Scientific Name(s): Myristica fragrans Houtt. Family: Myristicaceae
Common Name(s): Nutmeg, mace, magic, muscdier, nux moschata, myristica oil, muskatbaum
Nutmeg and mace, widely accepted as flavoring agents, have been used in higher doses for their aphrodisiac and psychoactive properties.
There are no clinical trials to support therapeutic dosing. Consumption of nutmeg at 1 to 2 mg/kg body weight was reported to induce CNS effects. Toxic overdose occurred at a 5 g dose.
Contraindications have not been identified. The excessive use of nutmeg or mace is not recommended in people with psychiatric conditions.
Generally recognized as safe when used in food as a flavoring agent. Safety for doses above those found in foods is unproven; avoid because of possible abortifacient effects.
None well documented.
Allergy, contact dermatitis, and asthma have been reported.
CNS excitation with anxiety/fear, cutaneous flushing, decreased salivation, GI symptoms, and tachycardia. Acute psychosis and anticholinergic-like episodes have been documented; death has rarely been reported following the ingestion of large doses of nutmeg.
Mace and nutmeg are 2 slightly different flavored spices, both originating from the fruit of the nutmeg tree, Myristica fragrans . This slow-growing evergreen grows to more than 20 m and is cultivated in India, Ceylon, Malaysia, and Granada. The fruit, which is called a drupe or a nutmeg apple, is similar in appearance to a peach or an apricot. When the mature fruit splits open, the nutmeg (stony endocarp or seed surrounded by a red, slightly fleshy network or aril) is exposed. The dried aril alone is called mace. The nut is removed and dried to produce nutmeg. 1 , 2 , 3
Nutmeg is a widely used food spice that has received attention as an alternative hallucinogen. Nutmeg and mace have been used in Indian cooking and folk medicine. In folk medicine, nutmeg has been used to treat gastric disorders and rheumatism, and also as a hypnotic and an aphrodisiac. During the 6th century AD, nutmeg and mace were imported by Arab traders, and by the 12th century, they were well known in Europe. At the turn of the 19th century, interest developed in the use of nutmeg as an abortifacient and a stimulant for menses. These properties have been largely discounted but remain a persistent cause of nutmeg intoxication in women. 2 , 3 , 4
Nutmeg seeds contain 20% to 40% of a fixed oil commonly called nutmeg butter. This oil contains myristic acid, trymiristin, and glycerides of lauric, tridecanoic, stearic, and palmitic acids. 5 , 6 Nutmeg also yields 8% to 15% of an essential oil that is believed to be partially responsible for the effects associated with nutmeg intoxication. The essential oil contains myristicin, elemicin, eugenol, and safrole. 5 , 6 , 7 The essential oils of nutmeg and mace are very similar in chemical composition and aroma, with wide color differences (brilliant orange to pale yellow). Mace oil appears to have a higher myristicin content than nutmeg oil. 8
Also present in the oil are sabinene, cymene, alpha-thujene, gamma-terpinene, and monoterpene alcohols in smaller amounts. Phenolic compounds found in nutmeg are reported to have antioxidant properties. 6 , 7 , 9 , 10 , 11 Other isolated compounds include the resorcinols malabaricone B and C, 12 as well as lignans and neolignans. 13 , 14 , 15
Uses and Pharmacology
There are no relevant clinical trials reported in the literature for nutmeg or mace.Aphrodisiac effects
Increased sexual activity (libido and potency) has been demonstrated in male rats with ethanolic extracts of nutmeg, providing some support for the use of nutmeg as an aphrodisiac. Eugenol may be responsible for some of the aphrodisiac effect because of its vasodilatory and smooth muscle relaxant properties. 16 , 17Clinical data
Despite anecdotal reports of aphrodisiac effects, clinical studies are lacking.Cancer
The National Cancer Institute has screened the Myristicaceae plant family for activity against selected leukemia lines. Of the tested extracts, 18.8% exhibited antileukemia activity, and in vitro studies with methanol extract and myristicin have shown increased apoptosis and decreased leukemia and neuroblastoma cell proliferation. 18 , 19 , 20 Several older experiments reveal some action on enzymes involved with activation and detoxification of carcinogens.Animal data
