Dong Quai health benefits

Dong Quai

In by Raphikammer

The root of dang gui (Angelica sinensis; also known as

dong quai; Fig. 1) is one of the primary botanicals used

in traditional Chinese medicine (TCM) for the treatment

of gynecological and circulatory conditions.

primary use is to both build and promote the movement

of blood, and on the basis of these actions it is utilized for

a myriad of conditions. Despite its widespread use among

practitioners of TCM, there have been few clinical studies

regarding its efficacy, although preclinical data support

many of these traditional uses as well as suggest benefit

for numerous other uses.

Traditional and Modern Uses Dang gui grows at high altitudes in comparatively cold,

damp, mountainous regions in China and other parts of

East Asia.

The plant is a fragrant perennial that has smooth

purplish stems and bears umbrella-shaped clusters (umbels)

of white flowers that grow to approximately 3 ft

in height. Dang gui produces winged fruits in July and

September. In the earliest known herbal text of China, the

Divine Husbandman’s Classic of the Materia Medica (Shen

Nong Ben Cao Jing), dang gui is described as a herb to

“supplement nature” (1). In the monumental 52-volume

Compendium of Materia Medica (Ben Cao Gang Mu), written

by Li Shizhen in the 16th century, dozens of uses for

dang gui were elaborated. These included the following:

to tonify the five major viscera, especially the heart; to generate

flesh; to stop headache, back pain, menstrual pain,

toothache, and pain associated with the “belt channel”

(dai mai); to treat a wide range of skin sores and rashes;

and to correct menstrual problems such as irregular menstruation,

amenorrhea, and dysmenorrhea (2).

Modern research has focused on the use of dang

gui for its ability to enhance circulation and oxygenation

in hypoxic conditions specifically in regard to brain and

cardiovascular effects. Despite the widespread popularity

and use of dang gui in gynecology, there is a lack of

research in modern English language journals regarding

this use, though some data suggest estrogenic and both

uterine relaxant and uterine stimulatory activity, depending

on the fraction studied. A number of studies report

on the ability of dang gui to promote the healing of tissues,

specifically in ulcerative colitis and gastric ulcers,

and other studies have focused on its anticancer and hepatoprotective

effects, among others.

Chemistry and Preparation of Products

The primary analytes of interest in dang gui are the Zalkylphthalides,

most notably ligustilide (Fig. 2), low- and

high-molecular-weight polysaccharides, and ferulic acid

(Fig. 2). The alkylphthalides are present in the essential

oil and are strongly aromatic. Both the crude extract and

individual compounds have been correlated with biological

activity (see preclinical studies; clinical studies). The

crude extract has been associated with positive human

clinical effects for the treatment of chronic obstructive pulmonary

disease (COPD) and COPD with hypertension,

increasing blood volume in postischemic patients, and

decreasing platelet aggregation (3). The alkylphthalides

and ferulic acid inhibit platelet aggregation and the formation

of platelet thromboxane A2 (4–6) and elicit in vitro

spasmolytic activity, increase coronary blood flow, slightly

decrease myocardial contractility, and markedly prolong

the effective refractory period (7). Total extracts have also

been associated with hepatoprotective effects. Thus dang

gui is utilized in portal hypertension and veno-occlusive

disease. At least part of this activity is associated with

the demonstrated antioxidant activity of ligustilide, ferulic

acid, and polysaccharides (8–10), as well as the ability

of dang gui to promote hepatic microcirculation. In human

clinical trials both an aqueous extract and ligustilide have

been found to be effective in treating dysmenorrhea (11).

Dang gui polysaccharides stimulate hematopoiesis and,

along with ferulic acid, elicit immunomodulatory activity

(e.g., increased phagocytosis) (12,13). Ligustilide and ferulic

acid elicit a strong uterine spasmolytic effect (14–17).

All of these actions are consistent with the use of dang gui

in traditional Chinese medicine.

Investigations of polysaccharides derived from

dang gui, specifically in conjunction with their potential

immunomodulatory effects have been conducted. The

polysaccharides, named A. sinensis polysaccharide fractions

(APF 1,APF2,APF3) and crude angelica polysaccharide

consist of rhamnose, galacturonic acid, glucose, galactose,

mannose, and arabinose in various ratios (18,19).

