Medication Guide App

Betel Nut

Scientific Name(s): Areca catechu L. Family: Palmaceae (palms)

Common Name(s): Betel nut , areca nut , paan , paan-gutkha pinlang , pinang , supari

Uses

Limited clinical applications exist, and long-term adverse reactions to betel quid chewing are well documented. A decrease in positive symptoms among men with schizophrenia was attributed to betel nut consumption.

Dosing

Limited clinical trials exist to guide dosage; limited clinical applications exist.

Contraindications

None well documented.

Pregnancy/Lactation

Documented adverse reactions, including teratogenic and fetotoxic effects. Avoid use.

Interactions

None well documented.

Adverse Reactions

Betel nut prevalence data strongly associates consumption with the incidence of metabolic syndrome.

Toxicology

Areca nut and the betel leaf have demonstrated mutagenic, carcinogenic, and genotoxic properties in in vitro and animal experiments. Prevalence studies show a dose- and duration-dependent association of betel quid chewing with precancerous oral submucous fibrosis and oral, pharyngeal, laryngeal, and esophageal cancer.

Botany

The areca tree is a tropical, feathery palm that grows to approximately 15 m in height and bears fruit year round. It is widely cultivated in tropical India, Bangladesh, Japan, Sri Lanka, south China, the East Indies, the Philippines, and parts of Africa. The nut is approximately 2.5 cm in length and may be used fresh, dried, or cured by boiling, baking, or roasting. 1 , 2 The quid is a mixture of areca nut, tobacco, and lime wrapped in the leaf of the betel vine ( Piper betel L. Family: Piperaceae).

History

The chewing of betel nut quids dates to antiquity. In the 1st century AD, Sanskrit medical writings claimed that betel nut possessed 13 qualities found in the region of heaven. It is pungent, bitter, spicy, sweet, salty, and astringent. It expels wind, kills worms, removes phlegm, subdues bad odors, beautifies the mouth, induces purification, and is said to kindle passion. 3

Because of its mild CNS-stimulating effects, betel nut is used in a manner similar to the western use of tobacco or caffeine. 4 Arecoline is thought to be responsible for some of the claimed effects of betel quid chewing, such as alertness, increased stamina, a sense of well-being, euphoria, and salivation. 5

Chewing the nut stimulates salivary flow, thereby aiding digestion. Betel nut also has been used as an appetite stimulant. 2

Extracts of the nut have been used for the management of glaucoma in traditional medicine. 6 Arecoline is a basic oily liquid that has been used in veterinary medicine as a cathartic (for horses) and a vermifuge.

Chemistry

The medicinal components are primarily associated with the nut and betel quid. The nuts contain at least 9 structurally related pyridine alkaloids, including arecoline, arecaidine, arecaine, arecolidine, guvacine, isoguvacine, guvacoline, and coniine. However, the most common is the parasympathetic stimulant alkaloid arecoline. The total alkaloid content can reach 0.45%. 2 , 4 , 7 , 8

The methyl esters of arecoline and guvacoline are hydrolyzed in the presence of alkali to the respective acids, arecaidine and guvacine. The hydrolysis is catalyzed by lime, which is added to the quid. Arecoline most likely is present in the nut as a salt of tannic acid, and the lime facilitates the release of the base from the salt. 8

Components of the betel quid, most likely from P. betel and not betel nuts, contain about 1% of a volatile oil, chalbetol, chavicol, cadinene, allylpyrocatechol, and safrole. 2 , 9

Uses and Pharmacology

Limited clinical applications exist, and long-term adverse reactions to betel quid chewing are well documented.

CNS Effects
Clinical data

Studies evaluating the effects of betel nut chewing suggest that a variety of the chemical compounds found in areca may exert activity. Arecoline demonstrates parasympathomimetic action on muscarinic and nicotinic receptors; arecaidine and guvacine act as gamma-aminobutyric acid uptake inhibitors, while phenolic compounds in the leaf stimulate the release of catecholamines. 5 Electroencephalograph changes have been observed, with alpha and beta wave activity increased and theta decreased. Increases in plasma noradrenaline and adrenaline have been observed among betel nut chewers. 5 , 8

