Wu Yao
StarLindera aggregata (Sims) Kosterm.
Traditionally used for
- Digestion
- Urinary & fluids
Cautions & contraindications
- Bleeding disorders
- Diabetes
☯ TCM Properties
Moves Qi and Alleviates Pain; Warms the Kidneys and disperses Cold; Regulates Qi Flow in the Chest, Abdomen and Lower Body; Warms the Bladder and reduces urination
Traditional Chinese Uses
Wu Yao (lindera root) is a warm, pungent herb that moves Qi and disperses cold throughout the body, with a particular affinity for the lower abdominal region and the Bladder. It is used for cold-type pain in the abdomen, hypogastrium, and flanks, hernia pain from Liver-channel cold, and urinary frequency or incontinence from Bladder cold. It is an important herb in formulas for cold-type gynecological conditions and Kidney-Bladder cold.
Western Herbalism Properties
Relationships
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Botanical Description
Lindera aggregata (Wu Yao, evergreen lindera) is an evergreen shrub or small tree in the Lauraceae family, growing 2 to 5 meters tall, with smooth dark gray bark and aromatic foliage characteristic of the laurel family. The alternate, leathery, broadly elliptic to ovate leaves are 3 to 8 centimeters long with three prominent veins arising from near the base, dark green and glossy above, paler and finely pubescent beneath, and emit a pleasant warming aroma when crushed. Small dioecious yellow-green flowers are borne in dense axillary umbel-like clusters in early spring, with six tepals and (in male flowers) nine stamens. The fruits are small, ovoid black drupes about 6 to 8 millimeters long borne on red pedicels. The medicinal root is fusiform, often spindle-shaped with constrictions giving the so-called Wu Yao Zhu Ling (string-of-beads) appearance, externally grayish-brown, internally pale brown with concentric ring patterns, with a warm, fragrant, slightly bitter aroma. Native to central, southern, and eastern China, Taiwan, and adjacent parts of Southeast Asia.
Active Constituents
Linderane
Furan-containing lindenane sesquiterpenoidConcentration: 23.47 plus or minus 0.18 mg/g of the ethanol extract of the dried root; the extract represented about 9 percent of the raw root mass, so the figure in the whole root is substantially lower
Linderane is one of the two markers the 2020 Chinese Pharmacopoeia uses for quality control of this drug, so its presence is definitional. It is also the single most clinically important molecule in the herb, because its furan ring is bioactivated by cytochrome P450 to a furanoepoxide and a gamma-ketoenal that irreversibly inactivate CYP2C9.
Norisoboldine
Aporphine alkaloidConcentration: 50.34 plus or minus 4.27 mg/g of the ethanol extract of the dried root, the most abundant compound quantified
The second pharmacopoeial marker for the drug and the dominant alkaloid. It is anti-inflammatory in vivo, reducing paw swelling and arthritis scores in collagen-induced arthritis rats at 10 to 40 mg/kg through IL-6 and STAT3 signalling and a shift in the Th17 to Treg balance, and it inhibited nitric oxide production by about 68 percent in lipopolysaccharide-stimulated macrophages at 100 micromolar.
Isolinderalactone
Sesquiterpene lactoneConcentration: 10.45 plus or minus 0.88 mg/g of the ethanol extract of the dried root
The most cytotoxic of the well-studied constituents, active against ovarian, breast, lung, colorectal, pancreatic and glioma cell lines with IC50 values from about 5 to 51 micromolar, acting through apoptosis induction and STAT3 suppression. It also reduced macrophage nitric oxide production by about 88 percent at 100 micromolar. The cytotoxicity is a cell-culture finding and has not been tested clinically.
Boldine
Aporphine alkaloidConcentration: 6.53 plus or minus 0.24 mg/g of the ethanol extract of the dried root
A well-known aporphine alkaloid, also the principal alkaloid of boldo, present here as a minor companion to norisoboldine.