In TCM, the roots of dang gui are commonly prepared

as a tea, extract, syrup, tablet, or capsule. In supplement

form, dang gui occurs predominantly in tablets

and capsules, and occasionally in tinctures. As with the

majority of Chinese herbs, dang gui is most often used in

combination with other botanicals and is predominantly

featured in formulas for promoting healthy gynecological

and cardiovascular systems and for a healthy liver.

Different portions of the roots are used for different indications.

The whole roots are said to “harmonize” the

Whole dang gui (Angelica sinensis) roots.

blood; the dang gui root bodies (dang gui tou; ) are

used to build and nourish the blood and are commonly

included in soups for convalescence and blood deficiency;

the tails (dang gui wei; ) are predominantly used to

“break the blood” and prevent and treat abnormal blood

stagnation.

Pharmacokinetics

There are limited data on the pharmacokinetics of some

of the compounds contained within dang gui. In a study

of the bioavailability of ferulic acid in humans (n = 5), the

peak time for maximal urinary excretion of ferulic acid

following the consumption of 360 to 728 g tomatoes (providing

approximately 21 to 44 mg ferulic acid) was 7 to

9 hours (20). A considerable proportion of ferulic acid was

excreted as glucuronide in all subjects. The recovery of

ferulic acid in the urine, on the basis of total free ferulic

acid and feruloyl glucuronide excreted, was 11% to 25% of

that ingested. The bioavailability of ferulic acid from beer

is consistent with the uptake of ferulic acid from other

dietary sources, such as tomatoes (21). Urinary and biliary

metabolites of ferulic acid were primarily glucuronic

acid and glycine conjugates of ferulic acid and vanillic

acid. Major constituents of dang gui.

model and suggest that ferulic acid is rapidly and almost

completely absorbed from the intestinal tract (23). It has

also been reported that ferulic acid crosses the blood–brain

barrier, although in very low concentrations (24). The major

metabolites of ferulic acid are nontoxic and water soluble,

being excreted through the urine and bile as free acids

and acid conjugates.

PRECLINICAL STUDIES

Pharmacodynamics

Dang gui is one of the most widely used of all Chinese

botanicals. Historically and in modern Chinese medicine,

it has been primarily used as a general blood tonic for the

TCM diagnosis of blood deficiency, a syndrome closely

related, but not exactly analogous or limited, to anemia.

Dang gui has also been used for a myriad of gynecological

indications, although there has been very little research

done in this regard in English language journals. More

recently, pharmacological research has focused on the potential

of constituents of dang gui to elicit cardiovascular,

hematopoietic, hepatoprotective, antioxidant, antispasmodic,

and immunomodulatory effects. Chinese botanicals

are most often used in multi-ingredient formulas

rather than as single agents. Therefore, there are very few

clinical trials on dang gui alone, although numerous preclinical

studies exist. Due to the lack of primary English

language literature, it is difficult to adequately access or

adequately review the available data by non-Chinese language

readers. Another difficulty in reviewing the available

studies is that many of the investigations are of disease

patterns that are unique to TCM and do not have

well-defined corresponding Western diagnoses, or viceversa;

studies are conducted for indications not synonymous

with TCM indications. While the TCM findings are

relevant to TCM practitioners, their importance may be ignored

or even criticized by non-TCM practitioners. Study

of non-TCM indications often is conducted for purposes

of modern drug discovery and therefore can be criticized

on different grounds. Lastly, it has been reported that up

to 99% of studies presented in the Chinese medical literature

show results favoring test intervention, suggesting

the potential for a positive publication bias and hence the

need for caution in interpreting the available data (25).

Conversely, publication bias against dietary supplement

research in the primary medical literature of the United

States has been reported and may similarly limit a critical

review of investigations of herbal products (26).

The bioactive compounds most studied in dang gui

are phthalides, polysaccharides, and ferulic acid. Studies

using these compounds have reported a number of therapeutic

effects, some of which are consistent with the use

of dang gui in TCM and some of which are not. The contribution

of ferulic acid to the therapeutic effect of dang

gui is unlikely given its low concentration in crude dang

gui (0.05–0.09%). The compounds used in pharmacological

studies are often administered at doses exceeding those

available from typical dosages of dang gui root preparations.

While these data are presented, it is not possible to

extrapolate results from such studies to clinical efficacy

of orally administered crude drug products; hence, the

reported findings must be evaluated critically.

