Warfarin overdose due to the possible effects of Lycium barbarum L.
H. Leunga,*, A. Hungb, A.C.F. Huia, T.Y.K. Chana
aDepartment of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong
bMatilda International Hospital, 41 Mount Kellett Road, The Peak, Hong Kong
Received 6 August 2007; accepted 7 January 2008
We reported an 80-year-old Chinese woman on chronic stable dose of warfarin who experienced two episodes of an elevated inter-
national normalized ratio (INR) after drinking herbal tea containing Lycium barbarum L. Our case illustrated the potential herbal-drug
interaction between warfarin and L. barbarum L. in keeping with a previous case report. Enquiry about herbal intake may be a crucial
part in the management of anticoagulation in this locality.
? 2008 Elsevier Ltd. All rights reserved.
Keywords: Warfarin; Lycium barbarum L.
Warfarin has been used for many decades as an
anticoagulant and it serves an important place in the
management of thromboembolism in the hospital and
community. However, warfarin is also infamous for its
drug interaction due to its metabolism by the cytochrome
P450 (CYP). Its narrow therapeutic index and route of
metabolism makes it one of the most intensely investigated
drugs. More research nowadays targets the investigation of
herb–drug interaction as the public in many societies has
free access to herbal medication such as the Chinese com-
munity. The co-administration of both western and tradi-
tional herbal medicine can pose a significant risk if not
being monitored closely.
Some herbal products have confirmed interactions with
warfarin, such as the St. John’s wort (Hypericum) (Maurer
et al., 1999). Moreover some notable interactions are found
to occur between warfarin and several herbs used in tradi-
tional Chinese medicine, such as dong quai (Page and Law-
rence, 1999), dan shen (Salvia miltoiorrhiza) (Makina et al.,
2002), garlic (Allium sativum) and ginko (Vaes and Chyka,
We performed a Medline search which identified one
article describing a case of possible interaction between
warfarin and Lycium barbarum L. (Lam et al., 2001). We
reported the second possible case which took place in Hong
2. Case report
An 80 year-old Chinese woman with a history of diabe-
tes mellitus, hypertension, cerebrovascular accident in 1999
and atrial fibrillation was followed up in our clinic on the
following medications: nifedipine 40 mg bd, glibenclamide
5 mg bd, metformin 500 mg bd, lorazepam 0.5 mg nocte
and a titrated dose of warfarin. When she participated in
a clinical study in November 2004, she was randomized
into irbesartan 150 mg daily or placebo and continued on
open-label warfarin. As part of the research study protocol,
the patient attended our clinic on a frequent basis and
given monthly INR monitoring. The patient did not smoke
Between November 2004 and April 2005, the patient
only received two warfarin dosage manoeuvres of small
magnitude. The patient had maintained the INR between
0278-6915/$ - see front matter ? 2008 Elsevier Ltd. All rights reserved.
*Corresponding author. Tel.: +852 6072 2110; fax: +852 3524 2435.
E-mail address: firstname.lastname@example.org (H. Leung).
Available online at www.sciencedirect.com
Food and Chemical Toxicology 46 (2008) 1860–1862
2.05 and 3.56 on a weekly warfarin dosage between 15.5 mg
and 16 mg. (The weekly dosage would be 15.5 mg if during
a typical week the patient took 2 mg on a sunday, 2.5 mg
on a monday, ending in 2 mg on a saturday for that week.
The weekly dosage would be 16 mg if the patient took
2.5 mg on a sunday, 2 mg on a monday and ending in
2.5 mg on a saturday for that week.) On 3rd May 2005,
the INR suddenly went up to 4.97. The patient reported
having consumed concentrated herbal tea containing L.
barbarum L. for 2 days. The dose of the herbs being decoct-
ed and consumed was higher during the first day of intake
(3 cups per day, estimated at 30 g) than on the second day
(2 cups per day, estimated at 20 g). In the wake of this, the
warfarin was withheld for 2 days and restarted at a reduced
dose of 2 mg daily, with an adjusted weekly dose of 14 mg.
The INR was then stabilized for nearly 2 months. On 7th
July 2005, the INR went up yet again to 3.86 and this time
the patient also reported consuming the herbal tea contain-
ing L. barbarum L. for one day prior to blood taking. The
dose of the herbs being decocted and consumed was 4 cups
per day (estimated at 40 g).
The warfarin was once again withheld for 2 days and
restarted at 2 mg daily (the weekly dose remained at
14 mg) (Graph 1). The patient was asked to refrain from
the herbal tea and the INR remained stable for the next
6 months without any warfarin dosage adjustment. During
all these times, the compliance of warfarin was good and
no other change in dietary habits can be found. We have
also excluded other possibilities which may account for
the rise in the INR, including the use of other common
concurrent medications such as antibiotics, vitamins,
over-the-counter cough and cold preparations and other
dietary interference by thorough interview with the patient
and her family.