In 65 patients with schizophrenia, a decrease in positive symptoms as measured by the Positive and Negative Syndrome Scale was observed among men who were high-consumption betel nut chewers (more than 7.5 whole betel nuts/day). No significant relationships existed between betel chewing and positive or negative symptoms among women. 10 , 11 The muscarinic cholinomimetic action of the alkaloids may be responsible for this effect, but a mechanism of action has not been determined. 11

Cardiovascular effects
Animal data

Betel nuts contain a tannin with angiotensin-converting enzyme inhibitory activity in vitro. The activity of this tannin was shown to be comparable with captopril in an older experiment in rats. 12

Clinical data

An acute cardiovascular response (hypertension and increased cardiac rate) to betel nut occurs in new chewers, but abates with chronic use. 8 , 13 A review of this data and further study suggests this effect has a genetic dependency. 13 A clinical application for this effect is unlikely considering the increased risk of cardiovascular disease associated with areca nut consumption.

Dosage

Limited clinical trials exist to guide dosage; limited clinical applications exist. A dose of arecoline 5 to 20 mg was used in a study of appetite suppression. 14

Betel nut is widely available in East Asian grocery stores in the United States, and is commonly sold with tobacco as an additive. Other additives may include catechun tree extract, spices, and sweeteners. 15 The quid generally is composed of a mixture of tobacco, powdered or sliced areca nut, and slaked lime (calcium hydroxide paste). 2 , 15 This mixture is wrapped in the leaf of the betel vine. Users may chew from 4 to 15 quids a day, with each quid being chewed for about 15 minutes. 2

Pregnancy/Lactation

Avoid use. Documented adverse reactions, including teratogenic and fetotoxic effects. 16 Arecoline has been found in the meconium and placenta, and case reports exist of neonatal withdrawal syndrome. 17 , 18

Interactions

Information is lacking. Arecoline may antagonize the anticholinergic action of procyclidine, causing extrapyramidal symptoms. 19 An experiment in rats showed inhibition of monoamine oxidase type A isolated from the brain. 20

Adverse Reactions

It is reported that between 10% and 25% of the world's population chews betel quid, and betel quid chewing is considered to be the world's 4th most common addiction. 21 , 22 , 23 , 24 , 25 , 26 Acute toxicity is considered rare, but may be clinically important. 8 , 27 , 28

Metabolic syndrome

The consumption of betel nut has been associated with the development of obesity and hyperglycemia in mice, and with type 2 diabetes in humans. 8 , 26 , 29

Large population-based prevalence studies have consistently shown an increased risk of cardiovascular disease among betel nut chewers. 26 , 30 , 31 , 32 Hypertriacylglycerol has shown the strongest statistical association with betel nut consumption, but hypertension and hyperglycemia are also important. Interference with vitamin D and homocysteine metabolism, factors associated with cardiovascular disease and metabolic syndrome, has also been demonstrated. 25 , 33 All-cause mortality has also been found to be higher among betel quid chewers. 32 A gender bias has been demonstrated in some, but not all, studies; men are higher consumers and for longer periods of time. 26 , 30 , 31

Other adverse reactions

An increased risk of peptic ulceration has been reported despite the use of betel quid chewing to aid digestion. 8 Older case reports suggest a worsening of bronchoconstriction and reduced forced expiratory volume in the first second of expiration in asthmatics chewing betel nut. 34 , 35

Toxicology

Betel nut and the betel leaf have demonstrated mutagenic, carcinogenic, and genotoxic properties in vitro and in animal experiments. 36 , 37 , 38 Additionally, the betel nut is suggested to possess immunosuppressive activity. 8 , 39 , 40 The addition of slaked lime to the quid facilitates the production of nitrosamines and reactive oxygen species, and nitrosamines from the betel nut have been shown to be mutagenic and carcinogenic. 36 , 40 , 41 , 42 Prevalence studies and other epidemiological data have shown a dose- and duration-dependent association of betel quid chewing with precancerous oral submucous fibrosis and oral, pharyngeal, laryngeal, and esophageal cancer. 23 , 39 , 41 , 42 , 43 , 44 , 45

Increases in serum aminotransferases have been noted in rats regularly fed betel nut, 8 and an increase in the incidence of hepatocellular carcinoma has been described among chewers of betel quid. 40 This effect may be due in part to the high level of safrole content of the betel leaf, which has been implicated in liver carcinogenesis, and was measured in the saliva of betel quid chewers as well as in the hepatocellular tissue. 4 , 40