Cardiovascular and Hemorheological Effects

Clinically, dang gui is widely used for the treatment of cardiovascular

disease, specifically conditions that can benefit

from enhanced circulation and a decrease in platelet

aggregation. Preclinical studies using dang gui and some

of its constituents suggest actions and mechanisms by

which it may exert a cardiovascular effect. These include

stimulation of circulation, platelet aggregation inhibition,

decrease in myocardial oxygen consumption, and vasorelaxation

(measured as a decrease in vascular resistance;

see also effects on smooth muscle).

A number of animal studies and in vitro assays support

some of the putative cardiovascular effects of dang

gui. These include an increase in myocardial perfusion,

decrease in myocardial oxygen consumption, increase in

blood flow, decrease in vascular resistance, and inhibition

of platelet aggregation, ventricular fibrillation, and

arrhythmias (3). However, a direct extrapolation of these

findings to humans cannot be made without confirmatory

human studies. A review of the activity of sodium ferulate

reported that it both inhibits platelet aggregation and

elicits a thrombolytic activity in vitro and in vivo. These effects

were due to inhibition of cyclooxygenase and thromboxane

A2 synthase with improvements in blood viscosity,

reduction in the concentration of plasma fibrinogen,

and increase in coronary perfusion. Additional cardiovascular

effects reported include reduction of cholesterol

biosynthesis and lowering of triglycerides, improvements

in myocardial oxygen consumption, and antiarrhythmic,

antioxidant, and antiatherogenic activity (24).

Hepatoprotective Effects

A number of preclinical studies indicate that dang gui,

dang gui polysaccharides, ferulic acid, and sodium ferulate

have antioxidant effects that can protect the liver

against damage due to chemically induced toxicity. Part

of this action is due to the ability of dang gui polysaccharides

to reduce the levels of nitric oxide (24.6%), serum

alanine aminotransferase (40.8%), and serum glutathione

S-transferase (18.4%) in animals with acetaminophen induced

or carbon tetrachloride-induced liver damage

(8,9,27,28).

Gynecological Effects

Dang gui is one of the most important herbal medicines in

TCM for the treatment of menstrual disorders, especially

when used in combination with other botanicals. It has

traditionally been used to treat conditions associated with

the TCM diagnosis of “blood stasis” and “blood vacuity,”

which can be correlated with Western syndromes such

as amenorrhea, dysmenorrhea, endometriosis, uterine fibroids,

and certain forms of infertility. Its efficacy appears

to have been demonstrated over the 750-year history of its

use for these indications and its continued, and apparent,

successful use by modern practitioners of TCM. However,

there are few studies substantiating these effects (11,29),

and those that are available lack methodological rigor.

Using ELISA-type immunoassays of two steroidregulated

proteins, presenelin-2 and prostate-specific antigen,

in breast carcinoma cell line BT-474, researchers reported

that dang gui extract showed “weak” estrogen and

androgen antagonistic effects of 50% and 71% blocking activity,

respectively, and no progestational activity (29). In

contrast to these findings, another group of researchers

found no estrogen receptor binding, cell proliferation, or

progestin activity of an aqueous-ethanol extract of dang

gui (30).

A study of ovariectomized rats showed that an extract

of dang gui (300 mg/kg SC; 1% ligustilide) resulted

in a thickening of the luminal epithelium suggesting a

estrogenic activity, but one much lower than comparison

with estradiol. The extract also suppressed luteinizing

hormone secretion. The researchers considered ligustilide

to be the active compound on the basis of previous in vitro

research they conducted (31). Several preclinical studies

have investigated the estrogenicity of dang gui or ferulic

acid, with mixed, but largely negative, results. Some in

vitro assays have reported that dang gui extract exhibited

a significant dose-dependent inhibition of estrogen receptor

binding, indicating that it competed with estradiol

for receptor sites (32). In the same study, dang gui extract

dose-dependently induced reporter gene expression in

estrogen-sensitive rat uterine leiomyoma cells, suggesting

a potentially proliferative effect on these cells. However,

when tested in conjunction with the maximum stimulatory

dose of estradiol, the extract inhibited estradiolinduced

reporter gene expression, suggesting the possibility

that dang gui may act as an estrogen antagonist when

in the presence of physiological levels of estradiol. Another

group of researchers reported similar findings (33).

