Health hazards of chewing arecanut and products containing arecanut.
Rooban T¹, Elizabeth Joshua²,Anusa Rooban³ ,Girish Kumar Govind⁴
 

1- Oral and Maxillofacial Pathologist, Chennai 2 -Dental Surgeon & Oral and Maxillofacial Pathologist, Dr. Rajendran Dental Clinic, Chennai.3 – Physician, Chennai 4- Oral and Maxillofacial Surgeon, Vijaya Dental Clinic, Nadakavu, Calicut .
 

Address for communication
T. Rooban MDS,
“ Liz Gardens ”
4, Paul Victor Street
Chromepet,
Chennai- 600 044.
E mail: drtroobanmds@rediffmail.com
Abstract:
Chewing arecanut is a habit practiced by several million people worldwide and is the fourth most commonly used psychoactive substance. This habit has an ethno psychopharmacologic back ground and is practiced from antiquity. The detrimental effects of chewing arecanut and associated morbidities are not adequately known. This review attempts to list the possible health hazards and diseases associated with habitual arecanut chewing.
Key Words: Arecanut, panmasala, health hazards, psychoactive substances.
 

Introduction:
Arecanut is the fourth most commonly used psychoactive substance in the world. Approximately 600 million people use arecanut in varying forms – raw ripe nuts to processed nuts in various combinations, especially with tobacco. Although its popularity has declined in the recent years, it is still widespread in Asia, particularly the South Pacific islands, Southeast Asia, Papua New Guinea, Bangladesh, Pakistan and India. Curiously enough, the use of arecanut has remained mostly within these ethnic and cultural subgroups and was unknown in the West, till various diseases and condition associated with the chewing habit started to manifest among the immigrant communities from these places4, 16.

The use of arecanut by humans is established since the 4th century AD in different parts of the world. In old Indian scripts, such as Vagabhata (4th century AD), and Bhavamista (13th century AD), arecanut has been described as a therapeutic agent. Its use was recommended in many diseases. In India, in the early Christian era, arecanut use was frequently referred to in Sanskrit medical literature and later also in the Hindu and Buddhist writings. Subsequently, the custom spread to southern Tibet and southern China as a result of the expansion of Buddhist practice. Use of arecanut in those early periods was both medical and psychosomatic, e.g. as a breath refresher, digestive agent, worm expellant, aphrodisiac and to maintain stamina.4, 16
The form in which the arecanut is consumed in India is dependent on several factors like- socio-cultural, economic, religious and traditional values. The basic forms of arecanut usage can be classified as the traditional form and the recent form. In the traditional form, naturally cured arecanut is used alone or wrapped in leaves of Piper betel, with lime, saffron and additives such as catechu, cinnamon, cloves. This preparation is referred as Betel quid or Pan. When tobacco is added to this preparation it is referred to as Betel quid with tobacco. The form in which arecanut has a loco regional variation. Depending upon the type of curing, there are many types of arecanut. (kotta paku,Challi, seeval, kali pakku) These preparations are often used by elderly people or during festivals and in religious ceremonies. In 1970’s and 80’s the arecanut industries, using traditional Indian technology, along with the tobacco industry has developed products similar to betel quid ready for immediate consumption, packed in small, beautiful and convenient sachets. This product without tobacco is known as ‘panmasala’ while the product with tobacco is known as ‘Gutka’. People consume this abundantly, even by those who do not have the habit of smoking or any other form of tobacco addiction. As printed on the packets, they consist of arecanut, catechu, lime, saffron, sandal wood fragrance and unspecified flavoring agents with or without tobacco. Even though tobacco with arecanut chewing is not a common practice among the school children, consumption of panmasala is gaining tremendous popularity even among children at the secondary school level. Both boys and girls are equally attracted. These preparations are favored by the younger generation.5 The other forms of arecanut include indigenous preparations like supari, mawa (a mixture containing mainly arecanut, over 90% by weight, some tobacco, and a few drops of lime) and mainpuri tobacco (finely cut arecanut, tobacco, slaked lime, camphor and cloves).

