IngredientsStephania is a large genus of flowering plants within the family Menispermaceae. The most pharmacologically and clinically studied species used as "Stephania root" is Stephania tetrandra S. Moore, though several related species — including Stephania rotunda Lour., Stephania japonica (Thunb.) Miers, Stephania cepharantha Hayata, and others — are also employed medicinally and share overlapping chemical profiles. Plant species belonging to the genus Stephania have been mentioned as traditional remedies, and various alkaloidal compounds have been identified and isolated, including aporphine, proaporphine, morphinane, hasubanane, protoberberine, benzylisoquinoline, and bisbenzylisoquinoline alkaloids, among others.
The genus belongs to the family Menispermaceae. S. tetrandra is a herbaceous perennial vine or scrambling subshrub native to southern China, Hainan, Taiwan, and Vietnam, growing from a short, woody caudex and climbing to a height of around three meters. The species was first formally described as Stephania tetrandra by Spencer Le Marchant Moore in 1875. In 2024, Lian Lian and Wei Wang reclassified it into the newly described monotypic genus Botryodiscia as Botryodiscia tetrandra, though the name Stephania tetrandra remains the predominant designation in the scientific and medical literature.
The root of Stephania tetrandra S. Moore is known as Fangji (Chinese: 防己) in China, and is a traditional Chinese medicine (TCM) with a long history of use. It is among the 50 fundamental herbs used in TCM. The standard pinyin according to the Chinese Pharmacopoeia of the People's Republic of China is fen fang ji, but it is more commonly known as Han Fang ji.
The plant is extensively referenced in the Chinese Pharmacopoeia for its use in the Chinese medicinal system as an analgesic and diuretic agent and also in the treatment of hypertension and various other ailments, including asthma, tuberculosis, dysentery, hyperglycemia, malaria, cancer, and fever. According to the Chinese Pharmacopoeia (2015 edition), the total fraction of tetrandrine and fangchinoline in Fangji should not be less than 1.6%.
In TCM, fen fang ji is used to dispel wind and dampness, to relieve pain, and to promote diuresis. It is classified as acrid, bitter, and cold. The part used medicinally is the root. The plant has a long growth cycle and can generally be excavated after 5–10 years of growth. The root is commercially available as dried sliced root, powdered extracts, standardized aqueous or ethanolic extracts, decoctions, capsules, and tablets. Tetrandrine tablets and injectable formulations are already available in China and are being used in clinical settings to treat rheumatic pain, joint pain, neuralgia, and silicosis.
Fangji was first recorded in the Shennong Bencao Jing (神农本草经), a classic work of traditional Chinese medicine composed during the Qin and Han Dynasties (approximately 100 BC–200 AD). Following the classical TCM principle that tonic drugs were top-grade, reconciling drugs were middle-grade, and laxative drugs were low-grade, Fangji was classified as a middle-grade product.
Known as Fangji in China, the root of Stephania tetrandra is a TCM with a long history of use. Fangji is a type of medicine used to treat various diseases, including rheumatism, arthralgia, edema and beriberi, unfavorable urination, and eczema. In TCM, it has been used primarily for its diuretic, anti-inflammatory, and anti-rheumatic properties. It has been used for treating rheumatic diseases for thousands of years in rural areas of China, with Stephania tetrandra radix showing promising immunomodulatory effects in the treatment of rheumatoid arthritis.
The traditional uses of Stephania rotunda were recorded in countries throughout Southeast Asia including Cambodia, Vietnam, Laos, and India, where different parts of the plant were used in traditional medicine to treat about twenty health disorders. Stephania japonica is widely distributed throughout Bangladesh, where it is traditionally considered one of the important medicinal plants in the treatment of a variety of ailments, including inflammation, pain, rheumatism, cancer, bone fracture, and fever.