Bibliography

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2. Arjungi KN. Areca nut: a review. Arzneimittelforschung . 1976;26(5):951-956.
3. Williams S, Malik A, Chowdhury S, Chauhan S. Sociocultural aspects of areca nut use. Addict Biol . 2002;7(1):147-154.
4. Lord GA, Lim CK, Warnakulasuriya S, Peters TJ. Chemical and analytical aspects of areca nut. Addict Biol . 2002;7(1):99-102.
5. Chu NS. Neurological aspects of areca and betel chewing. Addict Biol . 2002 Jan;7(1):111-114.
6. Morton JF. Major Medicinal Plants: Botany, Culture, and Uses . Springfield, IL: Charles C. Thomas Publishing Ltd; 1977.
7. Duke JA. CRC Handbook of Medicinal Herbs . Boca Raton, FL: CRC Press; 1985.
8. Boucher BJ, Mannan N. Metabolic effects of the consumption of Areca catechu . Addict Biol . 2002;7(1):103-110.
9. Chen CL, Chi CW, Chang KW, Liu TY. Safrole-like DNA adducts in oral tissue from oral cancer patients with a betel quid chewing history. Carcinogenesis . 1999;20(12):2331-2334.
10. Sullivan RJ, Allen JS, Otto C, Tiobech J, Nero K. Effects of chewing betel nut ( Areca catechu ) on the symptoms of people with schizophrenia in Palau, Micronesia. Br J Psychiatry . 2000;177:174-178.
11. Sullivan RJ, Andres S, Otto C, Miles W, Kydd R. The effects of an indigenous muscarinic drug, betel nut ( Areca catechu ), on the symptoms of schizophrenia: a longitudinal study in Palau, Micronesia. Am J Psychiatry . 2007;164(4):670-673.
12. Inokuchi J, Okabe H, Yamauchi T, Nagamatsu A, Nonaka G, Nishioka I. Antihypertensive substance in seeds of Areca catechu L. Life Sci . 1986;38(15):1375-1382.
13. Chung FM, Shieh TY, Yang YH, et al. The role of angiotensin-converting enzyme gene insertion/deletion polymorphism for blood pressure regulation in areca nut chewers. Transl Res . 2007;150(1):58-65.
14. Strickland SS, Veena GV, Houghton PJ, Stanford SC, Kurpad AV. Areca nut, energy metabolism and hunger in Asian men. Ann Hum Biol . 2003;30(1):26-52.
15. Blank M, Deshpande L, Balster RL. Availability and characteristics of betel products in the U.S. J Psychoactive Drugs . 2008;40(3):309-313.
16. Brinker FJ. Herb Contraindications and Drug Interactions: With Appendices Addressing Specific Conditions and Medicines . 2nd ed. Sandy, OR: Eclectic Medical Publications; 1998.
17. García-Algar O, Vall D, Alameda F, et al. Prenatal exposure to arecoline (areca nut alkaloid) and birth outcomes. Arch Dis Child Fetal Neonatal Ed . 2005;90(3):F276-F277.
18. López-Vilchez MA, Seidel V, Farré M, García-Algar O, Pichini S, Mur A. Areca-nut abuse and neonatal withdrawal syndrome. Pediatrics . 2006;117(1):e129-e131.
19. Deahl M. Betel nut-induced extrapyramidal syndrome: an unusual drug interaction. Mov Disord . 1989;4(4):330-332.
20. Dar A, Khatoon S. Behavioral and biochemical studies of dichloromethane fraction from the Areca catechu nut. Pharmacol Biochem Behav . 2000;65(1):1-6.
21. Strickland SS. Anthropological perspectives on use of the areca nut. Addict Biol . 2002;7(1):85-97.
22. Pickwell SM, Schimelpfening S, Palinkas LA. 'Betelmania'. Betel quid chewing by Cambodian women in the United States and its potential health effects. West J Med . 1994;160(4):326-330.
23. Warnakulasuriya S. Areca nut use following migration and its consequences. Addict Biol . 2002;7(1):127-132.
24. Winstock A. Areca nut-abuse liability, dependence and public health. Addict Biol . 2002;7(1):133-138.