The effects of nutmeg on the CNS are variable and reflect anticholinergic and CNS excitatory and depressant effects. Dopaminergic and serotonin pathways may be involved. 24 , 25 , 26 , 27 , 28 Anticonvulsant activity in mice has been demonstrated. 29 , 30 , 31 The chemical constituents responsible for the CNS effects appear to be myristicin, which is a hallucinogenic and weak monoamine oxidase (MAO) inhibitor, elemicin, safrole, and trimyristin (anxiogenic effects), with some components being structurally similar to serotonin agonists. 26 , 32 , 33 , 34Clinical data
Nutmeg has long been known for its psychoactive properties of producing anxiety/fear and hallucinations; however, clinical studies are lacking. 24 , 35 , 36 Long-term nutmeg abuse has been reported. 35 Laboratory tests have detected nutmeg metabolites, which are reported to be unlike amphetamine derivatives. 37Diabetes
Serum glucose and lipid profiles improved in mice when mace lignan was administered. 40 In rabbits given an ethanolic extract of nutmeg, total and low-density lipoprotein (LDL) cholesterol and triglyceride were reduced; however, high-density lipoprotein levels were not changed. 41Clinical data
Clinical studies are lacking.Other effects
The oils of mace and nutmeg and their individual components (trimyristin, myristic acid, myristin, mace lignan) have been assessed for in vitro activity, which has been shown against some oral microorganisms 42 , 43 ; however, activity against other human pathogens has been demonstrated in vitro. 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 A modulatory effect on the protein/toxins produced by some bacteria, but not on the microorganisms themselves, has also been described. 42 , 44 , 45 , 46 Reports of activity against fungi are conflicting. 55 , 56 , 57Antioxidant effects
Experiments have evaluated the antioxidant potential of the oils of nutmeg and mace and their chemical components. Eugenol and mace lignans, as well as the phenolic content, have been identified as components of nutmeg with antioxidant activity, and inhibition of nitric oxide production, NO-scavenging, and decreased LDL-oxidation were demonstrated in experiments. 6 , 10 , 15 , 58 , 59 , 60 , 61 , 62 , 63 , 64Other effects
Screening and in vitro experiments in nutmeg components demonstrated ultraviolet-protectant effects and inhibition of melanin biosynthesis. 65 , 66 Anti-inflammatory and analgesic activities of nutmeg have been recorded in mice, as well as antithrombotic activity. 67 , 68 Other studies document hepatoprotective properties, 69 effects on osteoblast differentiation, 70 and reduced acidity and volume of gastric secretion. 71 , 72
There are no clinical trials to support therapeutic dosing.
Generally recognized as safe when used in food as a flavoring agent. Nutmeg traditionally has been used as an abortifacient. Although this use has been largely discounted, it remains a persistent cause of nutmeg intoxication in women. 2 , 3 , 4
Because of anxiogenic properties, a theoretical interaction may occur with nutmeg/mace and anxiolytics. 2 , 4 Interactions with nutmeg and diazepam, ondansetron, or buspirone occurred in rats. 30 One death has been associated with concurrent ingestion of large amounts of nutmeg and flunitrazepam. 33 Weak MAO inhibitory properties have been noted for the compound myristicin. 25
Allergy, contact dermatitis, and asthma have been reported. The chemical constituents limonene and eugenol are contact allergens. Immunoglobulin E reactivity has been demonstrated in nutmeg and mace. 73 , 74
Acute psychosis and anticholinergic-like episodes caused by nutmeg ingestion have been reported with a wide variety of symptoms. Effects occurred within 0.5 to 8 hours following ingestion and are characterized by cutaneous flushing, tachycardia, decreased salivation, GI symptoms (eg, nausea, vomiting, abdominal pain), fever, and CNS excitation with anxiety/fear; miosis or mydriasis are not considered to be reliable signs, as either may be present. There have been rare reports of shock, coma, and death. Treatment is supportive, with the use of antipsychotic therapy when necessary. 24 , 25 , 32 , 35 , 36
The cytotoxic and apoptotic effects of myristicin have been explored. Cell viability was reduced by exposure to myristicin in a dose- and time-dependent manner. 20 Myristic acid found in nutmeg, as in many other plant and animal fats, is a key component of human cellular biochemistry. It is recognized by the US Food and Drug Administration as safe when used as a flavoring agent or food-additive and is of low acute toxicity in rodent studies. 75 Safrole, a minor component of the oil, promoted hepatocarcinomas in mice. 76 , 77 , 78
Bibliography1. Myristica fragrans Houtt. USDA, NRCS. 2010. The PLANTS Database ( http://plants.usda.gov/java/profile?symbol=MYFR3 ). The National Plant Data Center, Baton Rouge, LA 70874-4490 USA.