Higenamine
Benzyltetrahydroisoquinoline alkaloidConcentration: 0.39 plus or minus 0.02 mg/g of the ethanol extract of the dried root
Higenamine is a beta-2 adrenoceptor agonist and has been on the World Anti-Doping Agency Prohibited List since 2017, banned both in and out of competition. Its measured presence in this root means Wu Yao is a potential source of an adverse analytical finding for a tested athlete, and a potential source of adrenergic effects such as tachycardia in a susceptible patient. This is a small amount, but higenamine is potent and the compound is detected in urine at trace levels.
Lindenenol and lindenenyl acetate
Lindenane sesquiterpenoidsConcentration: 16.70 plus or minus 1.17 mg/g and 11.57 plus or minus 0.08 mg/g respectively, of the ethanol extract of the dried root
Two of the most abundant sesquiterpenoids after linderane. They are structurally close to linderane and contribute to the sesquiterpenoid character of the root, though their pharmacology is far less well defined.
Reticuline
Benzyltetrahydroisoquinoline alkaloidConcentration: 3.30 plus or minus 0.16 mg/g of the ethanol extract of the dried root
A benzylisoquinoline alkaloid and a biosynthetic relative of higenamine and the aporphines, quantified among the sixteen compounds measured in the root extract.
Methyllinderone and linderin B
Cyclopentenedione and related root constituentsBoth suppressed nitric oxide production by roughly 87 to 88 percent in lipopolysaccharide-stimulated RAW 264.7 macrophages at 100 micromolar, with docking suggesting hydrogen bonding and hydrophobic interaction with inducible nitric oxide synthase. They are minor constituents by mass but among the more potent anti-inflammatory compounds identified from the root.
⚠ Drug Interactions
CYP2C9 substrates (warfarin, phenytoin, tolbutamide and other sulfonylureas, celecoxib, losartan)
Linderane, a main furanosesquiterpenoid of this root and one of its pharmacopoeial markers, is a mechanism-based inactivator of CYP2C9. Inactivation was time-, concentration- and NADPH-dependent and irreversible, with a KI of 1.26 micromolar, a kinact of 0.0419 per minute and a partition ratio of about 227; more than half of CYP2C9 activity was lost after 15 minutes with 10 micromolar linderane. Glutathione, catalase and superoxide dismutase did not protect the enzyme, while the substrate diclofenac did, confirming the reaction happens in the active site. Two reactive intermediates were identified, a furanoepoxide and a gamma-ketoenal, and these covalently modify lysine and cysteine residues of the CYP2C9 apoprotein and also destroy the haem. In rats, pretreatment with 20 mg/kg linderane for 15 days measurably altered the pharmacokinetics of the CYP2C9-derived metabolites of both tolbutamide and warfarin. Because the inactivation is covalent, activity only returns as new enzyme is synthesised, so the effect outlasts the herb by days.
Clinical note: Treat this as the principal hazard of Wu Yao. Avoid it in patients on warfarin, phenytoin or a sulfonylurea, or monitor INR, phenytoin levels or blood glucose closely and continue monitoring for at least a week after the herb is stopped, since CYP2C9 activity does not recover immediately. Dose reductions made during herb use may need reversing afterwards.
Anti-doping testing in competitive athletes
Higenamine has been quantified in the root of this species at 0.39 mg/g of the ethanol extract, and higenamine is a beta-2 adrenoceptor agonist that the World Anti-Doping Agency added to its Prohibited List in 2017, prohibited at all times rather than only in competition. Unintentional ingestion from herbal products is a documented route to a positive test.
Clinical note: Do not prescribe Wu Yao to an athlete subject to anti-doping testing. Where a patient competes, check every formula for this herb and for other higenamine-containing drugs such as Fu Zi and lotus plumule.
Beta-blockers and beta-2 agonists (salbutamol, formoterol)
The higenamine content of the root gives it a measurable beta-2 adrenoceptor agonist constituent. The direction of effect is opposite to a beta-blocker and additive with a prescribed beta-2 agonist. The dose delivered by a decoction has not been characterised pharmacokinetically, so the size of the effect in a patient is unknown; the concern rests on the identity and receptor activity of the constituent, not on an observed clinical event.
