Medication Guide App

Hawthorn

Scientific Name(s): Crataegus oxyacantha L. and Crataegus monogyna Jacquin. Family: Rosaceae (roses)

Common Name(s): Hawthorn , Cardiplant , Crataegisan , Crataegutt , English hawthorn , Faros , haw , Korodin , LI 132 , maybush , whitethorn , WS 1442

Uses

Hawthorn may have a role as adjunctive therapy in mild heart failure and exhibits some advantages over digoxin. In more severe cases of congestive heart failure (CHF), its place in therapy is less clear. Studies in animals suggest that hawthorn extracts exert effects on the CNS, including anxiolytic and analgesic action; however, clinical studies are limited. Although limited clinical studies have shown improvement in hyperlipidemia with hawthorn extracts, specific, well-designed trials are needed before hawthorn extracts can be recommended.

Dosing

Trials have evaluated dosages ranging from 160 to 1,800 mg/day standardized extracts (mostly WS 1442 ) in divided doses over 3 to 24 weeks. A minimum effective dose for adjunctive therapy in mild CHF is suggested to be standardized extract 300 mg daily, and maximum benefit appears after 6 to 8 weeks of therapy. Clinical trials conducted in patients with class II and III CHF found hawthorn extract 900 mg daily to be safe, but not superior to placebo.

Contraindications

Known allergy to members of the rose family.

Pregnancy/Lactation

In the absence of clear data, hawthorn extracts should be avoided in pregnancy and during lactation. Animal studies, however, have not shown any adverse effect on embryonic development.

Interactions

None well documented.

Adverse Reactions

Serious adverse reactions are rarely reported. Mild to moderate dizziness, headache, rash, palpitations, and nausea and other GI symptoms have been reported.

Toxicology

Hawthorn is reportedly toxic in high doses; low doses of hawthorn usually lack adverse effects. No increase in the frequency of fetal malformations or teratogenicity has been found in animal studies.

Botany

Some 280 species of hawthorn exist, with C. oxycantha (synonym Crataegus laevigata [Poir]) and C. monogyna commonly used in commercial preparations. Hawthorn is a spiny bush or small tree that grows up to 7.5 m in height. Its deciduous leaves are divided into 3 to 5 lobes. The white, strong-smelling flowers grow in large bunches and bloom from April to June. The spherical bright red fruit contains 1 nut ( C. monogyna ) or 2 to 3 nuts ( C. oxyacantha ). The flowers, leaves, and fruits are all used for therapeutic preparations. 1 , 2 , 3

History

The use of hawthorn dates back to the Greek physician Dioscorides (40 to 90 AD). Hawthorn has been traditionally used as a diuretic for kidney and bladder disorders, to treat stomach ache, stimulate appetite, and improve circulation. Other traditional uses for hawthorn include treatment of stress, nervousness, and sleep disorders.

Preparations containing hawthorn remain popular in Europe for the treatment of high or low blood pressure, tachycardia, or arrhythmias, with the revised Complete German Commission E Monographs approving the use of leaves and flowers for the treatment of long-term heart failure classes I and II (New York Heart Association [NYHA] classification). Some acceptance has also been gained in the United States, with clinical trials being conducted in cardiac failure. 2 , 3 , 4

Chemistry

The leaves, flowers, bark, and fruits primarily contain flavonoids, oligomeric proanthocyanidins, tyramine, and tannins. The flavonoids and proanthocyanidins are considered to be the most pharmacologically active compounds and preparations are standardized for these constituents. Most trials have used extracts standardized to 2.2% flavonoids or 18.75% oligomeric proanthocyanidins. 2 , 3

A complete characterization of the chemical constituents of all plant parts has been conducted. 5

Uses and Pharmacology

Pharmacodynamic properties of hawthorn have been elucidated, and relevant cardiovascular actions include positive inotropic effects, peripheral vasodilation, increased myocardial perfusion, as well as stroke volume and decreased afterload. Hawthorn also increases the refractory period, an action thought to be one reason for observed antiarrhythmic activity. 6 , 7

Cardiovascular disease
Heart failure
Animal data

Large-scale clinical trials have been conducted using hawthorn extracts, making animal data largely irrelevant.