Effects on Smooth Muscle

Dang gui and its constituents have been shown to relax

the smooth muscle tissue of the vascular system, trachea,

intestines, and uterus. The spasmolytic effects of dang

gui on trachea and uterine tissues are consistent with

TCM indications. While the mechanism of the relaxant

action has not been fully elucidated, preclinical studies

suggest that it may be due, in part, to histamine receptor

blocking activity, calcium ion channel effects, or modulation

of cholinergic receptors. Both relaxing and stimulating

effects on uterine tissue have been reported, with

various constituents eliciting different actions. The therapeutic

relevance of in vitro findings to humans is unknown

given the lack of clinical evidence. Ex vivo studies

demonstrate that ligustilide and butylidenephthalide

isolated from the volatile oil of dang gui exhibit a strong

spasmolytic effect on isolated uteri (34,35). Ligustilide was

shown to relax early pregnant and nonpregnant uteri of

experimental animals (34). Ligustilide and butylidenephthalide

showed an inhibitory effect on prostaglandin F2-,

oxytocin-, or acetylcholine-induced contraction of nonpregnant

rat uteri (14,36). This could explain the spasmolytic

effect of the volatile oil. Other studies indicated

that the observed spasmolytic effect may be due to an

effect on calcium channels (14,37). Three of the available

studies reviewed found that ferulic acid elicited a uterine

spasmolytic effect. At oral doses of 300 to 1000 mg/kg

and IV doses of 30 to 300 mg/kg, ferulic acid inhibited

spontaneous uterine contraction in rats (16,17). The inhibitory

effect of IV ferulic acid was not blocked by either

propranolol or by cimetidine and it strongly inhibited the

uterine contraction induced by oxytocin (0.3 unit/kg), but

not that induced by acetylcholine (0.1 mg/kg) or serotonin

(10 g/kg). It was suggested that the uterine relaxant effect

of ferulic acid is partially due to the oxytocin receptor

system rather than its inhibitory effect on prostaglandin

biosynthesis (38). Another study, however, suggested that

ferulic acid may not be responsible for the spasmolytic

effect of dang gui, since its content in raw material is low

(approximately 0.03% to 0.06%) (39).

Hematopoietic Effects

One of the traditional applications of dang gui in TCM

is its use in the treatment of “blood vacuity,” which

closely, but not completely, corresponds to aWestern medical

diagnosis of anemia. Limited clinical and preclinical

data support this use. One proposed mechanism of action

is its reported effect in stimulating hematopoiesis.

These actions appear to be primarily associated with the

polysaccharide fraction (13,40). One study demonstrated

the hematopoietic effects to at least partially be associated

with proliferation of bone marrow mononuclear cells

through signal transduction pathways (e.g., MAPK/ERK

pathway) (41).

Antioxidant Effects

There have been numerous studies demonstrating an antioxidant

effect of dang gui and its constituents. Much of

these have focused on the antioxidant activity of ferulic

acid, which is well known for its ability to prevent lipid

peroxidation, inhibit superoxide anion radical formation,

scavenge free radicals, and protect against radiation damage

(42–44). Dang gui contains only trace amounts of ferulic

acid, so these in vitro findings cannot be extrapolated

to the use of crude dang gui preparations. There are, however,

animal studies showing that dang gui polysaccharides

have a protective effect against chemically induced

ulcerative colitis and inflammation. In one study, dang

gui polysaccharides elicited anti-inflammatory effects in

the gastrointestinal mucosa through inhibition of neutrophil

infiltration in the stomach (45). In another study,

dang gui polysaccharides (5 mg and 10 mg/mL in drinking

water) attenuated colonic lesions caused by oxidative

damage induced by 2,4-dinitrobenzene sulfonic acid in

rats in a dose-dependent manner. This action was associated

with a preservation of endogenous glutathione levels.

Other studies reported tissue-healing effects of dang

gui to be associated with ornithine carboxylase activity,

c-Myc protein expression, and epidermal growth factormediated

pathway (27,46). A follow-up study by the same

group of researchers showed that crude extract of dang gui

(50 mg/kg PO) significantly accelerated the healing of gastric

ulcers in animals and showed an anti-angiogenic activity

and a quicker restoration of mucosal synthesis and

mucosal cell proliferation (47).

