Review Article Chemical Composition, Pharmacological, and Toxicological Effects of Betel Nut
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Evidence-Based Complementary and Alternative Medicine
Volume 2021, Article ID 1808081, 7 pages
https://doi.org/10.1155/2021/1808081
Review Article
Chemical Composition, Pharmacological, and Toxicological
Effects of Betel Nut
Xiaoxiao Chen ,1 Yongzhi He ,1 and Yanru Deng 2
1
College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine,
Tianjin 301617, China
2
College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
Correspondence should be addressed to Yanru Deng; dengyanru@tjutcm.edu.cn
Received 25 July 2021; Accepted 7 August 2021; Published 18 August 2021
Academic Editor: Songwen Tan
Copyright © 2021 Xiaoxiao Chen et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Betel nut, the fruit of Areca catechu L, has a long medical history in Southeast Asia. It is native to Malaysia and is cultivated and
processed extensively in subtropical regions, such as South China and India. Betel nut almost appears as a “snack” in various
occasions in most parts of China. Clinically, betel nut can play a certain pharmacology role and was used in malaria, ascariasis,
arthritis, enterozoic abdominalgia, stagnation of food, diarrhea, edema, and beriberi. The nervous excitement of betel nut chewing
has made it gradually become popular. However, chewing betel nut can induce oral submucosal fibrosis (OSF) and oral cancer
(OC). At the same time, long-term chewing of betel nut also causes inhaled asthma, sperm reducing, betel quid dependence
(BQD), and uterine and esophageal cancers. The main components of processed betel nut are the goal of this review. This study
will mainly start from the pharmacological activity and toxicology study of betel nut in recent years, aiming to seek its advantages
and disadvantages. In the meantime, this study will analyze and emphasize that betel nut and arecoline are the high-risk factors for
oral cancer, which should arouse attention and vigilance of the public.
1. Introduction 2.1. Alkaloids. The alkaloids in betel nut are the main
active ingredients in research currently, while arecoline
Betel nut is the dried seed of the fruit from the Areca palm, (methyl 1-methyl-3,6-dihydro-2H-pyridine-5-carboxylate)
which is cultivated particularly in South and Southeast Asian is considered the most important alkaloid in betel nut. It is
countries. According to the statistics, India, Malaysia, and the main active ingredient and also the major toxic com-
Bangladesh have the world’s largest annual production in the pound. The total alkaloid content of betel nut is estimated
world. Meanwhile, betel nut is an important traditional between 0.3% and 0.7%. The alkaloids also include arecai-
Chinese medicine (TCM), which has been used since an- dine, arecoline, arecolidine, guvacoline, guvacine, areca-
tiquity [1]. It is estimated [2] that about more than 600 tannin A1, arecatannin A2, isoguvacine, homoarecoline,
million people chew and eat betel nut. In addition to its nicotine, and dichroine [4]. Recently [5], there are two new
medicinal use, there is a widespread abuse of addiction of alkaloids, acatechu A and acatechu B (as shown in Figure 1),
betel nut, which is considered the fourth most used which are separated from betel nut and obtained their
stimulant. structures, and the study of the component in betel nut like
alkaloids is still deepening.
2. Chemical Composition Arecoline is a pyridine-type alkaloid which can quickly
cross the blood-brain barrier and that depends on its
So far, a variety of chemicals have been identified from betel chemical structure [6], which lacks quaternary ammonium
nut, including alkaloids, tannins, flavonoids, triterpenoids, ions compared with methacholine and has higher lip-
steroids, and fatty acids [3]. ophilicity, so it can cross the cell membrane into the body
2 Evidence-Based Complementary and Alternative Medicine
better. In each period of betel nut from young fruit to mature O OH
and then to processing and placement, the content of OCH3
O
arecoline changed accordingly. The general trend is that the O
N
content will decrease after the peak of ripeness [7]. OH O O
O O
HO NH2
OH HO OH
2.2. Tannins. Tannin is the major component which makes OH OH
betel nut bitter and astringent. Proanthocyanidins are the acatechu A acatechu B
main tannin component of betel nut, including catechins,
Figure 1: Chemical structures of acatechu A and B.
arecatannin, and proanthocyanidin A and B [8, 9].
3.2. Antiparasitic and Antibacterial Effects. Some of the
2.3. Flavonoids. Flavonoids [9], with various biological ac- examples are antimalaria, treatment of leprosy, and anti-
tivities such as antibacterial and antitumor, are also isolated bacteria. Chusri et al. [20] investigated the biological activity
from betel nut. The main classes of flavonoids in betel nut are of traditional herbal formulas to heal wounds and found that
isorhamnetin, chrysoeriol, luteolin, quercetin, glycyrrhizin, ethanol extracts containing betel nut and other four herbs
jacareubin, flavan-3-ol, flavan-3,4-diols, 4′,5-dihydroxyl- can play an antibacterial role including against Staphylo-
3′,5′,7-trimethoxyflavone, and 5,7,4′-trihydroxy-3′,5′- coccus aureus (SA), methicillin-resistant Staphylococcus
dimethoxydihydroflavone [10, 11]. aureus (MRSA), and so on. It also has significant antioxidant
capacity for scavenging hydroxyl-free radicals.
