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Myristica fragrans

 Synonyms

 Myristica moschata Thunb; Myristica aromatica Lam., Myristica officinalis Linn. [1]

Vernacular Names:

Malaysia: Buah Pala, Pokok Pala
Indonesia:  PahaIo / Paala / PaIa bibinek
Thailand:  Chan thet, Chan ban, Chan ban, Chand nattes, Luk chand
Vietnam:  Dau khau, Nhuc dau khau
Cambodia:  Pock kak
Burma:  Mutwinda
Laos:  Chan thed
Philippines:  Duguan
China:  Dauh kau syuh, Yuhk dauh kau (Cantonese); Dou kou shu, Rou dou kou (Mandarin)
Korea:  Neotumek, Notumek, Yuktugu
Japan:  Natumegu
India:  Jaiphol (Assam); Jayphal (Bengal); Jaipatri (Gujerat); Jaiphal (Hindi); Jakaya, Jatipala (Kannada); Jaiphar (Maithili); Jathi, Jathikka, Jathikkayu, Jathikosham (Malayalam); Jayphal (Marathi); Jaiphal (Nepal); Jaiphala (Oriya); Jaiphal (Punjab); Jatiphala (Sanskrit); Atipalam, Jatikkai, Jatippu (Tamil); Jaiphal (Urdu) [1]

General Information

Description

Myristica fragrans is an evergreen tree that can grow up to 30 m in height with an undivided trunk. The bark is smooth and greyish brown with branches greenish in colour. The leaves are dark green in colour, ovate-elliptical in shape, leathery with edges sharp and margins entire. The petioles are short in length. Male and female flowers are normally borne on separate trees but sometime they can appear on the same tree. The male flowers are small, white and appear on the leaf axil. The female flowers appear in an inflorescence of 3-4 flowers. They are white with bell-shaped perianth and a one celled ovary ending in a 2-lobed stigma. The fruit is light yellow in colour, fleshy and almost round and acuminate at the stem at the stem end. It measure 3-6 cm long and 2-5 cm thick. The fruit begins to ripen 7-10 months after flowering. [3]

Plant Part Used

What is termed nutmeg is actually referring to the seeds of the plant M. fragrans and mace it the red net-like aril found encasing the fruit. Other parts of the plant are seldom used as medicine. [3]

Chemical Constituents

1,8-cineole; 1-(3,4,5-trimethoxyphenyl)-2-(4-allyl-2,6-dime...propan-1-ol; 1-(4-hydroxy-3-methoxyphenyl)-2-(4-allyl-2,6di...propan-1-ol; 2-(4-allyl-2,6-dimethoxyphenoxy)-1-(3,4-methylenedioxyphenyl)-1-propanol; 2-(4-allyl-2,6-dimethoxyphenoxy)-1-(4-hydroxy-3-methoxyphenyl)-1-propanol; 5-methoxydehydrodi-isoeugenol; 6-methoxydihydroisoeugenol; alpha-terpineol; cis-p-ment-2-en-1-ol; terpinen-4-ol; 1-(3,4,5-trimethoxyphenyl)-2-(4-allyl-2,6-dimethox...propane; 2-(4-allyl-2,6-dimethoxyphenoxy)-1-(3,4,5-trimethoxyphenyl)-propane; 1-(3,4-methylenedioxyphenyl)-2-(4-allyl-2,...propyl-acetate;1-(3,4-methylenedioxyphenyl)-2-(4-allyl-2,...propyl-benzoate; 1-(5-acetoxy-3,4-dimethoxyphenyl) -2-(4-ally...propyl-acetate; -bergamoptene; -cubebene; -copaene;- pinene; -terpineol and esters.; -thujene; -phellandrene; -terpinene; acetic-acid; amylodextrin; -bisabolene; -cariophylene; -pinene; borneol; butyric-acid; camphene; catechin; cineole; citronellal; cis-sabinene; cis-piperitol; cis-p-menth-2-enol; cis-piperitol; cis-sabinene-hydrate; camphene; caprylic acid and their esters; cerotinic-acid; copaene; cymene; cyanidin; -cadinene, decanal; dehydroisoeugenol; dihydroisoeugenol, dipentene, -cymene, -terpinene, geraniol, sabinene, linalool, limonene, malabaricon B & C, terpinen-4-ol, myristicin, elemicin, isoelemecin, safrole, isosafrole, eugenol, isoeugenol, methyleugenol, methylisoeugenol, methoxyeugenol; lauric acid, tridecanoic acid, palmitic, stearic acid, mysritic acid;formic acid, proanthocynidins, lignans, prolignans; eugenol; furfurol; geraniol; isoeugenol; kaempferol; linalol; methyl-eugenol; methyl-isoeugenol; methoxyeugenol; geranyl-acetate; terpinen-4-yl-acetate; trans-sabinene-hydrate [1]