Clinical data

Several randomized, double-blind clinical trials have been conducted with objective measurements in cardiac performance in heart failure. 6 A meta-analysis of trials found that hawthorn, as adjunctive therapy, is superior to placebo in the treatment of long-term heart failure I and II (NYHA classification), as measured by exercise tolerance tests. Symptomatic measurements (shortness of breath, fatigue) also improved with hawthorn over placebo. In the trials included in the meta-analysis, most patients were also treated concomitantly with diuretics, angiotensin-converting enzyme inhibitors, or calcium antagonists. 7

Clinical trials evaluating hawthorn in CHF conducted since the meta-analysis include the Hawthorn Extract Randomized Blinded Chronic Heart Failure (HERB-CHF) and Survival and Prognosis: Investigation of Crataegus Extract WS 1442 in Congestive Heart Failure (SPICE) trials. 8 , 9 , 10 , 11 Both trials evaluated the extract WS 1442 ( Crataegutt forte ) 900 mg/day versus placebo over a period of 6 and 24 months, respectively, in patients with CHF class II or III (NYHA). In the HERB-CHF trial, no difference was found for the primary end point of a 6-minute walk distance or for quality of life and functional capacity measures for hawthorn over placebo. 10 , 11 In the SPICE trial, no difference was found for hawthorn in the primary measures of time to first cardiac event and no difference in trend for cardiac mortality reduction. 9 In a subgroup analysis, patients with a left ventricular ejection fraction of at least 25% experienced a reduction in sudden cardiac death with hawthorn. 9 , 12 Clinical efficacy, therefore, remains unclear in CHF. 12 Adverse events in these clinical trials were similar to those of placebo, suggesting certain advantages for hawthorn over digoxin, including a wider therapeutic range, a lower risk in cases of toxicity, is safer in renal impairment, and can safely be used with diuretics. 6

Blood pressure
Animal data

Hawthorn extracts decrease peripheral vascular resistance and hypertension in animal models. 2

Clinical data

Studies in humans have not established a role for hawthorn in the management of hypertension. Modest reductions in diastolic pressure alone, and in both diastolic and systolic pressure, have been demonstrated. 13 , 14 , 15 , 16 In some studies a short-term increase in diastolic pressure was found, 17 , 18 and efficacy in preventing orthostatic hypotension was shown in limited clinical studies. 19 , 20

Central Nervous System
Animal data

Studies in animals suggest hawthorn extracts exert effects on CNS, including anxiolytic and analgesic actions. 21 , 22 Antagonism of naltrexone has also been reported. 21 Reduced oxidative stress in induced ischemia/reperfusion cerebral injury in rats has been demonstrated. 23

Clinical data

Limited clinical studies have been conducted. One trial found no effect on anxiety, mood, or well-being, 14 while other studies have evaluated hawthorn in combination with other agents. Conclusions cannot be drawn. 17 , 24

Hyperlipidemia
Animal data

Animal studies have demonstrated lipid-lowering effects with hawthorn extracts 25 , 26 , 27 , 28 , 29 and inhibition of low-density lipoprotein (LDL) oxidation in laboratory models. 30

Clinical data

Hyperlipidemia was improved in limited clinical studies with hawthorn extracts, as well as reductions in total cholesterol, LDL cholesterol, and ratio total. High-density lipoprotein cholesterol has been noted. 31 , 32 Specific, well-designed trials are required before recommendations for hawthorn extracts in hyperlipidemia can be made.

