B, tenuifoliside C, sibiricose A3, sibiricose A5, and sibiricose A6. In a study by Son et al., three saponins, ten phenylpropanoid sucrose esters, one benzoic acid sugar ester derivative, two hydroxy benzophenone, four xanthone derivatives, two phenolic derivatives, and two ionones were extracted from the roots of Polygala tenuifolia, including onjisaponin J, onjisaponin Fg, onjisaponin B, sibiricose A3, sibiricose A5, sibiricose A6, tenuifoliside A, tenuifoliside B, tenuifoliside C, among others.

Organic Acids and Other Compounds

Organic acids from PT exert antiseizure, anti-inflammatory, neuroprotective, and antiamnesic effects. Identified compounds include polygalacic acid, 3,4,5-trimethoxycinnamic acid methyl ester, and p-hydroxybenzoic acid. Active compounds like tenuifolin and 3,4,5-trimethoxycinnamic acid promote sleep through modulation of neurotransmitters.

4. Established Mechanisms of Action

Neurotrophic Factor Modulation

P. tenuifolia root extracts and their active ingredients proved to be neuroprotective against psychotic or neurodegenerative disease models by regulating the HPA axis, regulating neurotransmitter release, increasing BDNF and NGF expression, improving neuronal synaptic plasticity, and promoting nerve cell proliferation. Onjisaponins of Polygala tenuifolia, which are ingredients of the Japanese herbal medicine Ninjin-yoei-to, induced nerve growth factor (NGF) synthesis in astrocytes, suggesting possible use in the treatment of Alzheimer's disease.

Cholinergic System

Research has indicated that active compounds in P. tenuifolia support the central cholinergic system. Polygala tenuifolia and its active components have multiplex neuroprotective potential associated with AD, such as anti-Aβ aggregation, anti-Tau protein, anti-inflammation, antioxidant, anti-neuronal apoptosis, enhancing the central cholinergic system, and promoting neuronal proliferation.

HPA Axis and Neurotransmitter Regulation

The multifold mechanisms of action include several properties such as antioxidant and associated apoptotic effects; anti-inflammatory and associated apoptotic effects; neurogenesis, regeneration, differentiation, and neuronal plasticity improvement; hypothalamic–pituitary–adrenal axis (HPA) regulation; neurotransmitter release; and receptor activation (A2AR, NMDA-R, and GluR).

A P. tenuifolia extract (YZ-50) reversed the harmful effects of chronic mild stress on mood and behaviors in rats, and it possesses an antidepressant property that is at least in part mediated by the neuroendocrine and neuroprotective systems, with the HPA system playing an important role in this process.

Anti-Neuroinflammatory and Antioxidant Mechanisms

The root of P. tenuifolia, which has been traditionally used as an expectorant, was found to inhibit TLR4 and Myd-88 expression. Moreover, P. tenuifolia roots suppress NF-κB translocation by blockade of IκB-α degradation in LPS-stimulated BV2 cells. Tenuigenin, a triterpenoid from P. tenuifolia, inhibits mitogen-activated protein kinases (MAPKs) and NF-κB signaling while inducing Nrf2/HO-1 signaling in macrophages.

The saponin components of P. tenuifolia can reduce β-amyloid accumulation, exhibit antioxidant effects, regulate neurotransmitters, improve synaptic function, possess anti-inflammatory properties, inhibit neuronal apoptosis, and modulate autophagy.

Monoamine Reuptake Inhibition

P. tenuifolia has been shown to exert expectorant, tonic, tranquilizer, and antipsychotic efficacies in clinical practice and can be seen in several empirical formulas for depression treatment, such as Kai-Xin-San (KXS). Its mechanism of action in depression treatment had not been well understood until Yuanzhi-1, a triterpenoid saponin isolated from Polygala tenuifolia Willd., was recently identified as a triple monoamine reuptake inhibitor with high potency.

Onjisaponin B Cellular Mechanisms

Onjisaponin B functions by inhibiting nuclear factor-kappa B (NF-κB) p65, RhoA, and Rho-kinase 2 (ROCK2) protein expression by activating the RhoA/ROCK2 signaling pathway. It also improves antioxidant enzyme activity. Onjisaponin B, isolated from ethanol extracts of Radix Polygalae, induced autophagy via the 5′-adenosine monophosphate-activated protein kinase–mammalian target of rapamycin (AMPK-mTOR) signaling in PC12 cells expressing mutant huntingtin. The compound was also implicated in modulating neurodegenerative disorders by reducing intracytosolic aggregation of toxic mutant proteins.