A critical historical and safety issue involves the confusion between Stephania species and plants of the genus Aristolochia. Other plants named "fang ji" are sometimes substituted for Stephania; notable among these is "guang fang ji" (Aristolochia fangchi), whose main toxic component is aristolochic acid, a potent carcinogen and nephrotoxin. Aristolochia fangchi, but not Stephania tetrandra, contains aristolochic acid. In Belgium in the 1990s, more than 100 young women who used a slimming formula containing A. fangchi instead of S. tetrandra had to have kidney transplants due to kidney damage, and several of these women developed kidney and bladder cancer.
Alkaloids are the main active pharmaceutical ingredients isolated from Stephania plants. Various alkaloidal compounds have been identified and isolated, including aporphine, proaporphine, morphinane, hasubanane, protoberberine, benzylisoquinoline, and bisbenzylisoquinoline alkaloids, among others. In S. rotunda, phytochemical analyses have identified forty alkaloids. The roots primarily contain l-tetrahydropalmatine (l-THP), whereas the tubers contain cepharanthine and xylopinine. The chemical composition differs from one region to another and according to the harvest period.
Tetrandrine (Tet) is the main component extracted from the root of Stephania tetrandra S. Moore, accounting for about 1% of the root. It is a bisbenzylisoquinoline (BBI) alkaloid. Tetrandrine is characterized by the molecular formula C38H42N2O6, with its structure comprising two benzylisoquinoline units connected by an ether linkage, forming a symmetrical bis-isoquinoline scaffold crucial for its bioactivity and chemical reactivity. Tetrandrine has been shown to exhibit a variety of biological activities, including anticancer activity, cardiovascular activity, central nervous system activity, anti-inflammatory activity, immunosuppressive activity, antifibrotic activity, and antimicrobial effects.
The roots of Stephania also contain the alkaloid fangchinoline, along with tetrandrine and disochondrodendrine. Fangchinoline is structurally related to tetrandrine and shares several pharmacological properties. The known anti-inflammatory ingredients of S. tetrandra, tetrandrine and fangchinoline, can also effectively prevent tumorigenesis. Fangchinoline can inhibit cell proliferation, induce cell cycle arrest, and promote apoptosis by suppressing the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) and mitogen-activated protein kinase (MAPK) signaling pathways.
Cepharanthine, a natural bisbenzylisoquinoline (BBIQ) alkaloid isolated primarily from the plant Stephania cepharantha Hayata, is the only bisbenzylisoquinoline alkaloid approved for human use and has been used in the clinic for more than 70 years. It is mainly obtained by isolation and extraction from the tuberous roots, with a content of approximately 19.5–33.5% in the root mass. Cepharanthine has anti-inflammatory, antibacterial, antioxidant, antihemolytic, and immunomodulatory effects. Clinically, it is used to treat snake bites, alopecia, malaria, and radioactive leucopenia.
Levo-tetrahydropalmatine (l-THP) is an active constituent of herbal preparations containing plant species of the genera Stephania and Corydalis and has been approved and used in China for a number of clinical indications under the drug name Rotundine. The pharmacological profile of l-THP includes antagonism of dopamine D1 and D2 receptors and actions at dopamine D3, alpha adrenergic, and serotonin receptors.
The main pharmacological activities of Stephania rotunda alkaloids are antiplasmodial, anticancer, and immunomodulatory effects. Sinomenine, cepharanthine, and l-stepholidine are the most promising components and have been tested in humans. Among the tetrahydroprotoberberine alkaloids isolated from Stephania, stepholidine is notably active against dopamine D-receptors.
One of the most important pharmacological findings regarding tetrandrine is that it is a blocker of the voltage-activated, L-type Ca2+ channel in a variety of excitable cells, such as cardiac, GH3 anterior pituitary, and neuroblastoma cells, as well as in rat neurohypophysial nerve terminals. Although tetrandrine does not belong to any of the three classical Ca2+ channel blocker groups, electrophysiological and radioligand binding studies show that it is an L-type Ca2+ channel blocker with its binding site located at the benzothiazepine receptor on the α1-subunit. Tetrandrine relaxes vascular tension produced by depolarization with KCl, and further studies show that it inhibits KCl-induced intracellular Ca2+ increase and L-type voltage-dependent Ca2+ channel currents, suggesting it relaxes vessels via inhibition of Ca2+ influx through Ca2+ channels.