Other uses

Animal studies suggest a role for hawthorn in preventing angioplasty-related restenosis and reperfusion injury, possibly facilitated by preventing oxidative stress. 33 , 34 Other antioxidant activities have been explored in animal models. 22 , 35 Hawthorn extracts exert protective effects against irradiation in animal models and in vitro with human cells. 36

Dosage

Trials have evaluated dosages ranging from 160 to 1,800 mg/day standardized extracts (mostly WS 1442 ) in divided doses, over 3 to 24 weeks. 3 , 24

CHF

A minimum effective dose is suggested to be standardized extract 300 mg daily, and maximum benefit appears after 6 to 8 weeks of therapy. 6 Clinical trials conducted in patients with class II and III CHF found hawthorn extract 900 mg daily to be safe, but not superior to placebo. 9 , 11

Pregnancy/Lactation

In the absence of clear data, clinical texts suggest that hawthorn extracts should be avoided in pregnancy and during lactation. 3 , 22 Animal studies, however, have not shown any adverse effect on embryonic development. 2 , 37

Interactions

Case reports of an interaction between hawthorn and digoxin are lacking, and a review of clinical trial data found no reports of drug interactions. 3

Hawthorn extract pharmacodynamic interactions with digoxin have been demonstrated in rats. A pharmacokinetic study in healthy humans demonstrated no decrease in the plasma concentration of digoxin, 38 while interference with immunoassay measurements of serum digoxin levels has been reported. 39

Until further evidence of interactions is established, caution should be exercised in the coadministration of hawthorn extracts with digoxin as well as with vasodilating drugs (theophylline, caffeine, papaverine, sodium nitrate and adenosine, beta-blockers, and class III anti-arrhythmics). 3 , 6

Adverse Reactions

Except for known allergy to members of the Rosaceae family, there are no known contraindications to hawthorn. 3

A review of clinical trial data found only rare serious adverse reactions that included palpitations, chest pain, GI hemorrhage, and migraine. 3 Most adverse reactions reported are mild to moderate and include moderate dizziness, nausea, GI symptoms, rash, and headache. Hawthorn extracts are considered to be relatively safe. 3 , 22

A case report exists of a multisystem hypersensitivity reaction with acute renal failure to consumption of the fruit and tea of the related species Crataegus orientalis . 40

Toxicology

No increase in the frequency of fetal malformations or teratogenicity has been found in animal studies. 2 , 3 , 37