formic-acid; hexadecanoic-acid; lauric-acid; linoleic-acid; macilenic-acid; palmitic-acid macilolic-acid; myristic-acid; oleanolic-acid; oleic-acid; stearic-acid; d-alpha-pinene; d-beta-pinene; dipentene; elemene; gamma-terpinene limonene; myrcene; p-cymene; pinene; sabinene; terpinolene; elemicin; guaiacin; myristicin; quercetin; riboflavin; thiamin d-borneol; sclareol; terpineol; furfural; malabaricone-b; malabaricone-c; pectin; pentosans; phytosterols; safrole 

Traditional Used:

Amongst the Malay community where M. fragrans is native the seeds are considered to be an aphrodisiac where it is believed to restore male virility. Knowledge of this use spreads westwards and is much revered by the Arab community as an aphrodisiac as mentioned in Purfumed Gardens. The Africans, Egyptians, Moroccans and Indian Muslims had attributed this property to the seeds and have recommended minute amounts of the seed for this purpose.  

The seeds is considered an abortifacient and had been used to procure it in many European countries is the past including the Britian and the Germany. It is considered an emmenagogue and is also recommended for cases of dysmenorrhoea. Roasted nutmeg is used internally for leucorrhoea. In India the leaves in combination with Vitex negundo, Mimosa pudica, Asparagus gonocladus, Cucumis melo, and Staryx officinalis evapourated in milk is made used of to impart sterility. [2][3] 

Nutmeg and their outer shell strengthens the stomach, promotes digestion, stops vomiting and diarrhoea. Grated nutmeg in a glass of old wine is a good remedy for diarrhoea. A slice of toasted bread, rubbed on with nutmeg powder and dip in wine when placed over the navel of pregnant women would allay gripes and all kinds of dysentery. It is believed that this could also strengthen the fetus and prevent premature birth. It will also provide excellent relieve of labour pains. [2]

To treat haemorrhoids a rectal suppository is made from the seeds by Morocan practioners. [3] 

Nutmeg is used in the treatment of headaches, bodyaches and joint pains apart from relieving stomach gripes. [2] 

The dried seeds are considered a diuretic and this had been taken advantage of in Brazil to be used in the treatment of hypertension. Its sedative action also helps in reducing the blood pressure. In Singapore it is the hot water extract of the leaves that is being used to treat hypertension. [3] 

Pre-Clinical Data

Pharmacology


Hepatoprotective activity 

The compound myristicin, one of the major compound in the M. fragrans, was found to have extraordinary hepatoprotective activity. It was found to have markedly inhibited the lipopolysaccharide (LPS) plus d-galactosamine (D-GalN)-induced enhancement of serum TNF-alpha concentrations and hepatic DNA fragmentation in mice. Thus it was suggested that the hepatoprotective activity of myristicin might be, at least in part, due to the inhibition of TNF-alpha release from macrophages. [4] 

Mace is known to have hepatic detoxification system inducing activities. A study was done to see whether areca nut has modulatory effects on this system. This was assessed by determining the levels of enzymes of the hepatic detoxification system, such as glutathione S-transferase (GST), cytochrome b5 and cytochrome P-450, and the content of acid-soluble sulphhydryl (-SH). At the end of the trial period it was found that areca nut decreases the mace-induced increases in hepatic GST and -SH levels and elevated further increases in the levels of cytochrome b5 and cytochrome P-450. [5] 

In a more recent study it was found that macelignans were responsible for the hepatoprotective activity of mace. Macelignan actually attenuated the expression of phosphorylated c-Jun in cisplatin-treated mice, suggesting that this effect could be related to the activation of the MAPK signaling pathway, especially JNK and c-Jun, its substrate. [6] 

Antidiarrhoeal activity 

The hexane fraction of the ethanol extract of the fruit and flowers of M. fragrans was found to have the most antisecretory activity against Eschericia coli heat labile and heat stable enterotoxin. In the rabbit and guinea pic ileal loops, this fraction (300 mg/loop) inhibited toxin-induced secretory responses. [7] 