Tetrandrine has recently been found to block endolysosomal two-pore channels, preventing Ebolavirus, SARS-CoV-2, MERS-CoV, or pseudoviruses from entering host cells. Tetrandrine is a potent inhibitor of Ebola virus replication by blocking NAADP-dependent calcium release through endolysosomal two-pore channels. Using a clickable photoaffinity probe, researchers identified lysosomal integral membrane protein-2 (LIMP-2) as a direct molecular target of tetrandrine and a key regulator of this calcium signaling. Tetrandrine binds LIMP-2's ectodomain, inhibiting lysosomal cholesterol and sphingosine transport, which alters lipid metabolism.
Tetrandrine's pharmacological properties have been attributed to its action on different signaling pathways including reactive oxygen species (ROS), enhanced autophagic flux, reversal of multidrug resistance, the caspase pathway, cell cycle arrest, and modification of calcium channels. Beyond anti-inflammatory, antifibrogenetic, and immunomodulating effects, tetrandrine presents antiallergic effects, inhibitory effects on pulmonary vessels and airway smooth muscle contraction, and inhibition of platelet aggregation via its nonspecific calcium channel antagonism. Several studies have found that tetrandrine and fangchinoline can inactivate the PI3K/Akt signaling pathway by reducing the expression and phosphorylation of AKT.
Tetrandrine, which possesses anti-inflammatory, immunosuppressive, and anti-cancer abilities, has been shown to be effective for the treatment of immune diseases, inflammation, rheumatoid arthritis, liver cirrhosis, lung silicosis, and cardiovascular disease. Its anti-cancer abilities include apoptotic, antimetastatic, and antiangiogenic activities. Tetrandrine's apoptotic effects include increased ROS levels and Ca2+ release, increased activity of caspase-8, -9, -3, and -12, upregulation of pro-apoptotic proteins Bax, AIF, Endo G, cytochrome c release associated with mitochondria dysfunction, and Fas/Fas-L-dependent death.
The pharmacological profile of l-THP includes antagonism of dopamine D1 and D2 receptors and actions at dopamine D3, alpha adrenergic, and serotonin receptors, suggesting that it may have utility for treating cocaine addiction and related dopaminergic disorders.
Tetrandrine is the only plant-derived drug approved in China for the treatment of silicosis. It is the main extract of the Chinese medicine Stephania tetrandra S. Moore and has been used in the clinical treatment of silicosis for 50 years. Silica-induced lung injury and the development of silicosis is one of the major occupational diseases, characterized by granulomatous and fibrotic lesions. Tetrandrine, isolated from the root of Stephania tetrandra, has been investigated in various trials for the causal treatment of silicosis. Tetrandrine, well-known to act as a calcium channel blocker, has been tested in clinical trials and found effective against silicosis, hypertension, inflammation, and lung cancer.
Tetrandrine is clinically used for the treatment of silicosis, inflammatory pulmonary, and cardiovascular diseases in China. The evidence for silicosis represents the most advanced and longest-standing clinical application of tetrandrine, though the body of formal randomized controlled trial data meeting current Western regulatory standards remains largely confined to the Chinese literature.
Several clinical-level studies have examined Stephania tetrandra preparations in rheumatoid arthritis (RA). It has been reported that S. tetrandra (ST) showed beneficial and immunomodulatory effects in the treatment of relatively mild RA, and crude preparations have been used for arthritis and silicosis in China. After the administration of ST for 12 weeks, the proportion of granulocytes and the granulocyte count in peripheral blood decreased significantly. The lipid peroxide and human granulocyte elastase levels of stored plasma declined significantly, and both the leukocyte/elastase ratio and granulocyte/elastase ratio increased significantly.