2. De Milto L, Frey RJ. Nutmeg. In: Longe JL, project ed. Gale Encyclopedia of Alternative Medicine . Vol 3. 2nd ed. Detroit, MI: Thomson Gale; 2005:1461-1463.
3. Van Gils C, Cox PA. Ethnobotany of nutmeg in the Spice Islands. J Ethnopharmacol . 1994;42(2):117-124.
4. Ernst E. Herbal medicinal products during pregnancy: are they safe? BJOG . 2002;109(3):227-235.
5. Spricigo CB, Pinto LT, Bolzan A, Novais AF. Extraction of essential oil and lipids from nutmeg by liquid carbon dioxide. J Supercritical Fluids . 1999;15:253-259.
6. Dorman HJ, Figueiredo AC, Barroso JG, Deans SG. In vitro evaluation of antioxidant activity of essential oils and their components. Flavour Fragr J . 2000;15:12-16.
7. Shan B, Cai YZ, Sun M, Corke H. Antioxidant capacity of 26 spice extracts and characterization of their phenolic constituents. J Agric Food Chem . 2005;53(20):7749-7759.
8. Hallström H, Thuvander A. Toxicological evaluation of myristicin. Nat Toxins . 1997;5(5):186-192.
9. Su L, Yin JJ, Charles D, Zhou K, Moore J, Yu L. Total phenolic contents, chelating capacities, and radical-scavenging properties of black peppercorn, nutmeg, rosehip, cinnamon and oregano leaf. Food Chem . 2005.
10. Valderrama JC. Distribution of flavonoids in the Myristicaceae. Phytochemistry . 2000;55(6):505-511.
11. Duan L, Tao HW, Hao XJ, Gu QQ, Zhu WM. Cytotoxic and antioxidative phenolic compounds from the traditional Chinese medicinal plant, Myristica fragrans . Planta Med . 2009;75(11):1241-1245.
12. Orabi KY, Mossa JS, el-Feraly FS. Isolation and characterization of two antimicrobial agents from mace ( Myristica fragrans ). J Nat Prod . 1991;54(3):856-859.
13. Zacchino SA, Badano H. Enantioselective synthesis and absolute configuration assignment of erythro-(3,4,5 trimethoxy-7hydroxy-1'allyl-2',6'-dimethoxy)-8.0.4'-neolignan from mace ( Myristica fragrans ). J Nat Prod . 1988;51:1261.
14. Kasahara H, Miyazawa M, Kameoka H. Absolute configuration of 8-o-4'-neolignans from Myristica fragrans . Phytochemistry . 1995;40:515-517.
15. Kwon HS, Kim MJ, Jeong HJ, et al. Low-density lipoprotein (LDL)-antioxidant lignans from Myristica fragrans seeds . Bioorg Med Chem Lett . 2008;18(1):194-198.
16. Tajuddin S, Ahmad S, Latif A, Qasmi IA. Aphrodisiac activity of 50% ethanolic extracts of Myristica fragrans Houtt. (nutmeg) and Syzygium aromaticum (L) Merr. & Perry. (clove) in male mice: a comparative study. BMC Complement Altern Med . 2003;3:6.
17. Tajuddin, Ahmad S, Latif A, Qasmi IA, Amin KM. An experimental study of sexual function improving effect of Myristica fragrans Houtt. (nutmeg). BMC Complement Altern Med . 2005;5:16.
18. Cragg GM, Newman DJ, Yang SS. Natural product extracts of plant and marine origin having antileukemia potential. The NCI experience. J Nat Prod . 2006;69(3):488-498.
19. Chirathaworn C, Kongcharoensuntorn W, Dechdoungchan T, et al. Myristica fragrans Houtt. methanolic extract induces apoptosis in a human leukemia cell line through SIRT1 mRNA downregulation. J Med Assoc Thai . 2007;90(11):2422-2428.