Health hazards
For understanding the detrimental effects of chewing arecanut the physiological effects of the individual components has to be understood. A cumulative effect of these substances is often observed when they are habitually taken. The complex interaction of the components of various arecanut products is vital in determining the effect. The net physiological effect and health hazards, is a result of the composition of individual components, their ratio, bioavailability, frequency of intake, duration of the habit and exposure time per use. The habitual placement (pouching) or spiting plays a vital role in determining the effect and health hazard.

Arecanut: It is the endosperm (nut) from the tropical tree Areca catechu Linnaeus. (Family: Palmaceae). The nuts are chewed as such or processed by roasting, sun drying, soaking or boiling prior to chewing. Chewers of soaked or boiled nuts have demonstrated lower incidence of mucosal changes than those chewers of raw, sun-dried or roasted nuts. Estimation of the active chemical constituents in the arecanut following treatments by sun drying, roasting, soaking and boiling, revealed reduction in active chemical contents. Marked reductions were observed when the arecanut was subjected to soaking and boiling. These reductions may explain the difference in the incidence of the mucosal changes among users of different processed nut varieties1.
Arecanut quid chewing has claimed to produce a sense of well being, euphoria, warm sensations of the body, sweating, salivation, palpitation, heightened alertness, tolerance to hunger and increased capacity and stamina to work. All these neurological effects suggest that chewing arecanut quid influences central and autonomic nervous system at various levels. It is interesting to observe that the effects of arecanut are habit related and dose related. They are stronger for fresh or occasional chewers than in habitual chewers. By epidemiological studies it has been concluded that chewing arecanut is associated with various oral conditions including arecanut chewer’s mucosa, chewer’s lichenoid mucositis, oral submucous fibrosis and oral squamous cell carcinoma2, 12, 13.
The initial effects of chewing arecanut are dizziness, hot sensation, palpitation, sweating, heightened alertness and epigastric discomfort. The subsequent effects are heightened alertness, hot sensation, palpitation, combat of cold, sweating, diminished thirst, diarrhea, happy feeling, calmness, dizziness, alleviation of constipation, epigastric discomfort, prevention of hunger and increased rate of respiration2, 12, 13.

The four major alkaloids isolated in arecanut are arecoline (7.5 mg/g weight), arecaidine (1.5 mg/g weight), guvacoline (2.0 mg/g weight) and guvacine (2.9 mg/g weight). Arecanut also contains phenolic compounds, mainly hydroxychavicol and saffrole12.
Arecoline, an alkaloid of arecanut, has parasympathomimetic properties acting on both the muscarinic and nicotinic receptors. It induces an arousal response in animals and a cardio-acceleratory response in humans. This leads to heightened alertness. EEG studies show desynchronization. EEG activity studies using spectral analysis and topographic mapping revealed that alpha and beta activities are increased while theta activities are reduced. Topographic mapping showed altered rhythms in occipital areas for alpha but widespread for beta and theta. All these suggest that chewing arecanut causes a state of arousal and to a lesser degree a state of relaxation.2, 12, 13
Arecaidine, another alkaloid, is also produced by the action of lime on arecoline along with alkaloids such as guvacine and guvacoline, which inhibits the uptake of gamma aminobutyric acid (GABA) in brain. It lacks the typical parasympathetic activity of arecoline. GABA receptors are chloride channels with structure similar to acetylcholine receptors. They are essential neurotransmitters. CNS suppressants such as benzodiazepines are thought to stimulate GABA; hence the effect of arecanut could be diametrically opposite to that of anxiolytics. Because of this GABA inhibitory property, arecanut was thought to reduce severity of symptoms in schizophrenia.2, 12, 13
Within 2 minutes of chewing there is an increase in heart rate with peak effect between 4 – 6 minutes and lasting for at least 16 to 18 minutes. The mean increase for habitual users was 13.3-beats/ minute to 17-beats/ minute for fresh users. Blood pressure was elevated in fresh chewers. When chewed it produces sweating, facial flush and a warm sensation of the body. Skin temperature increases any where between 0.5° C to 2.0° C and this response was abolished by atropine and partially by propranolol. In external and common carotid arteries, there is an increase in blood flow probably leading to facial flush and palpitations. They have an antimuscarinic effect on the smooth muscle.2, 12, 13