A meta-analysis incorporating data from randomized controlled studies reported that tetrandrine significantly improved the total effective rate (OR=3.27, 95% CI: 2.01–5.37, P<0.01), ESR (SMD=1.12, 95% CI: 0.06–2.19, P<0.05), and CRP (SMD=0.75, 95% CI: 0.28–1.22, P<0.01). These findings are from the Chinese literature and predominantly involve Chinese-language randomized controlled trials; independent replication in large Western trials has not yet been conducted.
Among its clinical applications, tetrandrine has been used in the treatment of rheumatoid arthritis, sepsis, endotoxin-induced uveitis, silicosis, and hypertension. In preclinical multi-omics modeling, expression signatures of proteins, post-translational modifications (PTMs), metabolites, and extract ingredients were profiled in collagen-induced arthritic (CIA) rats treated with S. tetrandra extract, revealing that the extract mainly regulated tryptophan metabolism, the inflammatory response, and cell adhesion pathways. This is rodent-based evidence and does not directly establish efficacy in human RA.
Tetrandrine, a bisbenzylisoquinoline alkaloid purified from Radix stephaniae tetrandrae, has been used traditionally for the treatment of congestive circulatory disorder and inflammatory diseases. It, together with a few structural analogues, has long been demonstrated to have antihypertensive action in clinical as well as animal studies. The primary anti-hypertensive action is attributed to its vasodilatory properties. Tetrandrine prevents or inhibits vascular contraction induced by membrane depolarization with KCl or alpha-adrenoceptor activation with phenylephrine (PE).
Tetrandrine presents inhibitory effects on pulmonary vessels and airway smooth muscle contraction and platelet aggregation via nonspecific calcium channel antagonism, with clinical results to date in asthma and pulmonary hypertension described as noteworthy. The evidence base for hypertension derives primarily from Chinese clinical literature and animal pharmacology; large, independently replicated phase III randomized controlled trials are not available in the Western literature.
Tetrandrine has been found to block endolysosomal two-pore channels, preventing Ebolavirus, SARS-CoV-2, MERS-CoV, or pseudoviruses from entering host cells. In China, a clinical trial (NCT04308317) was initiated to investigate the use of tetrandrine as adjuvant therapy for COVID-19 patients. Tetrandrine blocks the two-pore calcium channel protein 2 (TPC2) that has been shown to be required for the release of the Ebola virus genome into target cells. Tetrandrine showed therapeutic efficacy in a mouse model, with a survival rate of roughly 50% if administered one day after challenge with a lethal dose of Ebola virus.
In a study screening 173 isolated natural product compounds and botanical extracts for blockade of wild-type SARS-CoV-2 infection in human 293T epithelial cells overexpressing ACE-2 and TMPRSS2, antiviral activity was demonstrated by an extract from Stephania tetrandra. Extract fractionation and antiviral assays revealed that the alkaloids tetrandrine, fangchinoline, and cepharanthine inhibited wild-type SARS-CoV-2 infection. However, the antiviral activity was not uniform across cell lines, and some of this activity may be associated with induction of phospholipidosis, especially at high concentrations; the antiviral potential of S. tetrandra should therefore be approached with careful and rigorous scrutiny. No published human trials have confirmed antiviral clinical efficacy in COVID-19 or Ebola as of the date of this writing.
Cepharanthine has become a promising therapeutic molecule owing to its remarkable antiviral effect, particularly the inhibitory effect on SARS-CoV-2. The combined use of nelfinavir and cepharanthine could effectively inhibit SARS-CoV-2 replication, wherein cepharanthine inhibits the entry of SARS-CoV-2 by blocking the binding of the virus to target cells, and nelfinavir inhibits viral replication by inhibiting proteases. This evidence is currently in vitro.
Tetrandrine is a bisbenzylisoquinoline alkaloid isolated from Stephania tetrandra and has been used as a herbal therapy in Chinese medicine for hundreds of years. It possesses antioxidant, anti-inflammatory, plasma glucose-lowering, immunosuppressive, antifibrotic, anticancer, antiviral, antihypertensive, and anti-silicosis activities, as well as the ability to reverse chemotherapy drug resistance. It has demonstrated antitumor activity in several types of cancers both in vitro and in vivo, including breast cancer, liver cancer, colon cancer, leukemia, lung cancer, prostate cancer, and cervical cancer.
