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Monograph
Crataegus oxycantha (Hawthorn)
Monograph
Introduction
Crataegus oxycantha has been used traditionally
as a cardiac tonic since the frst century A.D., as
noted by the Greek herbalist, Dioscorides, and
became even more popular among European and
American herbalists in the late 19th century.
1

Currently it is used as a cardiotonic for a variety of
functional heart disorders. Recent research shows
Crataegus extracts exert a wide range of positive
actions on heart function, supporting and validat-
ing historical observations.
2,3
Description
C. oxycantha is a thorny deciduous tree found
primarily in Europe, North America, and Western
Asia, growing to heights of 25-30 feet. Te tree is a
member of the Rosaceae family and common
names include hawthorn, English hawthorn, May
bush, and whitehorn. Large bunches of fragrant
white or pink fowers bloom in the spring and
develop into small, bright red, apple-shaped fruit
in the autumn.
4
Active Constituents
Te primary cardiovascular protective activity of
the plant is generally attributed to its favonoid
content, particularly the oligomeric proanthocyani-
dins (OPCs). Te OPCs are highly concentrated in
the leaves, berries, and fowers and are responsible
for providing the pigment that colors the berries.
3

Tese favonoids have very strong vitamin P (also
known as citrin biofavonoid) activity, working
synergistically with vitamin C to promote capillary
stability.
5
Other constituents of Crataegus include
quercetin, quercetrin, triterpene saponins, vitamin
C, and several cardioactive amines.
Mechanisms of Action
Because of its high favonoid content, particu-
larly the OPCs, Crataegus has signifcant antioxi-
dant activity. Crataegus oxycantha extract has been
shown to reduce oxidative stress in reperfused
myocardium and appears to inhibit apoptosis,
resulting in a cardioprotective efect.
6-8
In addition, Crataegus increases coronary blood
fow,
9
enhancing oxygen fow and utilization by the
heart. Crataegus extracts also have a positive
inotropic efect on the contraction amplitude of
myocytes.
10
Crataegus exerts a simultaneous
cardiotropic and vasodilatory action. Because of
these actions, it can be safely and efectively
utilized for cardiac conditions for which digitalis is
not yet indicated.
11
Due to the favonoid content,
extracts of this herb exert considerable collagen-
stabilizing efects, enhancing integrity of blood
vessels.
12
In rats fed a hyperlipidemic diet, extracts of
Crataegus prevented elevation of plasma lipids,
including total cholesterol, triglycerides, and
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Monograph
LDL- and VLDL-fractions.
13
Crataegus up-regulates
hepatic LDL-receptors, resulting in greater infux
of plasma LDL-cholesterol into the liver. It also
prevents the accumulation of cholesterol in the
liver by enhancing cholesterol degradation to bile
acids, promoting bile fow, and suppressing
cholesterol biosynthesis.
14
Clinical Indications
Crataegus provides efective and low-risk
phytotherapy for patients with coronary heart
disease, atherosclerosis, hypertension, or
hypercholesterolemia.
Congestive Heart Failure
Research indicates administration of Crataegus
provides subjective and objective benefts in
individuals with signs and symptoms of mild
congestive heart failure (CHF) New York Heart
Association stage II (NYHA-II). Over a period of
eight weeks, supplementation with Crataegus
resulted in a clear improvement in the perfor-
mance of the heart. Patients reported improvement
in subjective symptoms, such as reduced perfor-
mance, shortness of breath, and ankle edema.
9
A
large multi-center observational study demon-
strated 450 mg Crataegus extract WS 1442
(standardized to 18.75% OPC) given twice daily for
24 weeks signifcantly improved exercise tolerance
and dyspnea, fatigue, blood pressure, ejection
fraction, and resting pulse in 1,011 patients with
NYHA-II cardiac insufciency. Ankle edema and
nocturia also were signifcantly decreased.
Physicians reported treatment was well tolerated in
most patients and had a good or very good
efcacy.
15
In a randomized, placebo-controlled trial, 209
Germans (average age, 67.6 years) with NYHA-III
cardiac insufciency were supplemented with
1,800 mg Crataegus extract WS 1442 daily for 16
weeks. Compared to placebo, Crataegus resulted in
a statistically signifcant improvement in maximal
tolerated workload during exercise under standard-
ized loading on a bicycle ergometer.
16
In the SPICE trial, a long-term, randomized,
double-blind, placebo-controlled, multi-center
study, 2,681 patients with NYHA-II or -III CHF and
left ventricular ejection fraction (LVEF) 35
percent received 900 mg WS 1422 or placebo daily
for 24 months in addition to regular treatments
(beta-blockers, angiotensin converting enzyme
[ACE] inhibitors, diuretics, and digoxin). Primary
endpoint was time until frst cardiac event. For
those in the treatment group the average time to
frst cardiac event was 620 days, compared to 606
days for those in the placebo group. Although the
diference between the two groups did not reach
statistical signifcance for the primary endpoint, a
trend toward cardiac mortality reduction was
observed in the treatment group. Furthermore, in
a subgroup of 1,139 patients with initial LVEF
between 25 and 35 percent, cardiac mortality was
decreased by 20 percent and sudden cardiac death
by 39.7 percent compared to placebo. Te treat-
ment was well tolerated with no signifcant side
efects or drug interactions reported.