5. Scientific Evidence by Area of Use

5.1 Cognitive Function and Memory

Strength of evidence: Preliminary — limited human clinical trials, supported by animal and in vitro data.

Polygala tenuifolia (called "Yuanzhi" in Chinese) has been widely used as a memory enhancer for people in Asian countries for many years, and it is also included in many traditional prescriptions used for treatment of amnesia and dementia. Preclinical trials showed that ethanol extracts of P. tenuifolia possess memory-enhancing effects in healthy and elderly volunteers.

In a clinical trial on 48 healthy people, Polygala tenuifolia root extract improved spatial and verbal memory. Only one clinical trial and some animal research support the use of Polygala tenuifolia to improve cognitive function in elderly people; further clinical research is required.

Numerous pharmacological studies have demonstrated that PT possesses multiple neuroprotective effects associated with AD, such as anti-apoptosis, anti-neuroinflammation, enhancing neurotrophy, and anti-neurotoxicity induced by β-amyloid (Aβ). Moreover, PT extract promoted neural stem cell (NSC) proliferation in vitro and enlarged the amount of NSCs in hippocampal CA1 regions in adult rats.

Animal studies have shown promising results for tenuifolin specifically. Oral administration of tenuifolin markedly improved the cognitive function of AD model animals. However, these findings are from preclinical models and should not be directly extrapolated to humans without further clinical validation.

5.2 Alzheimer's Disease and Dementia

Strength of evidence: Preliminary in clinical studies; stronger evidence from animal/in vitro models; one systematic review of combination therapy.

Among Chinese herbal formulas for AD treatment, Polygala tenuifolia (PT) and Acorus tatarinowii (AT) appear as the most commonly used herbal pairs in combination. A systematic review aimed to evaluate the clinical efficacy and safety of the combination of PT and AT in the treatment of AD by systematically searching and screening randomized controlled trials in eight databases with a search deadline of June 26, 2023. Primary outcomes assessed included mini-mental state examination (MMSE), activities of daily living (ADL), and AD assessment scale-cognitive subscale (ADAS-cog), while secondary outcomes included efficiency and adverse events.

Polygala tenuifolia and its active components have multiplex neuroprotective potential associated with AD, such as anti-Aβ aggregation, anti-Tau protein, anti-inflammation, antioxidant, anti-neuronal apoptosis, enhancing the central cholinergic system, and promoting neuronal proliferation. Hence, P. tenuifolia is a potential drug against Alzheimer's disease, especially in terms of prevention.

Accumulating evidence indicates that the saponin compounds in PT possess neuroprotective effects, and they are primarily utilized in treating AD within the spectrum of dementia. There is also limited evidence suggesting their potential for intervention in Parkinson's disease dementia (PDD) and vascular dementia (VaD) subtypes. The focus of research on these compounds includes tenuigenin, tenuifolin, polygalasaponins XXXII, and onjisaponin B.

These findings remain predominantly preclinical. Rigorous double-blind, placebo-controlled human trials specifically evaluating isolated PT preparations for Alzheimer's disease remain scarce.

5.3 Depression and Mood Disorders

Strength of evidence: Animal/in vitro — no verified published human clinical trials specifically for depression with isolated PT preparations.

Polygala tenuifolia Willd. (Yuan Zhi) is a traditional Chinese herb that is commonly used in the treatment of psycho-emotional disorders and managing depression.

Polygala tenuifolia and its derivatives had antidepressant effects in rats and mice. In mice, a saponin from its extract was more effective than the drug duloxetine (used to treat depression). These are animal data only and do not constitute human clinical evidence.

One study confirmed antidepressant effects of the YZ-50 extract in a chronic mild stress (CMS) model of depression in Sprague-Dawley rats and investigated whether YZ-50 influences HPA axis function and hippocampal BDNF mRNA correlated with neuroendocrine and neuroprotective processes in the stressed animals.

The compound Yuanzhi-1 derived from P. tenuifolia has been characterized as a triple monoamine reuptake inhibitor in preclinical research, but clinical translation remains to be established.