Clinical note: Watch for palpitations or tremor in patients on beta-2 agonists, and be alert to unexplained loss of rate control in a patient on a beta-blocker who has started a Wu Yao containing formula.
Metformin, sulfonylureas and other antihyperglycaemic drugs
Antidiabetic sesquiterpenoids have been isolated from this root and Lindera aggregata extracts improve insulin sensitivity in animal models. Separately, if the herb is combined with a sulfonylurea, the CYP2C9 inactivation described above raises the sulfonylurea concentration, which is a second and larger route to hypoglycaemia. No human data exist for either pathway.
Clinical note: Advise blood glucose monitoring when the herb is added to an existing diabetic regimen, and treat the sulfonylurea combination as a CYP2C9 problem first rather than a pharmacodynamic one.
Other CYP substrates via reactive metabolite formation (CYP1A2, 2B6, 2C19, 2D6, 3A4, 3A5)
Multiple P450 enzymes, including CYP1A2, 2B6, 2C9, 2C19, 2D6, 3A4 and 3A5, participate in the metabolic activation of linderane to its reactive intermediates. Only CYP2C9 was shown to be inactivated by them; the involvement of the others in bioactivation does not by itself establish that they are inhibited. Recorded here so that the CYP2C9 finding is not over-generalised into a claim of broad P450 inhibition that the data do not support.
Clinical note: No specific action. Do not extrapolate the CYP2C9 interaction to CYP3A4 or CYP2D6 substrates without evidence.
Dosage
| Form | Amount | Frequency | Duration | Population | Notes |
|---|---|---|---|---|---|
| decoction | 6–10 g | Daily | — | — | 中国药典 2020 【用法与用量】6～10g。 【性味与归经】辛，温。归肺、脾、肾、膀胱经。 — 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.
Together they move qi and descend rebellion, relieving chest and abdominal fullness from qi counterflow due to emotional constraint.
Core pair of a classical formula — Si Mo Tang, Ji Sheng Fang (Yan Yonghe)
The pair moves qi and relieves pain through the chest, abdomen and lower burner.
Core pair of a classical formula — Qing Nang Wan, Han Shi Yi Tong (Han Mao)
The kidney is warmed and urine astringed while cold is dispersed from the bladder, reducing frequent urination and enuresis.
Core pair of a classical formula — Suo Quan Wan, Wei Shi Jia Cang Fang (also recorded in Fu Ren Liang Fang)
Evidence Tier
Moderate evidence · 5 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
0
Randomized controlled trial
0
Other clinical trial
0
Observational / case report
0
In vitro / animal
5
0 verified · 5 unverified
Show 5 studies
- Mechanism-based inactivation of CYP2C9 by linderane
- Drug-drug interactions induced by Linderane based on mechanism-based inactivation of CYP2C9 and the molecular mechanisms
- Characterization and quantification of the phytochemical constituents and anti-inflammatory properties of Lindera aggregata
- Lindera aggregata intervents adenine-induced chronic kidney disease by mediating metabolism and TGF-β/Smad signaling pathway
- Norisoboldine, a Natural Alkaloid from Lindera aggregata (Sims) Kosterm, Promotes Osteogenic Differentiation via S6K1 Signaling Pathway and Prevents Bone Loss in OVX Mice
Other / unclassified
0
Verified: design read from PubMed for a DOI that resolves to the cited paper Unverified: taken from the study's recorded description
Clinical Studies
Mechanism-based inactivation of CYP2C9 by linderane
Linderane caused time-, concentration- and NADPH-dependent irreversible inactivation of CYP2C9, with more than half the activity lost after 15 minutes at 10 micromolar, a kinact of 0.0419 per minute, a KI of 1.26 micromolar and a partition ratio of about 227. Glutathione, catalase and superoxide dismutase failed to protect the enzyme while the substrate diclofenac did, and a furanoepoxide and a gamma-ketoenal were confirmed by chemical synthesis as the reactive intermediates. CYPs 1A2, 2B6, 2C9, 2C19, 2D6, 3A4 and 3A5 were all involved in the bioactivation.