In studies using NSCLC (non-small cell lung cancer) cell lines treated with total alkaloids of S. tetrandra (TAS), MGLL and BBC3 were identified as possible differentially expressed genes, and TAS may regulate fatty acid metabolism and induce apoptosis through the upregulated expression of MGLL and BBC3. The combination of TAS at noncytotoxic concentrations (A549: 1.0 μg/ml; H1299: 3.0 μg/ml) and cisplatin significantly inhibited the viability of both cell lines, suggesting TAS and its main alkaloid components have potential as multi-targeted drugs for lung cancer treatment. These are in vitro findings.
Fangchinoline (FCN) has been shown to be a natural inhibitor of nuclear receptor NR4A1, inducing NR4A1-dependent apoptosis in human pancreatic cancer cells. Tetrandrine (TTD) showed the highest inhibitory effect on NR4A1 transactivity among structural analogs evaluated, and directly bound to the ligand binding domain of NR4A1 with a KD value of 10.60 μM. At a dose of 25 mg/kg/day, TTD reduced tumor growth in an athymic nude mouse xenograft model bearing Panc-1 cells. These findings are preclinical (in vitro and animal). No completed phase III human trials in oncology have been reported in the reviewed literature.
Tetrandrine has been tested in clinical trials and found effective against lung cancer, but the scale, design, and regulatory status of these trials (primarily Chinese clinical literature) must be distinguished from the rigorous phase III evidence required for mainstream oncological approval outside China.
Tetrandrine has been shown to be effective for the treatment of liver cirrhosis and lung silicosis. Preclinical and early clinical data suggest antifibrotic potential in both hepatic and pulmonary contexts. The antifibrotic activity is mechanistically linked to calcium channel blockade, suppression of transforming growth factor-beta (TGF-β) signaling, and inhibition of hepatic stellate cell activation, as established in animal model and cell culture studies. The clinical evidence for liver fibrosis specifically remains preliminary relative to silicosis.
The main pharmacological activities of Stephania rotunda alkaloids include antiplasmodial effects. All bisbenzylisoquinoline alkaloids tested from Stephania erecta inhibited the growth of cultured Plasmodium falciparum strains D-6 and W-2. The efficacy of tetrandrine was also tested against Mycobacterium tuberculosis, Candida albicans, Plasmodium falciparum, and Ebola virus. These are predominantly in vitro and early-phase preclinical findings. The antimalarial evidence does not support current clinical use as a standalone antimalarial agent.
Levo-tetrahydropalmatine (l-THP), a primary active constituent of Stephania species, has been approved and used in China for a number of clinical indications under the drug name Rotundine. Its dopamine receptor antagonism has generated interest in addiction medicine. The pharmacological profile of l-THP, including antagonism of dopamine D1 and D2 receptors and actions at dopamine D3, alpha-adrenergic, and serotonin receptors, suggests that it may have utility for treating cocaine addiction. Human evidence for this indication is limited, and research remains at early investigational stages.
Tetrandrine tablets and injectable formulations are available in China and used clinically to treat rheumatic pain, joint pain, neuralgia, and silicosis. However, various factors limit its clinical applicability, including poor pharmacokinetic qualities, low water solubility, and low bioavailability.
Prior studies of tetrandrine for various uses indicated minimal toxicity at doses of from 100 to 300 mg/day.
In pharmacokinetic studies of sinomenine (a related alkaloid found in some Stephania preparations), when administered orally in 8 healthy male volunteers at a dose of 80 mg, the concentration-vs.-time curves were fitted using a two-compartment model with first-order elimination. The time to reach maximum plasma concentration (Tmax) was approximately 1 hour, with a maximum plasma concentration (Cmax) of 247 ± 71 ng/mL, and the elimination half-life (t1/2) was 9.4 ± 2.4 hours.