5.4 Insomnia and Sedation

Strength of evidence: Preliminary — primarily traditional use and animal data.

P. tenuifolia is known for its pharmacological effects on the neurological system, including anti-neuroinflammatory, neuroprotective, antidepressant, and sedative-hypnotic activities, particularly in the treatment of insomnia. Its effects are mediated through modulation of neurotransmitters such as 5-HT, norepinephrine, and dopamine, and it contains active compounds like tenuifolin and 3,4,5-trimethoxycinnamic acid that promote sleep.

In preclinical studies, onjisaponin B (OJB) and tenuifolin (TEN), but not senegenin (SNG), significantly increased the number of sleeping mice and prolonged sleeping time. These are animal findings and no dedicated human clinical trials for insomnia using isolated PT have been identified in the peer-reviewed literature.

5.5 Anti-Inflammatory Activity

Strength of evidence: In vitro and animal models; no human clinical data specific to inflammation.

Twenty-three compounds were isolated from P. tenuifolia roots, including three saponins, ten phenylpropanoid sucrose esters, one benzoic acid sugar ester derivative, four xanthones, two hydroxy benzophenone derivatives, two phenolic derivatives, and two ionones. All isolates were tested for their inhibitory effects of LPS-stimulated NO and PGE₂ production in RAW 264.7 macrophages. Among these, 3-O-(3,4,5-trimethoxy-cinnamoyl),6′-O-(p-methoxybenzoyl) sucrose ester (TCMB) together with compounds 3 and 21 exhibited significant inhibitory effects on NO production.

Tenuifoliside A, a unique phenolic sugar ester, has an anti-inflammatory effect in LPS-stimulated macrophages by inhibiting the c-Jun N-terminal kinase (JNK) and NF-κB signaling.

5.6 Respiratory/Expectorant Use

Strength of evidence: Traditional use supported by pharmacological rationale; no rigorous modern clinical trials identified.

Due to its tonic, sedative, and expectorant properties, the root of Polygala tenuifolia (Polygalae Radix) is the primary source of the traditional Chinese medicine Yuan Zhi. Saponins, oligosaccharide esters, and xanthones from Polygala Radix show significant bioactivity including phlegm expulsion, coughing cessation, antifungal activity, and others. Pharmacological studies show that saponins exert the functions of relieving excitement, sedation, relieving cough, and expelling phlegm.

5.7 Antipsychotic Activity

Strength of evidence: Preclinical and limited traditional-use evidence; no modern human clinical trials specifically for psychosis.

Saponin compounds (onjisaponins A, B, E, F, and G) from the roots of P. tenuifolia have been used to treat psychosis within traditional medicine. Previous in vivo studies have revealed that the extract of Radix Polygala can improve cognitive deficits and has antipsychotic, antidepressive, and anti-inflammatory activities. Additionally, exposing mice to Radix Polygala extract resulted in the attenuation of cocaine-induced hyperlocomotion and prolonged pentobarbital-induced sleep duration.

6. Body Systems and Health Areas

Modern pharmacological studies indicate that Polygalae Radix has rich pharmacological activities in vitro and in vivo, including protective effects on the nervous system, immune system, cardiovascular system, and respiratory system, as well as antioxidant and antiepileptic pharmacological activities.

• Central Nervous System: Memory, cognition, neuroprotection, sedation, antidepressant effects, and antipsychotic activity. The compounds and extracts isolated from Polygalae Radix possess wide-ranging pharmacological activities, such as neuroprotective, antidepressant, hypnotic-sedative, anti-inflammatory, antiviral, antitumor, antioxidant, antiaging, and antiarrhythmic effects, among others.
• Respiratory System: Expectorant, mucolytic, and antitussive properties linked to saponin content. Triterpenoid saponins are the main pharmacological substances of PT, and they exhibit tranquilizing, phlegm-expelling, and cough-stopping functions.
• Immune/Inflammatory System: Inhibition of pro-inflammatory cytokines, NF-κB pathway suppression, and dendritic cell modulation documented in cell-based and animal models.
• Cardiovascular System: Antiarrhythmic activity has been cited in pharmacological reviews, though clinical human evidence is absent.