Anticancer activity 

It had been demonstrated that the methanol extract of M. fragrans significantly inhibited Jurkat cell proliferation and induced apoptosis. There was a downregulation of the SIRT1 (Silent Iinformation Regulator Two ortholog 1; it is one of the regulators of cell life span and is involved in aging-associated processes) mRNA expression in the Jurkat cells even when the amount of the extract was 10mg/mL. [8] 

Memory enhancing activity 

The recovery ability of learning and memory of extracts of M. fragrans, on young and aged mice were studied against their impairment induced by scopolamine (0.4mg/kg intraperitoneal) and diazepam (1mg/kg intraperitoneal). n-hexane extract of M. fragrans was given orally in a dose of 5, 10, & 20 mg/kg p.o. and the mice were observed for three days. It was found that the extract even at the lowest dose exhibit significant improvement in the learning and memory of both the young and aged mice. It had reversed the impairment induced by scopolamine and diazepam in young mice and it also enhanced the learning and retention capabilities of both young and aged mice. The mechanism of action was not illicited in this studies but the authors believed that it is a multipronge mechanism based of the proven anti-oxidant, anti-inflammatory and the procholinergic activities of this plant. [9] 

Anticholinesterase inhibition currently forms the basis of treatment of Alzheimer’s Disease by reducing the cognitive decline caused by reduced cholinergic deficits. In the search for a herbal solution to the problem of Alzheimer’s Disease, Mukherjee et.al found that hydroalcohol extract of M fragrans did show significant (50%) inhibition of acetylcholinesterase. [10] 

Radioprotective activity 

Irradiation resulted in significant elevation of testicular lipid peroxidation (LPO) level and acid phosphatase (ACP) and decrease in hepatic glutathione (GSH), and alkaline phosphatase (ALP). This forms the basis of a study on the radioprotective effects of ethanol extract of seeds of M. fragrans on Swiss Albino mice. It was found that pre-treatment with the extracts effectively protected these mice against the effects of irradiations as evidenced by the decrease in LPO level and ACP activity and the increase in GSH and ALP activities. [11] 

Antimicrobial activity

Two resorcinol compounds isolated from the mace of M. fragrans has been found to have strong antifungal and antibacterial activities. These two compounds are malabaricon B & C. [12] 

In the process of early formation of plaques on teeth, oral primary colonizers such as Streptococcus mutans, Streptococcus sanguis and Actinomyces viscosus are initially attached to the pellicle-coated tooth surface3 to form a biofilm. It was found that exposure of these biofilm to macelignan, isolated from M. fragrans . could help reduce the extent of these biofilms. [13] 

Anti-inflammatory activity 

The anti-inflammatory activity of methanol extract of mace was carried out on carrageenin-induced edema in rats and acetic acid-induced vascular permeability in mice and was compared with those of indomethacin. It was found that fraction FIV of the n-hexane soluble fraction of methanol extract of mace (myristicin) had anti-inflammatory actions. [14] 

Anticancer activity 

Induction of precancerous and cancerous growth was done in virgin female Swiss albino mice cervical canal as a way of determining the chemoprotective activity of mace. It was found that pre-treatment of these mice with 10mg per mouse of mace per day for 7 days and 90 day following insertion of carcinogenic thread, has resulted in a decrease of incidence of cancer. [15] 

Aphrodisiac activity 

A 50% ethanolic extract of the seeds of M. fragrans was given to a group of mice and their mounting behaviour, mating activity and short term toxicity was observed against those being given c50% clove extract and sildenafil citrate. It was found that the extracts of cloves and nutmeg did stimulate the mounting behaviour and mating activities. The drugs were devoid of short term toxicity. [16] 

Antilipidaemic activity 

When M. fragrans seed extracts were given in hypercholesterolaemic rabbits, it would found that there were reduction in serum cholesterol and LDL Cholesterol by 69.1% and 76.3% respectively and also lowered cholesterol/phospholipid ratio by 31.2% and elevated the decreased HDL-ratio significantly. It was also observed that it also prevented the accumulation of cholesterol, phospholipids and triglycerides in liver, heart and aorta and dissolved atheromatous plaques of aorta by 70.9-76.5%. Fecal excretion of cholesterol and phospholipids was also increase in treated rabbits. [17] 

Osteoblast proliferation stimulation activity 

Compounds isolated from M. fragrans showed ability to stimulate osteoblastic differentiation. Machilin A does this by activating p38 MAP kinase. Other lignans from M. fragrans also showed similar action and they include macelignan, machilin F, nectandrin B, safrole, licarin A, licarin B, myristagenol and mesodihydrogaularetic acid. This suggests that lignans from M. fragrans have anabolic activity in bone metabolism. [18] 

