Betel Nut

July 2009

Areca catechu L. Family: Palmaceae (palms)

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.

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).

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.

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

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.

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

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

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

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

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

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