7. Dosage Forms and Reported Dosages

The standard dosage of polygala cited in traditional references is 1.5–3 grams of dried root, 1.5–3 grams of a fluid extract, or 2.5–7.5 grams of a tincture. A polygala tea can also be made, with a maximum of three cups per day.

In modern clinical research, the dosing used differs from traditional preparations. In clinical trials, it was administered as 100 mg per dose three times a day. In clinical trials, it was administered as 100 mg per dose 3 times a day. The same dose was generally safe in a clinical trial on 60 children and teenagers aged 9–19.

Preclinical dosing in rodent studies has varied widely; for example, the anti-inflammatory effects of onjisaponin B were investigated at doses of 20 and 40 mg/kg in animal models of Parkinson's disease.

Two galenic preparations are listed in the Chinese Pharmacopoeia: Yuanzhi Liujingao (Extractum Polygalae liquidum) and Yuanzhi Ding (Tinctura Polygalae), which are used as mucolytics.

The 2020 Chinese Pharmacopoeia specifies quality standards for Polygalae Radix. According to the Chinese Pharmacopoeia, only the dry root of Polygala Radix is considered medicinal, while the majority of the aboveground portions are rejected.

8. Safety Considerations and Known Interactions

Gastrointestinal Toxicity

Previous research has highlighted the severe gastrointestinal toxicity associated with PT, leading to gastrointestinal motility disorders, mucosal damage, and even death in mice at high doses. Saponins have been identified as the primary toxic components of PT, significantly hampering its application and development.

In routine clinical usage, Radix Polygalae can cause mild nausea. If taken in larger doses, it can cause nausea, vomiting, abdominal distension, diarrhea, and adverse reaction of hemolysis.

Toxicological studies showed that tenuifolin (TEN) could trigger gastrointestinal toxicity, significantly inhibit gastrointestinal motility, cause gastrointestinal flatulence and intestinal wall thinning. Research shows that long-term and large doses of Radix Polygalae can cause gastric mucosal injury. Non-processed Radix Polygalae caused obvious inhibition of gastrointestinal motility and led to flatulence, thinner, or necrotic intestinal tissue. Pharmacy workers always process Radix Polygalae to reduce gastrointestinal irritation, such as honey-stir-baking.

Processing with licorice or other herbal preparations is a traditional mitigation strategy. In processing Polygala, glycosyl breaking may be related to the decline of pharmacological activity and gastrointestinal toxicity of polygala saponins.

Adverse Events Reported in Clinical Trials

Polygala tenuifolia has been reported to cause vomiting, diarrhea, changes in body weight, and/or mild indigestion in clinical trials. There was one case where it caused occupational asthma and rhinitis due to long-term inhalation.

Contraindications in Traditional Medicine

Eastland Herb Materia Medica notes that Yuan Zhi is contraindicated for those with yin deficiency with heat signs, as well as those with peptic ulcers or gastritis.

Drug Metabolism Interactions

Polygala tenuifolia contains specific compounds that inhibit chlorzoxazone 6-hydroxylation catalyzed by CYP2E1, a crucial enzyme in drug metabolism. This suggests that Polygala tenuifolia could interact with other medications and affect their metabolism.

Bioavailability Concerns

Studies have found that the oral bioavailability of tenuifoliside A (TFSA) is only 1.2%, which poses challenges to explaining its good efficacy. Intestinal bacteria were the main metabolism site of TFSA, and the process of biotransformation by microbial carboxylesterase, including the release of four characteristic metabolites, was elucidated. This suggests that gut microbiota composition may substantially influence the pharmacological activity of P. tenuifolia preparations in vivo.

Overall Toxicological Profile

Processing or compatibility can change the quality, effectiveness, or toxicity of PR. The general toxicological picture from animal studies suggests low acute toxicity at moderate doses but clinically relevant gastrointestinal toxicity at higher or unprocessed doses. The detailed mechanisms underlying this array of pharmacological effects observed in vitro and in vivo still need further investigation to attain a coherent neuroprotective profile.