L. barbarum L. is a native Chinese deciduous shrub with
bright red berries. L. barbarum L. (family: Solanaceae) or
Lycium chinense, is also known as Gou Qi Zi in Asia or
Fructus Lycii Chinensis and Wolfberry in the West (Natu-
ral Medicines Comprehensive Database, 2007). The use of
this herbal substance was first described in the first century
AD in Chinese literature. Traditionally, it has been used to
promote longevity (Natural Medicines Comprehensive
Database, 2007). The applicable parts of L. barbarum L.
are the dried berries and root bark. Both parts contain
pharmacologically active constituents which offer a variety
of indications that affect different organs of the body. It is
believed to tonify yin-deficiency in liver and kidney, and
thus it is valued in the Chinese culture to use as an eye tonic
for blurred vision, macular degeneration, and other oph-
thalmic disorders which are signs of yin-deficiency of liver
(Hsu, 1986). A trial performed by Cheng et al. (2005) used
lycium berries rich in zeaxanthin dipalmitate to prevent
age-related macular degeneration. The root bark of the
plant has also been reported to have hypoglycaemic effects
(Hsu, 1986; Huang, 1999). The berries also contain b-caro-
tene, niacin, pyridoxine and ascorbic acid (Hsu, 1986;
Chang and But, 1987). L. barbarum L. most probably
has many medicinal contents although it may be difficult
to relate them to a single treatment purpose. Traditionally
though it is used to supplement the deficiency of liver and
kidneys, promote sperm and blood, clear vision, relieve
low-back pain and dizziness (Hsu, 1986; Chang and But,
1987). L. barbarum L. is usually taken as tea; however
the strength can vary depending on the indication and
the dosage range from 6 to 18 g per day (Hsu, 1986). A typ-
ical dose is one or more cups of tea daily. Typically, the tea
is made by boiling the required amount of berries or root
bark in 3 cups of water and simmered until volume is
concentrated to around 2 cups.
This case illustrated a clinically important herbal–drug
interaction between L. barbarum L. and warfarin. By far,
there is only one case report documenting the possible
interaction with warfarin (Lam et al., 2001) in which a pre-
viously stabilized INR was elevated following ingestion of
L. barbarum L. containing tea. The authors in the last case
- Intake of Lycium
Graph 1: INR Level Vs Warfarin Dosage (mg)
Graph 1. INR level vs. warfarin dosage (mg).
H. Leung et al./Food and Chemical Toxicology 46 (2008) 1860–1862
report performed an in vitro analysis by the use of human Download full-text
liver microsomes as a source of cytochrome P450. The eval-
uation showed weak inhibition of S-warfarin metabolism
by CYP2C9 by the tea of L. barbarum L. The dissociation
constant value of 3.4 mg/mL suggesting that the interac-
tion may be caused by other factors such as absorption,
p-glycoprotein, or an anti-coagulant effect of the herb itself
(Lam et al., 2001). For comparison purpose, we may take
for example the drug interaction between chloral hydrate
and warfarin: chloral hydrate has been documented to
increase prothrombin times within 12 h after the first dose
and the proposed mechanism of action was the displace-
ment of warfarin from its binding site by metabolites of
chloral hydrate (Severs and Koch-Weser, 1970). A similar
time frame was observed to cause an increase in INR in
our case report and this may suggest a comparable mecha-
nism of action. Further investigation and study into the
herb L. barbarum L. is required in order to unveil the true
mechanism behind such interactions. These may include
the identification and constitution of the herb, further
in vitro studies to classify mechanisms of interactions such
as pharmacokinetic considerations including P450 enzyme
encourage future case reporting because these are the true
reflections of the clinical presentation of drug interaction.
As the use of herbal medicine is very common and conve-
niently available in herbal dispensaries, it is important for
physicians to warn patients who are on warfarin not to
take any other medication including herbal products. Phy-
sicians should be vigilant to the risk of herbal–drug interac-
tion when the anticoagulation control deviates from the
Conflict of interest statement
There are no conflicts of interests.
Chang, H.M., But, P.H., 1987. In: Pharmacology and Applications of
Chinese Materia Medica, vol. 2. World Scientific Publishing Co. Pvt.
Ltd., p. 852–853.
Cheng, C.Y., Chung, W.Y., Szeto, Y.T., Benzie, I.F., 2005. Fasting
plasma zeaxanthin response to Frutus barbarum L. (wolfberry; kei tze)
in a food-based human supplement trial. British Journal of Nutrition
93 (1), 123–130.
Hsu, H.Y., 1986. Oriental Materia Medica a Concise Guide. Oriental
Healing Arts Institute, p. 544–545.
Huang, K.C., 1999. The Pharmacology of Chinese Herbs, 2nd ed. CRC
Press, LLC, Boca Raton, FL, pp. 72–74.
Lam, A.Y., Elmer, G.W., Mohutsky, M.A., 2001. Possible interaction
between warfarin and Lycium barbarum L.. Annals of Pharmacother-
apy 35, 1195–1199.
Lycium. Natural Medicines Comprehensive
<http://www.naturaldatabase.com> (Accessed 03.01.07.).
Makina, K., Wakushima, H., Okamoto, T., et al., 2002. Pharmacokinetic
interactions between warfarin and kangen-karyu, a traditional Chinese
medicine, and their synergistic action. Journal of Ethnopharmacol 82,
Maurer, A., Johne, A., Bauer, S., 1999. Interactions of St. John’s wort
with phenprocoumon. European Journal of Clinical Pharmacology 20,
Page, R.L., Lawrence, J.D., 1999. Potentiation of warfarin by dong quai.
Annals of Pharmacotherapy 19, 870–876.
Severs, E.M., Koch-Weser, J., 1970. Potentiation of warfarin induced
hypoprothrombinaemia by chloral hydrate. New England Journal of
Medicine 283 (16), 827–831.
Vaes, L.P., Chyka, P.A., 2000. Interactions of warfarin with garlic, ginger,
ginko or ginseng: nature of the evidence. Annals of Pharmacotherapy
H. Leung et al./Food and Chemical Toxicology 46 (2008) 1860–1862