Studies suggest that the antioxidant activity of dang

gui may reduce ischemia–reperfusion induced injury

(48,49), ameliorate cognitive dysfunction associated with

postischemic brain damage (49), and inhibit the damage

associated with aggregation of amyloid- peptide, suggesting

a possible use of dang gui in Alzheimer’s. These

effects were reported to be correlated with both ferulic

acid and Z-ligustilide (50).

Other studies show that dang gui provides antioxidant

protection against free radical induction of rat

adrenal medulla (PC12) cell lines (51) and suppressed

radiation-induced expression of tumor necrosis factor-

and tumor growth factor–1 (52), and prevented

doxorubicin-induced cardiotoxicity, without decreasing

the antitumor activity of the drug (53).

Wound-Healing Effects

In addition to the beneficial effects of dang gui’s

antioxidant activity on tissues noted earlier, specific

wound-healing properties have been reported. One

group of researchers found that a crude extract of dang

gui (characterization and dosage not available) significantly

accelerated epithelial cell proliferation in wounds

(27,46,54). The activity was reportedly associated with an

increase in DNA synthesis and epidermal growth factor

mRNA expression. The same researchers observed direct

wound-healing effects of dang gui crude extract, with

activity associated with increased ornithine carboxylase

activity and increased c-Myc expression. Another study

found that dang gui prevented bleomycin-induced acute

injury to rat lungs. Alveolitis and the production of malondialdehyde

were all reduced (P < 0.01 or P < 0.001), suggesting

immunomodulatory and antioxidant effects (55).

Immunomodulatory Effects and Potential

Anticancer Activity

Limited animal and in vitro studies have reported on

specific immunomodulatory effects of dang gui, including

stimulation of phagocytic activity and interleukin-2

production, and an anti-inflammatory effect. There is evidence

to suggest that the polysaccharide fraction of dang

gui may contribute to these effects. However, there is no

clinical evidence supporting these effects, and there appears

to be no direct correlation betweenTCMuse of dang

gui and immunomodulatory activity (56–58).

A new direction in investigation of the use of dang

gui is for its potential anticancer activity. Ligustilide has

been shown to have direct cytotoxic activity against several

human and animal cell lines (59–61). In the absence of

clinical and directly applicable toxicological investigation,

little emphasis should be placed on these in vitro findings.

There have, however, been a number of animal studies

suggesting immunomodulatory and anticancer activity.

In one study, n-butylidenephthalide suppressed growth

of subcutaneous rat and human brain tumors, reduced

tumor volume, and significantly prolonged survival in

treated rats. This activity was reported to be due to an

induction of cell cycle arrest and apoptosis (62). Polysaccharides

have similarly been shown to inhibit growth of

murine tumors (S180, EAC, L1210) in vivo, resulting in a

prolonged survival of treated animals. In vitro, dang gui

polysaccharides were shown to inhibit the metastasis of

human hepatocellular cancer cell lines (63).

A variety of immunomodulatory activities have

been reported for dang gui polysaccharides, including

enhanced macrophage and T cell numbers, increased

production of interleukin and interferon, improved

CD4/CD8 ratios, and a general regulation of Th1- and

Th2-related cytokines (18). Other actions reported for

polysaccharides include release of nitric oxide from

peritoneal macrophages and enhanced cellular lysosomal

enzyme activity (64,65).

Effects on Bone Cells

Dang gui is traditionally used in formulas for bone

and tendon injuries. A recent study investigated the

212 Upton

pharmacology behind this indication by testing the in

vitro effects of a 1% aqueous extract of dang gui on human

osteoprecursor cells. Cells were incubated for five

days in medium with (12.5–1000 g/mL) and without

the extract. Compared to untreated control cell cultures,

cell proliferation was enhanced at extract concentrations

less than 125 g/mL (P < 0.05), whereas it was inhibited

at concentrations greater than 250 g/mL (P < 0.05

at 1 mg/mL). Protein secretion in osteoprecursor cells

and type-I collagen synthesis were significantly increased

(P < 0.05) (66).

dong quai CLINICAL STUDIES

The clinical data regarding the use of dang gui alone are

scarce and of poor methodological quality.