References

• Singh K et al. "Pharmacology of Polygala tenuifolia and its significance in traditional Chinese medicine." ScienceDirect / Journal of Traditional Chinese Medical Sciences, 2023.
• Kim EJ et al. "Bioactive Compounds from Polygala tenuifolia and Their Inhibitory Effects on Lipopolysaccharide-Stimulated Pro-inflammatory Cytokine Production in Bone Marrow-Derived Dendritic Cells." PMC / Evidence-Based Complementary and Alternative Medicine, 2020.
• Son YR et al. "Chemical Constituents of the Roots of Polygala tenuifolia and Their Anti-Inflammatory Effects." PMC / Molecules, 2022.
• Li D et al. "Active constituent of Polygala tenuifolia attenuates cognitive deficits by rescuing hippocampal neurogenesis in APP/PS1 transgenic mice." PMC / BMC Complementary Medicine and Therapies, 2021.
• Peng W et al. "Polygala tenuifolia: a source for anti-Alzheimer's disease drugs." Pharmaceutical Biology, 2020.
• Chen X et al. "Saponin components in Polygala tenuifolia as potential candidate drugs for treating dementia." Frontiers in Pharmacology, 2024.
• "Polygalae Radix: review of metabolites, pharmacological activities and toxicology." Frontiers in Pharmacology, 2024.
• Wang H et al. "A review of the botany, metabolites, pharmacology, toxicity, industrial applications, and processing of Polygalae Radix: the 'key medicine for nourishing life'." PMC / Frontiers in Pharmacology, 2024.
• Zhang S et al. "Protective Effects and Mechanism of Radix Polygalae Against Neurological Diseases as Well as Effective Substance." Frontiers in Psychiatry, 2021.
• He Y et al. "Neuroprotective Effects and Mechanisms of Senegenin, an Effective Compound Originated From the Roots of Polygala Tenuifolia." PMC / Frontiers in Pharmacology, 2022.
• Wang Y et al. "The Gastrointestinal Irritation of Polygala Saponins and Its Potential Mechanism In Vitro and In Vivo." PMC / Evidence-Based Complementary and Alternative Medicine, 2015.
• "Magnolia officinalis alcohol extract alleviates the intestinal injury caused by Polygala tenuifolia." Drug Design, Development and Therapy, 2024.
• Hu Y et al. "Antidepressant effects of the extract YZ-50 from Polygala tenuifolia in chronic mild stress treated rats and its possible mechanisms." Pharmaceutical Biology, 2010.
• "Preclinical Evidence of Rapid-Onset Antidepressant-Like Effect in Radix Polygalae Extract." PMC / Evidence-Based Complementary and Alternative Medicine, 2014.
• Xue W et al. "Cognitive-Enhancing Effects of Polygalasaponin Hydrolysate in Aβ 25–35-Induced Amnesic Mice." PMC / PLOS ONE, 2011.
• "Senegenin Attenuates Hepatic Ischemia-Reperfusion Induced Cognitive Dysfunction by Increasing Hippocampal NR2B Expression in Rats." PMC / PLOS ONE, 2012.
• Tang JZ et al. "Polygala tenuifolia and Acorus tatarinowii in the treatment of Alzheimer's disease: a systematic review and meta-analysis." Frontiers in Pharmacology, 2023.
• Tang JZ et al. "Polygala tenuifolia and Acorus tatarinowii in the treatment of Alzheimer's disease." PubMed / Frontiers in Pharmacology, 2024.
• Luo H et al. "Chinese Herbs for Memory Disorders: A Review and Systematic Analysis of Classical Herbal Literature." Innovations in Acupuncture and Medicine, 2012.
• "Genome assembly of Polygala tenuifolia provides insights into its karyotype evolution and triterpenoid saponin biosynthesis." PMC / Plant Communications, 2023.
• "Protective Effects and Mechanism of Radix Polygalae Against Neurological Diseases as Well as Effective Substance." PMC / Frontiers in Psychiatry, 2022.
• "Polygalae Radix: A review of its traditional uses, phytochemistry, pharmacology, toxicology, and pharmacokinetics." Fitoterapia, 2020.
• "Integrated Gut Microbiota–Drug Interaction Analysis and Network Pharmacology for the Investigation of Renal-Protective Effect of Polygala tenuifolia Willd." PMC / International Journal of Molecular Sciences, 2025.
• Kan Herb Company. "Yuan Zhi (Polygala tenuifolia): Memory and Cognition." KanHerb.com.
• Acupuncture Today. "Polygala (yuan zhi)." AcupunctureToday.com.