It is suggested that the arecanut components may affect the entry of calcium into cells through high voltage channels. Other effects reported include vasoconstriction of blood vessels, increased salivary secretion with resultant dilution of amylase and potassium ion. It was also observed that with the increase in tobacco content, a further reduction in potassium ion concentration occurred. The effects on gastric mucosa include a reduced mucous secretion, increased acid back diffusion and increased susceptibility to gastric ulceration. Regular arecanut consumption is shown to have an increased risk of peptic ulceration and abnormal liver function in rodents. It is also shown to be a diabetogenic and share a structural similarity in configuration to the chair shaped hexomeric glucose. It may account for the diabetogenicity, by this blockage and destruction of beta cells of islets and local generation of free radical cascades. GABA inhibitory action on insulin receptors may account for the short-term hypoglycemia that occurs with arecanut consumption.2, 12, 13
Arecanut is also suggested to aggravate asthma and interfere with thyroid function. It is also suggested they cause a vitamin D, foliate and homocystiene deficiency. By virtue of stimulating fibroblast to secrete matrix metalloproteinases (MMP-9) they cause unstable plaque in the arterial wall. These unstable plaques could further cause vessel occlusion and thereby resulting in myocardial infraction2, 12, 13.
Nitrosoamines from the arecanut alkaloids are produced either during curing or storage or by the acid in the gut. The polyaromatic hydrocarbons, nitrosamine, toxic metals such as lead, cadmium and nickel and residual pesticides like DDT and BHC and their isomers in arecanut and products containing arecanut, are known to be carcinogenic. Besides this, various types of fungi, like Aspergillus sp. were isolated from stored arecanut. Aflatoxigenic strain of Aspergillus is known to produce aflatoxin, a potent liver carcinogen. Arecoidine and its methyl ester, arecoline have been suspected to exhibit carcinogenic or mutagenic or claustogenic properties since they are capable of reacting with cysteine in vivo and in vitro to produce cysteine /3-alkylation adducts. In addition, free radical ions associated with multi-step process of carcinogenesis is generated due to auto-oxidation of polyphenols and interaction of catechin with lime. All these contribute to the carcinogenic potential of arecanut and products containing arecanut. 2, 14

Betel Leaf: Piper betel leaf contains a large amount of carotenes (80.5 mg/g weight), as well as smaller amounts of phenolic compounds (21.9 mg/g weight) and ascorbic acid (1.9 mg/g weight). Phenolic compounds of the betel leaf cause the release of catecholamines from the chromaffin cells.2, 10
Tobacco: It is the most commonly abused psychoactive substance all over the world. In the smokeless form, it is a major component of the quid or the commercial products containing arecanut such as gutka, mainpuri tobacco. Though there are hundreds of compounds in tobacco, the main active ingredient is nicotine. Nicotine has structural resemblance with acetylcholine, the predominant neurotransmitter in humans. It acts on the cholinergic receptors in the brain and other organs. This activation leads to the release of other neurotransmitters and hormones such as acetylcholine, nor epinephrine, dopamine, vasopressin and endorphin. The predominant effect such as behavioral arousal and sympathetic neural activation reinforces the repeated use. Tobacco probably with arecanut synergistically increases the risk of habituation and addiction.

The effects of tobacco have been well researched and reported. Tobacco is cited to cause coronary heart diseases, promote atherosclerosis (which could lead to stroke, peripheral vascular heart disease and gangrene of extremities), cause peptic ulcers, aggravate diabetes type II and is the cited as the single major cause for the cancers of upper aero digestive tract and larynx. In larynx and oral cavity it causes leukoplakia (a premalignant lesion). With pouching, proliferative verrucous leukoplakia and verrucous carcinoma are common. Apart from staining soft and hard dental tissues, it aggravates inflammatory gingival diseases (gingivitis and periodontitis) 3.
Lime: Chemically it is calcium hydroxide, an alkali which is often derived from sea shells or grinding lime stones. This chemical is responsible for the reddish staining of saliva and oral structures. In the presence of lime, with its high alkalinity, arecoline and guvacoline are largely hydrolyzed into arecaidine and guvacine, respectively. Both arecanut and Piper betel contain phenolic compounds. After release from the betel quid during chewing, the contents of these compounds are reduced. Appreciable reduction is seen in safrole, catechin, hydroxychavicol, eugenol and methyl eugenol.2,11 It has been observed that the catechu extracts and betel nut extracts induced mitotic conversion in alkaline pH, whereas they lacked this capacity at acid pH levels. This phenomenon might be due to the rapid auto-oxidation of phenolic compounds under alkaline conditions, which leads to the generation of free radicals. This indicates that arecanut- betel leaf phenolics may pose as a genotoxic hazard during chewing of lime-containing arecanut quid and tobacco, which causes the salivary pH to rise above 8.15 In rare instances they also cause metabolic alkalosis.17