Cardiovascular and Hemorheological Effects

One study reported that 0.08 g/day/IV of sodium ferulate

relieved symptoms of angina pectoris after three

to seven days of treatment (24). Limited clinical studies

have investigated the use of dang gui for the treatment

of patients with acute ischemic stroke or COPD with pulmonary

hypertension. Results provide fairly weak evidence

that dang gui exerts hypotensive and cardioprotective

effects. In general, the study design of the available

reports was poor and the patient populations extremely

limited.

One study looked at the effects of dang gui in 60

patients with COPD (67). In the dang gui group, levels of

blood endothelin-1, angiotensin II, endogenous digitalislike

factor, mean pulmonary arterial pressure, and pulmonary

vascular resistance were decreased significantly

(P < 0.05 or P < 0.01) compared to those in the controls

(20 °æ 6%, 36 °æ 9%, 38 °æ 11%, 17 °æ 5%, and 27 °æ 8%,

respectively). Another study showed that dang gui decreased

the mean pulmonary arterial pressure in patients

with COPD without changing blood pressure and heart

rate, suggesting a vasodilatory effect on pulmonary vessels

without effect on systemic circulation (3).

In another study, it was suggested that dang gui

and dextran exhibited positive effects on neurological and

hemorheological symptoms in patients recovering from

stroke (68). However, no control group was included,

and so any claimed effects are questionable. Other clinical

studies with very small numbers of patients (11,69)

have reported on an ability of dang gui to decrease blood

viscosity, an effect consistent with its traditional use. While

this effect may be real, the mechanisms by which this may

occur and the constituents involved have not been well

articulated.

Hepatoprotective Effects

There is some evidence to suggest that dang gui and its

constituents can decrease portal hypertension in patients

with liver cirrhosis without affecting systemic hemodynamics.

This use is consistent with the traditional actions

of dang gui in improving circulation, because portal hypertension

is thought to be due to the obstruction of hepatic

microcirculation (70,71).

Hormonal Effects and Effects on Menopausal Symptoms

Because of the putative effects of dang gui in gynecological

imbalances, various studies have investigated its

potential for eliciting hormonal effects. In one human

study (72), one of the few double-blind, placebo-controlled

trials with dang gui, no statistically significant differences

in endometrial thickness, vaginal cell maturation, or

menopausal symptoms were observed between subjects

taking dang gui and those taking placebo. This contrasts

with a study of ovariectomized rats which showed that an

extract of dang gui (300 mg/kg SC;1%ligustilide) resulted

in a thickening of the luminal epithelium suggesting estrogenic

activity, but one much lower than comparison with

estradiol (see gynecological effects).

Analgesic Effects

Two uncontrolled clinical trials were found that addressed

the traditional Chinese use of dang gui as an analgesic for

pain due to “blood stasis”; both used injectable preparations.

In one, an ethanol extract was administered (intramuscularly)

on alternate days for a total of 20 doses into

the pterygoideus externus of 50 patients with temporomandibular

joint syndrome. A 90% cure rate was claimed

(73). Thirty cases of refractory interspinal ligament injury

were treated by local injection of 2 mL of 5% or 10% dang

gui twice weekly for two to three weeks. Twenty-four

(80%) of these patients reported a disappearance of pain,

no tenderness, and the ability to work as usual; four (13%)

patients reported alleviation of pain; two (7%) reported

no improvement (74). These uses are consistent with the

traditional use of dang gui in TCM. However, the effects

of injectable preparations cannot be extrapolated to oral

use of dang gui.

Dosages

Crude herb: 6 to 12 g daily to be prepared as a decoction.

Fluid extract (1:1): 3 to 5 mL three times daily (75).

SAFETY PROFILE

Side Effects

On the basis of a review of the available traditional and

scientific data, dang gui is a very safe herb with a low

probability of side effects when used within its normal

dosage range. One review article that claimed to cover

200 reports on dang gui pharmacology stated that dang

gui had no major side effects (35). Individual case reports

regarding the potential of dang gui to promote bleeding

have been prepared.

Contraindications

On the basis of a review of the available literature and the

experience of practitioners, dang gui is contraindicated

prior to surgery and, generally speaking, in those with

bleeding disorders.