In one preclinical anticancer study, tetrandrine at a dose of 25 mg/kg/day reduced tumor growth in an athymic nude mouse xenograft model. In an antifibrotic Chinese traditional formula (Fang-Ji-Huang-Qi-Tang, FJHQT) rodent study, the content of tetrandrine in the FJHQT extract was 2.5 mg/g.
Tetrandrine exhibits low aqueous solubility, which significantly hampers its bioavailability. Poor water solubility challenges drug dissolution, a critical step for absorption in the gastrointestinal tract, resulting in insufficient absorption, extensive first-pass metabolism, and rapid clearance.
According to the Chinese Pharmacopoeia (2015 edition), the total fraction of tetrandrine and fangchinoline in Fangji (dried root material) should not be less than 1.6% as a quality control marker.
The most critical documented safety concern associated with products sold as "Stephania root" is not from Stephania tetrandra itself but from adulteration or misidentification with Aristolochia species. After investigations into cases of Chinese herb nephropathy, it was found that Stephania tetranda was inadvertently substituted by Aristolochia fangchi, which contained nephrotoxic aristolochic acid constituents, leading to adverse events. Aristolochic acids were substantiated as the chief culprit because AA-derived DNA adducts were detected in the kidneys and ureteric tissues of patients who required transplants.
The toxicity of the aristolochic acid constituents has been shown to be nephrotoxic, carcinogenic, and mutagenic. In many EU Member States, Stephania species have been restricted because of the difficulty in excluding Aristolochia contamination from the supply chain. Unless appropriate quality control procedures are in place, the prohibition of species at risk of being confused with Aristolochia — including Stephania tetrandra — is considered necessary by regulators.
Among the plants that the FDA considers to have a possibility of adulteration with Aristolochia are species of Stephania. The American Herbal Products Association (AHPA) currently has trade recommendations advising companies using Stephania tetrandra root to test for Aristolochia adulteration. In May 2000, the FDA began detaining any plants or medicines suspected of containing aristolochic acid, unless laboratory testing indicated they were negative for aristolochic acid.
Tetrandrine faces limitations in clinical use due to toxicity, poor solubility, and low bioavailability. Researchers are working to address these issues by developing tetrandrine derivatives with greater therapeutic potential through structural modification. Since Aristolochia fangchi was removed from the Chinese Pharmacopoeia, Stephania tetrandra is the only prescribed Fangji medicine, and toxicity research on the root of Stephania tetrandra has become an area of concern. Reports cover the toxicities of water and ethanol extracts of Fangji, as well as the toxicity of tetrandrine, its main active component.
The weak self-recovery ability of S. tetrandra after mining depends entirely on wild resources. The inclusion of this medicinal material in the Chinese Pharmacopoeia has contributed to the current shortage of resources. Supply scarcity can incentivize adulteration, making laboratory verification of botanical identity essential in any commercial preparation.
Tetrandrine faces limitations in clinical use due to toxicity, poor solubility, and low bioavailability. Like many lipophilic drugs, tetrandrine exhibits low aqueous solubility, which significantly hampers its bioavailability, as poor water solubility challenges drug dissolution, a critical step for absorption in the gastrointestinal tract. These pharmacokinetic challenges are among the reasons that researchers are actively pursuing structural modifications and novel delivery systems for tetrandrine derivatives.
A large number of studies have shown that tetrandrine exhibits broad-spectrum anticancer activity through a variety of mechanisms, including induction of apoptosis and autophagy, inhibition of proliferation, and angiogenesis suppression. Its P-glycoprotein inhibitory properties mean that tetrandrine may theoretically alter the pharmacokinetics of co-administered drugs that are P-gp substrates, though specific human drug interaction data are limited and require further investigation.
Many Stephania species have rarely been studied, and the ethnomedicinal potential of those discovered has not been fully scientifically evaluated. Quality control and toxicology studies are warranted in the future.
Across the body of research, the following gradations of evidence strength apply:
Health conditions that Stephania root may help support.
Body systems that Stephania root may help support.
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