Drug-drug interactions induced by Linderane based on mechanism-based inactivation of CYP2C9 and the molecular mechanisms
Rats pretreated with linderane at 20 mg/kg for 15 days showed inhibited CYP2C9-mediated metabolism of both tolbutamide and warfarin: for 4-hydroxytolbutamide, Cmax fell, half-life lengthened and apparent volume of distribution rose, while for 7-hydroxywarfarin the AUC fell and apparent clearance rose, all significantly. The mechanism was confirmed as covalent modification of lysine and cysteine residues of the CYP2C9 apoprotein by furanoepoxide and gamma-ketoenal intermediates, with time- and dose-dependent adduct formation and significant loss of haem content. This is the in vivo confirmation that the in vitro CYP2C9 finding translates into altered handling of warfarin.
Characterization and quantification of the phytochemical constituents and anti-inflammatory properties of Lindera aggregata
Eighty compounds were identified in the ethanol extract of the dried root by UHPLC-HR-ESI-Q-Orbitrap and sixteen were quantified, giving the concentration data used throughout this record. In lipopolysaccharide-stimulated RAW 264.7 macrophages the extract, and norisoboldine, isolinderalactone, methyllinderone and linderin B individually, inhibited nitric oxide production and iNOS, TNF-alpha and IL-6 expression, with nitric oxide reductions of 68 to 88 percent at 100 micromolar. Values are per gram of extract, and the extract was 13.6 g from 150 g of raw herb, so root concentrations are roughly a tenth of the quoted figures.
Lindera aggregata intervents adenine-induced chronic kidney disease by mediating metabolism and TGF-β/Smad signaling pathway
Ethanol and water extracts of Lindera aggregata were given to rats with adenine-induced chronic kidney disease. Both significantly limited rises in serum creatinine, blood urea nitrogen, NGAL, urinary protein and kidney index, with some exceptions at the lower doses, and reduced renal pathology; metabolic profiling and an indoxyl-sulfate HK-2 cell model implicated TGF-beta and Smad signalling. The authors frame this as support for the classical use of the herb in the Suo Quan Wan tradition for kidney disorders, which corresponds to the warming the Kidneys function attributed to the drug. It is an animal model only.
Norisoboldine, a Natural Alkaloid from Lindera aggregata (Sims) Kosterm, Promotes Osteogenic Differentiation via S6K1 Signaling Pathway and Prevents Bone Loss in OVX Mice
Norisoboldine, the most abundant quantified constituent of the root, promoted osteogenic differentiation through S6K1 signalling and prevented bone loss in ovariectomised mice. This is a pharmacological property of an isolated constituent in an animal model and does not correspond to any classical indication for Wu Yao; it is recorded to keep constituent-level and drug-level claims separate.
Historical Texts
Ben Cao Shi Yi
Tang dynasty, 739, by Chen CangqiKai Bao Ben Cao
Northern Song dynasty, 973Ri Hua Zi Ben Cao
Five Dynasties to early SongBen Cao Gang Mu
Ming dynasty, 1596Ben Cao Tong Xuan
Ming dynasty, 17th centuryReferences
- Lv Y, Zou Y, Zhang X, Liu B, Peng X, Chu C. A review on the chemical constituents and pharmacological efficacies of Lindera aggregata (Sims) Kosterm . Frontiers in Nutrition (2023) [DOI]
- Hudzik TJ, Patel M, Brown A. β2-Adrenoceptor agonist activity of higenamine . Drug Testing and Analysis (2021) [DOI]
- Rangelov Kozhuharov V, Ivanov K, Ivanova S. Higenamine in Plants as a Source of Unintentional Doping . Plants (2022) [DOI]
- Li WX, Gan L, Liao YL, Wu YW, Zhang BH, Guo D, Li W. Linaggrenoids A−I, structurally diverse lindenane sesquiterpenoids with anti-hepatic fibrosis effects from Lindera aggregata . Phytochemistry (2025) [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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