17
Hypertension
Crataegus exerts mild blood pressure-lowering
activity, which appears to be a result of a number
of diverse pharmacological efects. It dilates
coronary vessels,
18
inhibits ACE,
19
acts as an
inotropic agent,
10
and possesses mild diuretic
activity.
4
A randomized, placebo-controlled, pilot
study of 36 untreated, mildly hypertensive,
middle-aged subjects (18 males, 18 females)
investigated the hypotensive efects of a standard-
ized Crataegus extract and magnesium (both
separately and in combination) for 10 weeks.
Subjects were divided into four groups: 600 mg
magnesium daily, 500 mg Crataegus extract daily, a
two-tablet combination of magnesium and
Crataegus (same dosages as in groups 1 and 2), or
cellulose placebo. Subjects were assessed at
baseline and at fve and 10 weeks for anthropomet-
ric measurement, dietary patterns, and blood
pressure. Both systolic and diastolic blood pressure
decreased in all treatment groups, but analysis
revealed no clear beneft of one group over another.
However, when looking at resting diastolic blood
pressure alone, subjects receiving Crataegus extract
demonstrated a signifcant decrease at week 10
compared to the other groups. Interestingly, this
group also showed a trend toward reduced anxiety
episodes compared to the other groups.
20
Crataegus extract has also been shown to lower
blood pressure in type 2 diabetics taking prescrip-
tion medications for hyperglycemia. In a random-
ized, double-blind, parallel, placebo-controlled trial,
80 type 2 diabetics (mean age, 60) with diastolic
blood pressures between 85-95 mmHg and systolic
blood pressures between 145-165 mmHg were
randomized to receive 1,200 mg Crataegus extract
(n=40) or placebo (n=40) daily.
21
Study length was
16 weeks and patients were assessed at baseline
and at eight and 16 weeks for anthropometric
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Monograph
measurements and blood pressure (primary
outcome was diastolic blood pressure). Subjects
were also assessed for electrolytes, liver and kidney
function, blood glucose, hemoglobin A1C, and
fructosamine at baseline and 16 weeks. At 16
weeks those in the Crataegus group showed a
statistically signifcant (although perhaps not
clinically signifcant) reduction of 2.6 mmHg in
diastolic blood pressure compared to placebo. No
other statistically signifcant diferences were
reported between the placebo and treatment
groups. Te Crataegus extract was well tolerated
and no adverse efects or drug interactions were
reported.
Hyperlipidemia
Crataegus extract demonstrates a lipid-lowering
efect in mouse and rat models of hyperlipidemia.
In a mouse study, group A mice (n=6) were fed a
normal diet and served as the negative control,
while group B mice (n=6) were fed a high choles-
terol diet (HCD) and demonstrated higher blood
lipid levels compared to group A, thus serving as
the positive control. Group C mice (n=6) were fed
an HCD and simvastatin, and group D mice (n=6)
were fed an HCD and a Crataegus fruit-kiwi fruit
extract for eight weeks. Mice in groups C and D
both demonstrated a signifcant reduction in
triglyceride levels as well as the LDL- to total-
cholesterol ratio. Only mice in the Crataegus-kiwi
extract group demonstrated a reduction in LDL
levels.
22
Another study in mice investigated the
mechanism behind hawthorn favonoids efect on
blood lipid levels and found they signifcantly
up-regulate adipogenesis gene expression and
modulate both lipogenesis and lypolisis, resulting
in decreased blood lipid concentrations.
23
Drug-Botanical Interactions
Te root, leaves, fruit, and fowers of Crataegus
contain cardioactive compounds. Crataegus
preparations may have a potentiating efect on
digitalis, anti-hypertensive agents, and lipid-lower-
ing medications, and concomitant use may neces-
sitate a reduction in the dosage of these drugs.
24
Side Efects and Toxicity
Crataegus has been shown to have low toxicity,
with an LD
50
of 25 mg/kg.
25
Te German
Commission E monograph states that mice and
rats have been safely given a standardized extract
at doses up to 3 g/kg body weight.
26
Serious side
efects are not associated with use of Crataegus
extracts, although mild, transient side efects
including dizziness, gastrointestinal complaints,
headaches, and heart palpitations have occasion-
ally been reported.
27
Dosage
Positive efects from supplementation will
usually be observed within the frst two weeks. In
most instances, as a cardiac tonic, Crataegus is
administered for prolonged intervals. Dosages vary
depending on the concentration of the extract. A
typical therapeutic dose of an extract standardized
to contain 1.8 percent vitexin-4 rhamnoside is
100-250 mg three times daily. A standardized
extract containing 18-percent OPCs is dosed in the
range of 250-500 mg daily.
References
1. Hobbs C, Foster S. Hawthorne a literature review.
Herbalgram 1990;22:19-33.