Inhibtion of melanogenesis activity 

Inhibitory activities of tyrosinase and DOPA auto-oxidation are two tests that would reflect on melanogenisis. In a study of 100 plants to determine their ability to inhibit melanogenesis Lee et.al found that extract of .M. fragrans could inhibit the activity of tyrosinase. [19] Cho Y et.al found that macelignan could effectively inhibit melanogenesis by inhibiting tyrosinase, tyrosinase-related protein-1 (TRP-1), and tyrosinase-related protein-2 (TRP-2) in melan-a murine melanocytes. In Western blot analysis, macelignan also significantly decreased tyrosinase, TRP-1, and TRP-2 protein expression. These results indicate that macelignan effectively inhibits melanin biosynthesis. [20]

Toxicities

Toxicokinetics 

The main toxic principle of nutmeg oil is myristicin (natural oranic compound of nutmeg) though other terpenes may be involved in the elicitation of the symptoms and signs of toxicity. Reported cases of toxicity shows that symptoms and signs appear after 2 – 3 hours of ingestion of 1 – 3 whole nuts or 1 – 2 tablespoons of the powder. The hepatic P450 system seems to metabolize myristicin into 5-ally-1-methoxy-2,3-dihydrobenzene which then undergoes glucuronidation and urinary excretion.  [21] 

Pathophysiology 

It appears that myristicin induced CNS toxicity may be the result of increased concentration of serotonin in the brain. Myristicin is an MAO inhibitor which could lead to an adverse reaction if taken with another MAO inhibitor. It was also shown that myristicin is also converted into an amphetamine derivative 3-methoxy-4,5-methylene dioxyamphetamine which accounts for it euphoric effects. There were noted liver fatty infiltration with nutmeg oil toxicities. [21] 

Clinical Features 

The most prominent feature of nutmeg oil toxicity is its CNS effects, which seems to mimic anticholinergic toxicity i.e. flushing, dryness, tachycardia, hypertension, agitation and altered mental status. One important feature differentiating anticholinergic toxicity from nutmeg oil toxicity is the presence of miosis. 

Increasing the does will result in increase drowsiness ending up in coma. The symptoms typically subside within 24 hours and so far only one case of death from nutmeg poisoning had been reported. [21] 

Clinical Data

Clinical Trials

No documentation

Adverse Effects in Human:

Sastre et al reported a case of allergic reaction to mace power in a 27 year old male subject. He had an immediate positive allergic reaction on skin prick test (SPT) against mace powder. It was demonstrated that inhalation of mace powder resulted in an IgE-mediated reaction. [22]

Used in Certain Conditions

Pregnancy / Breastfeeding

Pregnant women should not take nutmeg or be wary of the presence of nutmeg in food due to its abortifacient properties and its traditional use for the procurement of abortion. [3]

Age Limitations

Neonates / Adolescents

Due to its hallucinating properties its use in children should be avoided. [21]

Geriatrics

No documentation

Chronic Disease Conditions

No documentation

Interactions

Interactions with drugs

No documentation

Interactions with Other Herbs / Herbal Constituents

No documentation

Contraindications

Contraindications

No documentation

Case Reports

A 23 year old patient was brought to the Emergency Department of the General Hospital Dr. Manual Gea Gonzales, Mexico, in a state of general discomfort and dizziness. Ten hours prior to this he had consumed a whiskey, 2 beers and 50 G of nutmeg. Five hours later he complained of nausea and dizziness and vomiting was induced. Eight hours later he complained of feeling of “impending doom”, palpitation and hallucination with visual impression of the wall of the room getting closer. Upon examination there was slight midriasis with reactive pupils, orthostatic hypotension (Lying BP 120/55; standing 70/30). [23]