Bibliography

1. Crataegus monogyna Jacq. USDA, NRCS. 2010. The PLANTS Database ( http://plants.usda.gov , August 2010). National Plant Data Center, Baton Rouge, LA 70874-4490 USA.
2. Hawthorn. In: WHO Monographs on Selected Medicinal Plants . Vol 1. Geneva, Switzerland: World Health Organization; 1999.
3. Daniele C, Mazzanti G, Pittler MH, Ernst E. Adverse-event profile of Crataegus spp.: a systematic review. Drug Saf . 2006;29(6):523-535.
4. Blumenthal M, Goldberg A, Brinckmann J, eds. Herbal Medicine: Expanded Commission E Monographs . Newton, MA: Integrative Medicine Communications; 2000.
5. Barros L, Carvalho AM, Ferreira IC. Comparing the composition and bioactivity of Crataegus Monogyna flowers and fruits used in folk medicine. Phytochem Anal . 2011;22(2):181–188.
6. Vogel JH, Bolling SF, Costello RB, et al. Integrating complementary medicine into cardiovascular medicine. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents (Writing Committee to Develop an Expert Consensus Document on Complementary and Integrative Medicine). J Am Coll Cardiol . 2005;46(1):184-221.
7. Pittler MH, Guo R, Ernst E. Hawthorn extract for treating chronic heart failure. Cochrane Database Syst Rev . 2008;(1):CD005312.
8. Holubarsch CJ, Colucci WS, Meinertz T, Gaus W, Tendera M. Survival and prognosis: investigation of Crataegus extract WS 1442 in congestive heart failure (SPICE)--rationale, study design and study protocol. Eur J Heart Fail . 2000;2(4):431-437.
9. Holubarsch CJ, Colucci WS, Meinertz T, Gaus W, Tendera M; Survival and prognosis: investigation of Crataegus extract WS 1442 in CHF (SPICE) trial study group. The efficacy and safety of Crataegus extract WS 1442 in patients with heart failure: the SPICE trial. Eur J Heart Fail . 2008;10(12):1255-1263.
10. Zick SM, Gillespie B, Aaronson KD. The effect of Crataegus oxycantha Special Extract WS 1442 on clinical progression in patients with mild to moderate symptoms of heart failure. Eur J Heart Fail . 2008;10(6):587-593.
11. Zick SM, Vautaw BM, Gillespie B, Aaronson KD. Hawthorn Extract Randomized Blinded Chronic Heart Failure (HERB CHF) trial. Eur J Heart Fail . 2009;11(10):990-999.
12. Furey A, Tassell M. Towards a systematic scientific approach in the assessment of efficacy of an herbal preparation: Hawthorn ( Crataegus spp.). Eur J Heart Fail . 2008;10(12):1153-1157.
13. Walker AF, Marakis G, Morris AP, Robinson PA. Promising hypotensive effect of hawthorn extract: a randomized double-blind pilot study of mild, essential hypertension. Phytother Res . 2002;16(1):48-54.
14. Walker AF, Marakis G, Simpson E, et al. Hypotensive effects of hawthorn for patients with diabetes taking prescription drugs: a randomised controlled trial. Br J Gen Pract . 2006;56(527):437-443.
15. Asgary S, Naderi GH, Sadeghi M, Kelishadi R, Amiri M. Antihypertensive effect of Iranian Crataegus curvisepala Lind.: a randomized, double-blind study. Drugs Exp Clin Res . 2004;30(5-6):221-225.
16. Schröder D, Weiser M, Klein P. Efficacy of a homeopathic Crataegus preparation compared with usual therapy for mild (NYHA II) cardiac insufficiency: results of an observational cohort study. Eur J Heart Fail . 2003;5(3):319-326.
17. Werner NS, Duschek S, Schandry R. D-camphor- crataegus berry extract combination increases blood pressure and cognitive functioning in the elderly—a randomized, placebo controlled double blind study. Phytomedicine . 2009;16(12):1077-1082.
18. Schandry R, Duschek S. The effect of Camphor- Crataegus berry extract combination on blood pressure and mental functions in chronic hypotension—A randomized placebo controlled double blind design. Phytomedicine . 2008;15(11):914–922.
19. Belz GG, Butzer R, Gaus W, Loew D. Camphor- Crataegus berry extract combination dose-dependently reduces tilt induced fall in blood pressure in orthostatic hypotension. Phytomedicine . 2002;9(7):581-588.
20. Kroll M, Ring C, Gaus W, Hempel B. A randomized trial of Korodin Herz-Kreislauf-Tropfen as add-on treatment in older patients with orthostatic hypotension. Phytomedicine . 2005;12(6-7):395-402.