Precautions

Precautions regarding the use of dang gui and other botanicals

used in traditional systems of medicine must be differentiated

between those recognized in the scientific literature

and those recognized traditionally. There is evidence

suggesting an anticoagulant effect for dang gui, and there

Dong Quai 213

are two published reports on its ability to enhance the

effects of chronic treatment with warfarin (see interactions).

A few unpublished case reports suggest that high

doses or chronic administration of dang gui alone during

pregnancy may be associated with miscarriage. There are

also anecdotal reports of administration of dang gui alone

causing increased blood flow during menses (R.U., personal

communication). Therefore, patients should consult

with a qualified health care professional prior to using

dang gui if they have bleeding disorders, are using anticoagulant

medications, or wish to use it during menses

or in the first trimester of pregnancy. It must, however, be

noted that in TCM, dang gui is specifically indicated for

certain bleeding disorders that are due to an underlying

diagnosis of blood stasis and in certain cases of threatened

miscarriage. For such uses, dang gui must be used according

to TCM principles under the guidance of a qualified

TCM practitioner.

Interactions

Two reports are available suggesting that dang gui can enhance

the effects of the anticoagulant warfarin. According

to one of these, a 46-year-old woman with atrial fibrillation

who had been stabilized on warfarin for almost two

years (5 mg daily) consumed a dang gui product concurrently

for four weeks (565–1130 mg daily). She experienced

a greater than twofold elevation in prothrombin

time (from 16.2 to 27 sec) and international normalized

ratio (from 2.3 to 4.9). No other cause for this increase

could be determined. Within one month of discontinuing

dang gui use, coagulation values returned to acceptable

levels (76).

Ananimal study investigated the interaction of dang

gui and a single dose or a steady-state dose of warfarin

(77). Six rabbits were administered a single dose of warfarin

(2 mg/kg SC). Seven days later, the same animals

were given an aqueous extract of dang gui (2 g/kg PO,

twice of a 2 g/mL extract daily) for three days, after which

they were again given a single dose of warfarin. Plasma

warfarin concentrations were measured at intervals up to

72 hour after each warfarin dose, and prothrombin time

was measured daily during dang gui treatment and after

the warfarin doses. Mean prothrombin time did not

change significantly during the dang gui treatment period.

However, when measured after coadministration of dang

gui and warfarin, prothrombin time was significantly lowered

at 24, 36, and 48 hours compared to that with warfarin

treatment alone (P < 0.05 or P < 0.01). No significant

variations in the single dose pharmacokinetic parameters

of warfarin were observed after treatment with

dang gui. Hence, the mechanism of decrease in prothrombin

time could not be correlated to the pharmacokinetics

of warfarin. Another group of six rabbits was given 0.6

mg/kg of warfarin SC daily for seven days; a steadystate

plasma concentration was achieved after day 4. On

days 4, 5, and 6, the rabbits were treated as above with

dang gui. Mean prothrombin time was again significantly

increased after coadministration with dang gui and two

rabbits died at days 6 and 7 after the dang gui treatment

had begun. Plasma warfarin levels did not change after

dang gui treatment. The authors suggested that these results

indicate that precautionary advice should be given

to patients who medicate with dang gui or its products

while on chronic treatment with warfarin. Another

study reported that dang gui acted synergistically with

aspirin (24).

General enhancement of cytochrome P450 isoforms

has been reported for both water (CYP2D6 AND 3A)

and ethanol extracts (CYP2D6) of dang gui in animal

models (78).

One study reported that dang gui might enhance

the antitumor effect of cyclophosphamide in mice with

transplanted tumors (79).

Pregnancy, Mutagenicity, and Reproductive Toxicity

Because of its blood-moving properties, dang gui should

be used in pregnancy only under the supervised care of

a qualified health professional. According to TCM practice,

dang gui is used in combination with other herbs in

various stages of pregnancy (29). Formula traditionally

used in pregnancy are prescribed within the context of

specific diagnoses in which the use of dang gui in pregnancy

is clearly indicated. In the West, dang gui is often

used alone out of this traditional medical context. Because

of this, several Western sources consider dang gui to be

contraindicated in pregnancy. Data regarding the effect of

dang gui preparations on the fetus are lacking.