Read More

  1) Botanical Info

  2) Essential Oil

References

  1. V. Silano, A. Robert. Plantes dans les cosmétiques. Strasbourg: Council of Europe; 2001.107.
  2. W. William. Weaver Sauer's herbal cures: America's first book of botanic healing 1762-1778. London: Taylor & Francis; 2001.225 – 226.
  3. A.R. Ivan. Medicinal plants of the world Volume 2. Totowa: Humana Press; 2001.334.
  4. T. Morita, K. Jinno, H. Kawagishi, Y. Arimoto, H. Suganuma, T. Inakuma, K. Sugiyama. Hepatoprotective effect of myristicin from nutmeg (Myristica fragrans) on lipopolysaccharide/d-galactosamine-induced liver injury. J Agric Food Chem. 12Mar2003;51(6):1560-1565.
  5. A. Singh, A.R. Rao. Modulatory effect of Areca nut on the action of mace (Myristica fragrans, Houtt) on the hepatic detoxification system in mice. Food Chem Toxicol. Jul1993;31(7):517-521.
  6. J.H. Sohn, K.L. Han, J.H. Kim, Y. Rukayadi, J.K. Hwang. Protective Effects of macelignan on cisplatin-induced hepatotoxicity is associated with JNK activation. Biol Pharm Bull. Feb2008;31(2):273-277.
  7. G. Shashi Gupta, J. N. S. Yadava, M. Rita, J. S. Tandon. Anti-diarrhoea Profile of an Extract and Some Fractions from Myristica fragrans (Nut-meg) on Escherichia coli Enterotoxin-Induced Secretory Response. Pharmaceutical Biology.1992; 30(3):179 – 183.
  8. C. Chintana, K. Wisatre, D. Thitiporn, L. Alisa, S. Pattaratida, P. Yong Poovorawan. 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.
  9. P. Milind, D. Dinesh, S.K. Kulkarni. Improvement of memory by Myristica fragrans Houtt. Seeds, Journal of Medicinal Food. June2004; 7(2): 157-161.
  10. P.K. Mukherjee, V. Kumar, P.J. Houghton. Screening of Indian medicinal plants for acetylcholinesterase inhibitory activity. Phytother Res. Dec2007;21(12):1142-1145.
  11. S. Mini and K. Madhu. Radioprotection of Swiss Albino mice by Myristica fragrans Houtt. J. Radiat. 2007;48:135 – 141.
  12. K.Y. Orabi, J.S. Mossa, F.S. Feraly. Isolation and characterization of two antimicrobial agents from mace (Myristica fragrans). J-Nat-Prod. May-Jun1991; 54(3): 856-859.
  13. Yanti, Y. Rukayadi, K.H. Kim, J.K. Hwang. In vitro anti-biofilm activity of macelignan isolated from Myristica fragrans Houtt. against oral primary colonizer bacteria. Phytother Res. Mar2008;22(3):308-312.
  14. O. Yukihiro, S. Soekeni, R.W. Yoke and G.S. Asep. Antiinflammatory Effect of Mace, Aril of Myristica fragrans HOUTT., and Its Active Principles. The Japanese Journal of Pharmacology. 49(2);1989.155-163.
  15. S.P. Hussain, A.R. Rao. Chemopreventive action of mace (Myristica fragrans, Houtt) on methylcholanthrene-induced carcinogenesis in the uterine cervix in mice. Cancer Lett. Mar 1991;56(3):231-234.
  16. Tajuddin, A. Shamshad, L.. Abdul and A.Q. Iqbal. 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 Complementary and Alternative Medicine. 3(6);2003. 
  17. A. Sharma, R. Mathur, V.P. Dixit. Prevention of hypercholesterolemia and atherosclerosis in rabbits after supplementation of Myristica fragrans seed extract. Indian J Physiol Pharmacol. Oct 1995;39(4):407-410.
  18. S.U. Lee, K.S. Shim, S.Y. Ryu, Y.K. Min, S.H. Kim. Machilin A isolated from Myristica fragrans stimulates osteoblast differentiation. Planta Med. Feb2009;75(2):152-157.
  19. K.T. Lee, B.J. Kim, J.H. Kim, M.Y. Heo, H.P. Kim. Biological screening of 100 plant extracts for cosmetic use (I): inhibitory activities of tyrosinase and DOPA auto-oxidation. Int J Cosmet Sci. Dec1997;19(6):291-298.
  20. Y. Cho, K.H. Kim, J.S. Shim, J.K. Hwang. Inhibitory effects of macelignan isolated from Myristica fragrans HOUTT. on melanin biosynthesis. Biol Pharm Bull. May2008;31(5):986-989.
  21. R.G. Lewis, F. Neal, A.H. Mary, S. Robert. Hoffman Goldfrank's toxicologic emergencies. New York: McGraw-Hill Professional; 2006.660.
  22. J. Sastre, M. Olmo, A. Novalvos, D. Ibañez, C. Lahoz. Occupational asthma due to different spices. Allergy. Feb1996;51(2):117-120.
  23. P.D Juan, J.B.N Juan, R.M. Santos b, O.M. Javier. Nutmeg Poisining. Med Clin (Barc). 2008, 131:639

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