21. Can OD, Ozkay UD, Oztürk N, Oztürk Y. Effects of hawthorn seed and pulp extracts on the central nervous system. Pharm Biol . 2010;48(8):924-931.
22. Tadić VM, Dobrić S, Marković GM, et al. Anti-inflammatory, gastroprotective, free-radical-scavenging, and antimicrobial activities of hawthorn berries ethanol extract. J Agric Food Chem . 2008;56(17):7700-7709.
23. Elango C, Jayachandaran KS, Niranjali Devaraj S. Hawthorn extract reduces infarct volume and improves neurological score by reducing oxidative stress in rat brain following middle cerebral artery occlusion. Int J Dev Neurosci . 2009;27(8):799-803.
24. Hanus M, Lafon J, Mathieu M. Double-blind, randomised, placebo-controlled study to evaluate the efficacy and safety of a fixed combination containing two plant extracts ( Crataegus oxyacantha and Eschscholtzia californica ) and magnesium in mild-to-moderate anxiety disorders. Curr Med Res Opin . 2004;20(1):63-71.
25. Akila M, Devaraj H. Synergistic effect of tincture of Crataegus and Mangifera indica L. extract on hyperlipidemic and antioxidant status in atherogenic rats. Vascul Pharmacol . 2008;49(4-6):173-177.
26. Luo Y, Chen G, Li B, et al Dietary intervention with AHP, a functional formula diet, improves both serum and hepatic lipids profile in dyslipidemia mice. J Food Sci . 2009;74(6):H189-H195.
27. Xu H, Xu HE, Ryan D. A study of the comparative effects of hawthorn fruit compound and simvastatin on lowering blood lipid levels. Am J Chin Med . 2009;37(5):903-908.
28. Ye XL, Huang WW, Chen Z, et al. Synergetic effect and structure-activity relationship of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors from Crataegus pinnatifida Bge. J Agric Food Chem . 2010;58(5):3132-3138.
29. Lin Y, Vermeer MA, A Trautwein E. Triterpenic Acids Present in Hawthorn Lower Plasma Cholesterol by Inhibiting Intestinal ACAT Activity in Hamsters. Evid Based Complement Alternat Med . 2009 Feb 19. [Epub ahead of print]
30. Quettier-Deleu C, Voiselle G, Fruchart JC, et al. Hawthorn extracts inhibit LDL oxidation. Pharmazie . 2003;58(8):577-581.
31. Rigelsky JM, Sweet BV. Hawthorn: pharmacology and therapeutic uses. Am J Health Syst Pharm . 2002;59(5):417-422.
32. Chen JD, Wu YZ, Tao ZL, Chen ZM, Liu XP. Hawthorn (shan zha) drink and its lowering effect on blood lipid levels in humans and rats. World Rev Nutr Diet . 1995;77:147-154.
33. Fürst R, Zirrgiebel U, Totzke F, Zahler S, Vollmar AM, Koch E. The Crataegus extract WS 1442 inhibits balloon catheter-induced intimal hyperplasia in the rat carotid artery by directly influencing PDGFR-beta. Atherosclerosis . 2010;211(2):409-417.
34. Swaminathan JK, Khan M, Mohan IK, et al. Cardioprotective properties of Crataegus oxycantha extract against ischemia-reperfusion injury. Phytomedicine . 2010;17(10):744-752.
34. Hwang HS, Bleske BE, Ghannam MM, et al. Effects of hawthorn on cardiac remodeling and left ventricular dysfunction after 1 month of pressure overload-induced cardiac hypertrophy in rats. Cardiovasc Drugs Ther . 2008;22(1):19-28.
36. Hosseinimehr SJ, Mahmoudzadeh A, Azadbakht M, Akhlaghpoor S. Radioprotective effects of Hawthorn against genotoxicity induced by gamma irradiation in human blood lymphocytes. Radiat Environ Biophys . 2009;48(1):95-98.
37. Yao M, Ritchie HE, Brown-Woodman PD. A reproductive screening test of hawthorn. J Ethnopharmacol . 2008;118(1):127-132.
38. Tankanow R, Tamer HR, Streetman DS, et al. Interaction study between digoxin and a preparation of Hawthorn ( Crataegus oxyacantha ). J Clin Pharmacol . 2003;43(6):637-642.
39. Dasgupta A, Kidd L, Poindexter BJ, Bick RJ. Interference of hawthorn on serum digoxin measurements by immunoassays and pharmacodynamic interaction with digoxin. Arch Pathol Lab Med . 2010;134(8):1188-1192.
40. Horoz M, Gok E, Genctoy G, et al. Crataegus orientalis associated multiorgan hypersensitivity reaction and acute renal failure. Intern Med . 2008;47(23):2039-2042.

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