Lactation

There are three unpublished case reports of a rash in infants

of lactating mothers who were taking dang gui. The

rashes reportedly resolved upon discontinuation of the

preparation by the mother. Specific details regarding

the preparations used were lacking (Romm, August 1,

2002, oral communication to AHP). Dang gui is a member

of the botanical family Apiaceae, a group of plants that

contain many types of photoreactive compounds known

to cause rashes.

Carcinogenicity

Data regarding the effects of dang gui in relationship to

carcinogenicity are mixed with both tumorigenic and antitumorigenic

activity reported. Antitumor activity due to

an induction of cell cycle arrest and apoptosis has been

reported for ligustilide (62). Polysaccharides have been

shown to inhibit growth of murine tumors (S180, EAC,

L1210) in vivo. This was accompanied by a prolonged

survival of animals and an inhibition of metastasis in vitro

(63). Another animal study identified a possible antitumor

effect of dang gui applied to mice with Ehrlich ascites tumors

(80). Regarding the potential effects of dang gui on

estrogen-positive tumors the data are mixed. One in vitro

assay found that dang gui stimulated the growth of MCF-

7 breast cancer cell lines 16-fold, with no measurable effect

on estrogen receptors (81), while another found a possible

antitumor effect in T-47D and MCF-7 cell lines (82). Data

regarding the potential estrogenic effects of dang gui have

been mixed.

Influence on Driving

On the basis of the experience of modern herbal practitioners,

no negative effects are to be expected.

Overdose

On the basis of the available literature, its use as a “food”

ingredient in soups, and the experience of modern herbal

practitioners, dang gui appears to be safe when used at

recommended doses.

Treatment of Overdose

No data available.

Toxicology

The following lethal dose (LD50) values have been reported

for dang gui extract (8:1 or 16:1), 100 g/kg PO in

rats (83,84); dang gui aqueous extract, 100 g/kg IV in mice

(85); dang gui 50% ethanol extract, greater than 40 g/kg

PO in mice (86); dang gui total acids, 1.05°æ0.49 g/kg IP in

mice (87). The LD50 of ferulic acid IV in mice was reported

to be 856.6 mg/kg, (16) and that of ligustilide, approximately

410 mg/kg IP (88). In a review of the toxicology

literature on dang gui, it was reported that IV injection

of the volatile fraction of dang gui could cause kidney

degeneration (76).

REGULATORY STATUS

Regulated as a dietary supplement (USC 1994).

CONCLUSIONS

Dang gui is one of the most important herbal drugs in

TCM, primarily being used for blood tonification and the

treatment of gynecological disorders. More recently, interest

has focused on dang gui’s possible cardiovascular, hepatoprotective,

hematopoietic, antioxidant, antispasmodic,

and immunomodulatory effects. Despite its long tradition

of use and current widespread clinical utility, there has

been very little clinical work verifying the therapeutic efficacy

of dang gui when used alone, primarily due to the

fact that in TCM, botanicals are generally used in combinations

rather than as single agents.

On the basis of the literature available and keeping

many of its limitations for an English readership in

mind, there is limited clinical support for the use of dang

gui alone for the following indications: pulmonary artery

and portal hypertension, acute ischemic stroke, dysmenorrhea,

infertility, and pain due to injury or trauma. The

use of dang gui for most of these indications is consistent

with TCM. One trial on menopausal symptoms found no

effect of dang gui on hormonal activity. Most of the trials

available are of poor methodological quality.

Clinical and preclinical studies provide some

support for a wide variety of actions of dang gui.

These include the promotion of circulation, vasodilation/

relaxation, and the inhibition of platelet aggregation,

all of which are consistent with the “blood quickening”

properties ascribed to dang gui in TCM. Similarly, the

hematopoietic effect of dang gui is consistent with its use

in TCM to “nourish blood.” Its smooth muscle (uterus,

vessels, trachea) relaxant effects are consistent with its use

for dysmenorrhea, asthma, and coughing. Dang gui may

relax or stimulate the uterus depending on a variety of

factors. In general, the volatile oil fraction appears to be

a uterine relaxant, while the nonvolatile constituents appear

to stimulate contractions. There is some support for

the traditional use of dang gui as an analgesic and vulnerary.

The radiation protective effect of dang gui in animals

is most likely due to its antioxidant activity. Assays for an

estrogenic effect of dang gui have had mixed, but largely

negative, results. The relevance of many of these actions

to the therapeutic use of dang gui in humans has not yet

been demonstrated.