20. Lee BK, Kim JH, Jung JW, et al. Myristicin-induced neurotoxicity in human neuroblastoma SK-N-SH cells. Toxicol Lett . 2005;157(1):49-56.
21. Sohn JH, Han KL, Kim JH, Rukayadi Y, Hwang JK. Protective Effects of macelignan on cisplatin-induced hepatotoxicity is associated with JNK activation. Biol Pharm Bull . 2008;31(2):273-277.
22. Checker R, Chatterjee S, Sharma D, et al. Immunomodulatory and radioprotective effects of lignans derived from fresh nutmeg mace ( Myristica fragrans ) in mammalian splenocytes. Int Immunopharmacol . 2008;8(5):661-669.
23. Sharma M, Kumar M. Radioprotection of Swiss albino mice by Myristica fragrans houtt. J Radiat Res (Tokyo) . 2007;48(2):135-141.
24. Forrester MB. Nutmeg intoxication in Texas, 1998-2004. Hum Exp Toxicol . 2005;24(11):563-566.
25. Sangalli BC, Chiang W. Toxicology of nutmeg abuse. J Toxicol Clin Toxicol . 2000;38(6):671-678.
26. El-Alfy AT, Wilson L, ElSohly MA, Abourashed EA. Towards a better understanding of the psychopharmacology of nutmeg: Activities in the mouse tetrad assay. J Ethnopharmacol . 2009;126(2):280-286.
27. Dhingra D, Parle M, Kulkarni SK. Comparative brain cholinesterase-inhibiting activity of Glycyrrhiza glabra, Myristica fragrans , ascorbic acid, and metrifonate in mice. J Med Food . 2006;9(2):281-283.
28. Dhingra D, Sharma A. Antidepressant-like activity of n-hexane extract of nutmeg ( Myristica fragrans ) seeds in mice. J Med Food . 2006;9(1):84-89.
29. Sonavane GS, Palekar RC, Kasture VS, Kasture SB. Anticonvulsant and behavioural actions of Myristica fragrans seeds. Indian J Pharm Sci . 2002;34:332-338.
30. Sonavane GS, Sarveiya V, Kasture V, Kasture SB. Behavioural actions of Myristica fragrans seeds. Indian J Pharm Sci . 2001;33:417-424.
31. Wahab A, Ul Haq R, Ahmed A, Khan RA, Raza M. Anticonvulsant activities of nutmeg oil of Myristica fragrans . Phytother Res . 2009;23(2):153-158.
32. Demetriades AK, Wallman PD, McGuiness A, Gavalas MC. Low cost, high risk: accidental nutmeg intoxication. Emerg Med J . 2005;22(3):223-225.
33. Stein U, Greyer H, Hentschel H. Nutmeg (myristicin) poisoning — report on a fatal case and a series of cases recorded by a poison information centre. Forensic Sci Int . 2001;118(1):87-90.
34. Sonavane GS, Sarveiya VP, Kasture VS, Kasture SB. Anxiogenic activity of Myristica fragrans seeds. Pharmacol Biochem Behav . 2002;71(1-2):239-244.
35. Kelly BD, Gavin BE, Clarke M, Lane A, Larkin C. Nutmeg and psychosis. Schizophr Res . 2003;60(1):95-96.
36. Brenner N, Frank OS, Knight E. Chronic nutmeg psychosis. J R Soc Med . 1993;86(3):179-180.
37. Beyer J, Ehlers D, Maurer HH. Abuse of nutmeg ( Myristica fragrans Houtt.): studies on the metabolism and the toxicologic detection of its ingredients elemicin, myristicin, and safrole in rat and human urine using gas chromatography/mass spectrometry. Ther Drug Monit . 2006;28(4):568-575.
38. Broadhurst CL, Polansky MM, Anderson RA. Insulin-like biological activity of culinary and medicinal plant aqueous extracts in vitro. J Agric Food Chem . 2000;48(3):849-852.
39. Yang S, Na MK, Jang JP, et al. Inhibition of protein tyrosine phosphatase 1B by lignans from Myristica fragrans . Phytother Res . 2006;20(8):680-682.
40. Han KL, Choi JS, Lee JY, et al. Therapeutic potential of peroxisome proliferators—activated receptor-alpha/gamma dual agonist with alleviation of endoplasmic reticulum stress for the treatment of diabetes. Diabetes . 2008;57(3):737-745.