Catechu: Catechu is a potent anti-inflammatory compound derived from Acacia catechu. The heartwood of the tree is immersed in boiling water to extract catechu. It contains predominantly catechin (4 -7%), epicatechin, tannins (20 -35%) and poly phenols2, 12, 13. These tannins cause denaturation of protein (act as a astringent) and thereby aid in healing of ulcers and boils. Native medicine uses this product to stop haemoptysis. It avoids the excessive mucous discharge, has astringent effets and aids in digestion. It is demonstrated to have a hepatoprotective effect. This compound has no demonstrable psychoactive properties.4, 8
Saffron: It is the flower of the tree Crocus sativus Linnaeus, commonly found in the subtropics and temperate climatic conditions. The main chemical constituents are crocin, picrocrocin, crocetin, safranal, zexanthin and micronutrients such as lycopene, β carotene, g carotene. The main actions of saffron are free radicals scavenging (antioxidant) and nerve sedating. It affects blood coagulation -increases fibrinolysis, inhibits platelet aggregation and increases prothrombin time and partial thromboplastin time. In large quantity it is suggested to have a narcotic type of reaction. 4, 7
Effect of chewing arecanut/ Products containing arecanut:
The physiological effect of each component of the quid/ arecanut products has been described. When chewed for longer time the pathological effects begin to manifest. The health hazards of arecanut chewing or products containing arecanut on different organ systems are listed in table 2.

Habituation, Addiction and Withdrawal:
Three medical syndromes associated with arecanut chewing have been described in the English literature: habituation, addiction and toxic psychosis. There are reported withdrawal symptoms and syndrome. The symptoms included craving, aches, pains, decreased performance, fatigability, irritability, lethargy and feeling down. The withdrawal syndrome is usually mild and manifests as poor concentration, sensation of uneasiness, general lassitude, anxiety, fidgeting, and even episodes of paranoia.2, 10, 12, 13Addiction to arecanut products chewing is usually mild to moderate. Heavy habitual users may consume over 60 gram of arecanut product quid per day. Neurological complications are rare. The acute toxic psychosis is characterized by auditory hallucinations or grandiose or persecutory delusions. These symptoms tend to occur in heavy users who have not been chewing for some time and then suddenly consume a large amount while visiting friends or relatives, or on ceremonial occasions. Acute psychosis seems more likely to occur in persons who are predisposed to mental illness. These neurological complications are reversible. In patients with Alzheimer or presenile dementia, arecoline, like physostigmine, significantly improved performance on a picture recognition test, but for the majority of patients, the improvement was only slight.2, 10, 12, 13

Conclusion:
Various physiological and pathological effects of habitual arecanut use are listed. Interpretation of these effects and hence pathophysiology, is difficult because the following conditions are yet to be ascertained: (1) the sites and modes of arecanut chewing effects; (2) the amounts of active compounds released from arecanut chewing and also those that are absorbed into the circulation and the brain (3) possible complex interactions between various absorbed active compounds in the brain and the autonomic nervous system12, 13 (4) the biological in-equivalence of all the components of arecanut products and (5) the sensitization of receptors and habituation with chronic arecanut and its product chewing. Hence the entire medical fraternity should concentrate primarily in causing adequate awareness regarding the ill effects of this ethnic, socio-culturally accepted habit and help in the prevention and treatment of all associated morbidities.

Table 1: Physiological effects of arecanut chewing

Table 2: Health consequences of arecanut chewing

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