2. Duke JA. Handbook of Medicinal Herbs. Boca Raton,
FL: CRC Press; 1985:146-147.
3. Mills S, Bone K. Principles and Practice of
Phytotherapy: Modern Herbal Medicine. Edinburg,
UK: Churchill Livingstone; 2000:439-447.
4. Weihmayr T, Ernst E. Terapeutic efectiveness of
Crataegus. Fortschr Med 1996;114:27-29. [Article in
German]
5. Vitamin P. http://www.thefreedictionary.com/
vitamin+P [Accessed April 5, 2010]
6. Jayalakshmi R, Tirupurasundari CJ, Devaraj SN.
Pretreatment with alcoholic extract of Crataegus
oxycantha (AEC) activates mitochondrial protection
during isoproterenol-induced myocardial infarction
in rats. Mol Cell Biochem 2006;292:59-67.
7. Swaminathan JK, Khan M, Mohan IK, et al.
Cardioprotective properties of Crataegus oxycantha
extract against ischemia-reperfusion injury.
Phytomedicine 2010 Feb 17. [Epub ahead of print]
8. Schussler M, Holzl J, Fricke U. Myocardial efects of
favonoids from Crataegus species.
Arzneimittelforschung 1995;45:842-845.
9. Weikl A, Assmus KD, Neukum-Schmidt A, et al.
Crataegus Special Extract WS 1442. Assessment of
objective efectiveness in patients with heart failure
(NYHA II). Fortschr Med 1996;114:291-296. [Article
in German]
10. Popping S, Rose H, Ionescu I, et al. Efect of a
hawthorn extract on contraction and energy
turnover of isolated rat cardiomyocytes.
Arzneimittelforschung 1995;45:1157-1161.
11. Blesken R. Crataegus in cardiology. Fortschr Med
1992;110:290-292. [Article in German]
12. Gabor M. Pharmacologic efects of favonoids on
blood vessels. Angiologica 1972;9:355-374.
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Copyright 2010 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.
Monograph
13. Shanthi S, Parasakthy K, Deepalakshmi
PD, Devaraj SN. Hypolipidemic activity
of tincture of Crataegus in rats. Indian J
Biochem Biophys 1994;31:143-146.
14. Rajendran S, Deepalakshmi PD,
Parasakthy K, et al. Efect of tincture of
Crataegus on the LDL-receptor activity
of hepatic plasma membrane of rats fed
an atherogenic diet. Atherosclerosis
1996;123:235-241.
15. Tauchert M, Gildor A, Lipinski J.
High-dose Crataegus extract WS 1442
in the treatment of NYHA stage II heart
failure. Herz 1999;24:465-474. [Article
in German]
16. Tauchert M. Efcacy and safety of
Crataegus extract WS 1442 in compari-
son with placebo in patients with
chronic stable New York Heart
Association class-III heart failure. Am
Heart J 2002;143:910-915.
17. Holubarsch CJ, Colucci WS, Meinertz T,
et al. Te efcacy and safety of
Crataegus extract WS 1442 in patients
with heart failure: the SPICE trial. Eur J
Heart Fail 2008;10:1255-1263.
18. Rewerski W, Lewak S. Some pharmaco-
logical properties of favan polymers
isolated from hawthorn (Crataegus
oxyacantha). Arzneimittelforschung
1967;17:490-491. [Article in German]
19. Uchida S, Ikari N, Ohta H, et al.
Inhibitory efects of condensed tannins
on angiotensin converting enzyme. Jpn
J Pharmacol 1987;43:242-246.
20. Walker AF, Marakis G, Morris AP,
Robinson PA. Promising hypotensive
efect of hawthorn extract: a random-
ized double-blind pilot study of mild,
essential hypertension. Phytother Res
2002;16:48-54.
21. Walker AF, Marakis G, Simpson E, et al.
Hypotensive efects of hawthorn for
patients with diabetes taking prescrip-
tion drugs: a randomised controlled
trial. Br J Gen Pract 2006;56:437-443.
22. Xu H, Xu HE, Ryan D. A study of the
comparative efects of hawthorn fruit
compound and simvastatin on lowering
blood lipid levels. Am J Chin Med
2009;37:903-908.
23. Xie W, Sun C, Liu S. Efects of hawthorn
favanone on blood-fat and expression
of lipogenesis and lipolysis genes of
hyperlipidemia model mouse. Zhongguo
Zhong Yao Za Zhi 2009;34:224-229.
[Article in Chinese]
24. McGufn M, Hobbs C, Upton R,
Goldberg A. Botanical Safety Handbook.
New York, NY: CRC Press; 1997:37.
25. Ammon HP, Handel M. Crataegus,
toxicology and pharmacology, Part I:
Toxicity. Planta Med 1981;43:105-120.
26. Blumenthal M, Busse W, Goldberg A, et
al. Te Complete German Commission E
Monographs. Boston, MA: American
Botanical Council; 1998:142-144.
27. Daniele C, Mazzanti G, Pittler MH,
Ernst E. Adverse-event profle of
Crataegus spp.: a systematic review.
Drug Saf 2006;29:523-535.