41. Rani P, Khullar N. Antimicrobial evaluation of some medicinal plants for their anti-enteric potential against multi-drug resistant Salmonella typhi . Phytother Res . 2004;18(8):670-673.
42. Shinohara C, Mori S, Ando T, Tsuji T. Arg-gingipain inhibition and anti-bacterial activity selective for Porphyromonas gingivalis by malabaricone C . Biosci Biotechnol Biochem . 1999;63(8):1475-1477.
43. Yanti, Rukayadi Y, Kim KH, Hwang JK. In vitro anti-biofilm activity of macelignan isolated from Myristica fragrans Houtt. against oral primary colonizer bacteria. Phytother Res . 2008;22(3):308-312.
44. Smith-Palmer A, Stewart J, Fyfe L. Influence of subinhibitory concentrations of plant essential oils on the production of enterotoxins A and B and alpha-toxin by Staphylococcus aureus . J Med Microbiol . 2004;53(pt 10):1023-1027.
45. Smith-Palmer A, Stewartt J, Fyfe L. Inhibition of listeriolysin O and phosphatidylcholine-specific production in Listeria monocytogenes by subinhibitory concentrations of plant essential oils. J Med Microbiol . 2002;51(7):567-574.
46. Singh G, Marimuthu P, DeHeluani CS, Catalan C. Antimicrobial and antioxidant potentials of essential oil and acetone extract of Myristica fragrans Houtt. (aril part). J Food Sci . 2005;70:141-148.
47. Chung JY, Choo JH, Lee MH, Hwang JK. Anticariogenic activity of macelignan isolated from Myristica fragrans (nutmeg) against Streptococcus mutans . Phytomedicine . 2006;13(4):261-266.
48. Takikawa A, Abe K, Yamamoto M, et al. Antimicrobial activity of nutmeg against Escherichia coli O157. J Biosci Bioeng . 2002;94(4):315-320.
49. De M, Krishna De A, Banerjee AB. Antimicrobial screening of some Indian spices. Phytother Res . 1999;13(7):616-618.
50. Gonçalves JL, Lopes RC, Oliveira DB, et al. In vitro anti-rotavirus activity of some medicinal plants used in Brazil against diarrhea. J Ethnopharmacol . 2005;99(3):403-407.
51. Narasimhan B, Dhake AS. Antibacterial principles from Myristica fragrans seeds. J Med Food . 2006;9(3):395-399.
52. Firouzi R, Shekarforoush SS, Nazer AH, et al. Effects of essential oils of oregano and nutmeg on growth and survival of Yersinia enterocolitica and Listeria monocytogenes in barbecued chicken. J Food Prot . 2007;70(11):2626-2630.
53. O'Mahony R, Al-Khtheeri H, Weerasekera D, et al. Bactericidal and anti-adhesive properties of culinary and medicinal plants against Helicobacter pylori . World J Gastroenterol . 2005;11(47):7499-7507.
54. Mahady GB, Pendland SL, Stoia A, et al. In vitro susceptibility of Helicobacter pylori to botanical extracts used traditionally for the treatment of gastrointestinal disorders. Phytother Res . 2005;19(11):988-991.
55. Sridhar SR, Rajagopal RV, Rajavel R, Masilamani S, Narasimhan S. Antifungal activity of some essential oils. J Agric Food Chem . 2003;51(26):7596-7599.
56. Zacchino SA, López SN, Pezzenati GD, et al. In vitro evaluation of antifungal properties of phenylpropanoids and related compounds acting against dermatophytes. J Nat Prod . 1999;62(10):1353-1357.
57. Zacchino S, Rodríguez G, Pezzenati G, Orellana G, Enriz R, Gonzalez Sierra M. In vitro evaluation of antifungal properties of 8.O.4'-neolignans. J Nat Prod . 1997;60(7):659-662.
58. Dew TP, Day AJ, Morgan MR. Xanthine oxidase activity in vitro: effects of food extracts and components. J Agric Food Chem . 2005;53(16):6510-6515.
59. Tomaino A, Cimino F, Zimbalatti V, et al. Influence of heating on antioxidant activity and the chemical composition of some spice essential oils. Food Chem . 2005;89:549-554.