25. Gamble MV, Ahsan H, Liu X, et al. Folate and cobalamin deficiencies and hyperhomocysteinemia in Bangladesh. Am J Clin Nutr . 2005;81(6):1372-1377.
26. Yen AM, Chiu YH, Chen LS, et al. A population-based study of the association between betel-quid chewing and the metabolic syndrome in men. Am J Clin Nutr . 2006;83(5):1153-1160.
27. Yen AM, Chiu YH, Chen LS, et al. A population-based study of the association between betel-quid chewing and the metabolic syndrome in men. Am J Clin Nutr . 2006;83(5):1153-1160.
28. Trivedy C, Warnakulasuriya S, Peters TJ. Areca nuts can have deleterious effects. BMJ . 1999;318(7193):1287.
29. Tung TH, Chiu YH, Chen LS, et al. A population-based study of the association between areca nut chewing and type 2 diabetes mellitus in men (Keelung Community-based Integrated Screening programme No. 2). Diabetologia . 2004;47(10):1776-1781.
30. Guh JY, Chen HC, Tsai JF, Chuang LY. Betel-quid use is associated with heart disease in women. Am J Clin Nutr . 2007;85(5):1229-1235.
31. Guh JY, Chuang LY, Chen HC. Betel-quid use is associated with the risk of the metabolic syndrome in adults. Am J Clin Nutr . 2006;83(6):1313-1320.
32. Lin WY, Chiu TY, Lee LT, Lin CC, Huang CY, Huang KC. Betel nut chewing is associated with increased risk of cardiovascular disease and all-cause mortality in Taiwanese men. Am J Clin Nutr . 2008;87(5):1204-1211.
33. Ogunkolade WB, Boucher BJ, Bustin SA, et al. Vitamin D metabolism in peripheral blood mononuclear cells is influenced by chewing "betel nut" ( Areca catechu ) and vitamin D status. J Clin Endocrinol Metab . 2006;91(7):2612-2617.
34. Kiyingi KS. Betel-nut chewing may aggravate asthma. P N G Med J . 1991;34(2):117-121.
35. Kiyingi KS. Betel nut chewing and asthma. Lancet . 1992;340(8810):59-60.
36. Ashby J, Styles JA, Boyland E. Betel nuts, arecaidine, and oral cancer. Lancet . 1979;1(8107):112.
37. Sundqvist K, Liu Y, Erhardt P, Nair J, Bartsch H, Grafström RC. Areca-nut toxicity in cultured human buccal epithelial cells. IARC Sci Publ . 1991;(105):281-285.
38. Bhide SV, Shivapurkar NM, Gothoskar SV, Ranadive KJ. Carcinogenicity of betel quid ingredients: feeding mice with aqueous extract and the polyphenol fraction of betel nut. Br J Cancer . 1979;40(6):922-926.
39. Warnakulasuriya S, Trivedy C, Peters TJ. Areca nut use: an independent risk factor for oral cancer. BMJ . 2002;324(7341):799-800.
40. Tsai JF, Jeng JE, Chuang LY, et al. Habitual betel quid chewing and risk for hepatocellular carcinoma complicating cirrhosis. Medicine (Baltimore) . 2004;83(3):176-187.
41. Eipe N. The chewing of betel quid and oral submucous fibrosis and anesthesia. Anesth Analg . 2005;100(4):1210-1213.
42. Yusuf H, Yong SL. Oral submucous fibrosis in a 12-year-old Bangladeshi boy: a case report and review of literature. Int J Paediatr Dent . 2002;12(4):271-276.
43. Zain RB, Ikeda N, Gupta PC, et al. Oral mucosal lesions associated with betel quid, areca nut and tobacco chewing habits: consensus from a workshop held in Kuala Lumpur, Malaysia, November 25-27, 1996. J Oral Pathol Med . 1999;28(1):1-4.
44. Trivedy CR, Craig G, Warnakulasuriya S. The oral health consequences of chewing areca nut. Addict Biol . 2002;7(1):115-125.
45. Tovosia S, Chen PH, Ko AM, Tu HP, Tsai PC, Ko YC. Prevalence and associated factors of betel quid use in the Solomon Islands: a hyperendemic area for oral and pharyngeal cancer. Am J Trop Med Hyg . 2007;77(3):586-590.

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