60. Kumaravelu P, Subramaniyam S, Dakshinamoorthy DP, Devaraj NS. The antioxidant effect of eugenol on Ccl,-induced erythrocyte damage in rats. J Nutr Biochem . 1996;7:23-28.
61. Tezuka Y, Irikawa S, Kaneko T, et al. Screening of Chinese herbal drug extracts for inhibitory activity on nitric oxide production and identification of an active compound of Zanthoxylum bungeanum . J Ethnopharmacol . 2001;77(2-3):209-217.
62. Sohn JH, Han KL, Choo JH, Hwang JK. Macelignan protects HepG2 cells against tert-butylhydroperoxide-induced oxidative damage. Biofactors . 2007;29(1):1-10.
63. Ho SC, Tsai TH, Tsai PJ, Lin CC. Protective capacities of certain spices against peroxynitrite-mediated biomolecular damage. Food Chem Toxicol . 2008;46(3):920-928.
64. Suganthi R, Rajamani S, Ravichandran MK, Anuradha CV. Effect of food seasoning spices mixture on biomarkers of oxidative stress in tissues of fructose-fed insulin-resistant rats. J Med Food . 2007;10(1):149-153.
65. Cho Y, Kim KH, Shim JS, Hwang JK. Inhibitory effects of macelignan isolated from Myristica fragrans HOUTT. on melanin biosynthesis. Biol Pharm Bull . 2008;31(5):986-989.
66. Anggakusuma, Yanti, Hwang JK. Effects of macelignan isolated from Myristica fragrans Houtt. on UVB-induced matrix metalloproteinase-9 and cyclooxygenase-2 in HaCaT cells. J Dermatol Sci . 2010;57(2):114-122.
67. Olajide OA, Ajayi FF, Ekhelar AI, Awe SO, Makinde JM, Alada AR. Biological effects of Myristica fragrans (nutmeg) extract. Phytother Res . 1999;13(4):344-345.
68. Ma J, Hwang YK, Cho WH, Han SH, Hwang JK, Han JS. Macelignan attenuates activations of mitogen-activated protein kinases and nuclear factor kappa B induced by lipopolysaccharide in microglial cells. Biol Pharm Bull . 2009;32(6):1085-1090.
69. Morita T, Jinno K, Kawagishi H, et al. Hepatoprotective effect of myristicin from nutmeg ( Myristica fragrans ) on lipopolysaccharide/d-galactosamine-induced liver injury. J Agric Food Chem . 2003;51(6):1560-1565.
70. Lee SU, Shim KS, Ryu SY, Min YK, Kim SH. Machilin A isolated from Myristica fragrans stimulates osteoblast differentiation. Planta Med . 2009;75(2):152-157.
71. Jan M, Faqir F, Hamida, Mughal MA. Comparison of effects of extract of Myristica fragrans and verapamil on the volume and acidity of carbachol induced gastric secretion in fasting rabbits. J Ayub Med Coll Abbottabad . 2005;17(2):69-71.
72. Jan M, Faqir F, Qureshi H, Malik SA, Mughal MA. Evaluation of effects of extract from seeds of Myristica fragrans on volume and acidity of stimulated gastric secretion, liver and kidney function. J Postgrad Med Inst . 2004;18:644-650.
73. Brancaccio RR, Alvarez MS. Contact allergy to food. Dermatol Ther . 2004;17(4):302-313.
74. Schöll I, Jensen-Jarolim E. Allergenic potency of spices: hot, medium hot, or very hot. Int Arch Allergy Immunol . 2004;135(3):247-261.
75. Burdock GA, Carabin IG. Safety assessment of myristic acid as a food ingredient. Food Chem Toxicol . 2007;45(4):517-529.
76. Miller EC, Swanson AB, Phillips DH, Fletcher TL, Liem A, Miller JA. Structure-activity studies of the carcinogenicities in the mouse and rat of some naturally occurring and synthetic alkenylbenzene derivatives related to safrole and estragole. Cancer Res . 1983;43(3):1124-1134.
77. De Vincenzi M, Silano M, Stacchini P, Scazzocchio B. Constituents of aromatic plants: I. Methyleugenol. Fitoterapia . 2000;71(2):216-221.
78. Barceloux DG. Nutmeg ( Myristica fragrans Houtt.). Dis Mon . 2009;55(6):373-379.
Copyright © 2009 Wolters Kluwer Health