In addition, Wang et al. [21] studied the anticoccidial
2.4. Triterpenoids and Steroids. Betel nut also contains tri-
effects of Areca nut extract (ANE) on coccidiosis, which
terpenoids compounds, including isotic acid and its deriv-
showed that ANE could make the food consumption of rats
atives and 3β-acetylursolic acid in betel nut, as well as
and the mucosal damage improved. It explains that the betel
aromatic alcohol, aromatic methyl ether, fernenol, aroin,
nut has a certain extent anticoccidial activity and beneficial
cyclic altonil, and cycloartenol [12]. He et al. extracted
effect on tissue damage caused by coccidiosis.
arborinol, fernenol, and arundoin from betel nut [13]. The
steroidal compounds are β-sitosterol, cycloartenol, stigmata-
4-en-3-one, and 22-dien-3-ol [9]. 3.3. Nervous System Effects. Betel nut can act on the nervous
system and has the effects of antiaging, improving learning
2.5. Fatty Acids. It is normal to use supercritical fluid ex- and memory. Arecoline has an acetylcholine-like effect,
traction (SFE) to distill fatty acids and use GC/MS to analyze which can activate M receptors, thus stimulating the
volatile components in betel nut [14]. According to the parasympathetic nerves. At the same time, arecoline also has
study, there are lauric acid, nutmeg acid, palmitic acid, an inhibitory effect on gamma-aminobutyric acid (GABA),
stearic acid, oleic acid, hexadanic acid, and (E,E)-2,4-dec- which can bring delight and excitement. After arecoline
adienaldehyde from the betel nut peel [15]. enters the oral cavity, it will have a mild systemic choline
effect [22]. Ono et al. [23] established an AD model in aged
2.6. Other Chemical Compounds. Studies of the betel nut rats and gave them 10 mg/kg arecoline for 6 consecutive
composition yet contain multiple categories of compounds, days. Experimental results found that this can improve the
for instance, He et al. [13] found chrysophanic acid and cognitive performance of elderly rats, which shows that
physcione. The polysaccharide in the betel nut is about arecoline has a certain pharmacological activity in im-
18.7%, mainly galactose and sucrose, and plays a main proving some symptoms of Alzheimer’s disease (AD).
antioxidant role in betel nut. Besides, resveratrol [16], erulaic Furthermore, the research results of Asthana [24] showed
acid, ferulic acid, hervanonic acid, and deoxymethyl-io- that arecoline has a certain pharmacological effect on en-
dinated lutein acrylic acid were also isolated from betel nut hancing the memory of AD patients.
seeds. Table 1 shows that the ingredients of betel nut.
3.4. Cardiovascular Effects. It can be used as an antihy-
3. Pharmacological Effects pertensive and diuretic. Some studies believe that betel nut is
an herbal medicine with antihypertensive and blood lipid-
3.1. Digestive System Effects. Salehi and his colleagues [18]
lowering activities. Chewing betel nut will cause accelerated
summarized the digestive system effects of betel nut, for
heartbeat, temperature rising, and heavy sweating within a
example, insect repellents, digestive function enhancers,
certain period of time, promoting blood circulation. The
treatment of diarrhea, constipation, antiheartburn, ulcers,
research of Inokuchi [25] is suggested that the extract of
and dyspepsia, and also treat gastrointestinal inflammation,
betel nut has good hypotensive activity.
flatulence, hyperemesis gravida, and so on. It has been
confirmed that arecoline can stimulate the sympathetic
nerve, stimulate the choline M receptor, promote the in- 3.5. Other Effects. Some researchers have begun to study the
crease of human saliva secretion, sweating, and excitement active ingredients in betel nut that inhibit α-glucosidase [26].
and gastrointestinal peristalsis, and help to improve human Arecoline is considered a natural α-glucosidase inhibitor to
digestive function [19]. treat postprandial hyperglycemia in diabetic patients. InEvidence-Based Complementary and Alternative Medicine 3
Table 1: Ingredients of betel nut [17]. vitro analysis, Nouri et al. [27] confirmed that the extract of
Classification Ingredient name
betel leaves with different dissolvents can provide inhibitory
effects on key enzymes (α-amylase and α-glucosidase) as-
Arecaidine
Arecaine
sociated with type 2 diabetes and hyperglycemia. This allows
Arecatannin a1 us to determine that betel nut polyphenol has the phar-
Arecatannin a2 macological activity of lowering blood sugar, and it is based
Arecolidine on the assumption that it plays a role in lowering blood sugar
Arecoline by inhibiting the activity of α-glucosidase.
Arecoline Lee [28] found that arecoline (50 μg/mL) can promote
4-Quinazolone the survival and growth of glial cells in vitro and found that
α-Dichroine arecoline in the body can stimulate local inflammation,
Alkaloids
β-Dichroine which can promote the repair of severe peripheral nerve
Guvacine damage.
Guvacoline
In addition, it can also treat beriberi, low back pain [29],
Homoarecoline
Isoguvacine and remove bad breath. It also includes the effects of
Methyl N-methylpiperidine-3-carboxylate controlling sweating, edema, curing jaundice, and sedative
Ethyl N-methylpiperidine-3-carboxylate effects [18].
Ethyl nicotinate
Nicotine
4. Toxicological Effects
Isorhamnetin
Chrysoeriol 4.1. Bronchoconstriction. In vitro trials, arecoline is known
Luteolin to stimulate parasympathetic nerves and cause bronchial
Flavonoids Quercetin smooth muscle contraction, which is equivalent to a tenth of
Glycyrrhizin acetylmethylcholine. Taylor et al. [30] found that in the
Jacareubin
double-blind trial, subjects who chewed betel nut had
4-Hydroxyhydrangenol
bronchocontraction in different degrees. In the trials of four
(+)-Catechin
Bangladeshis asthmatic patients (AAPs) that chew betel nut
Procyanidin A1, B1, B2, B3
Tannins Arecatannin A1, A2, A3
regularly, there was one showing FEV1 that decreased 30%
Arecatannin B1, B2 with symptoms of chest tightness within 150 minutes of
Arecatannin C1 chewing. It is speculated that betel nut contains arecoline,
3-Carene which acts as cholinergic alkaloids that stimulates the dose-
Procurcumenol related bronchocontraction.
Ursonic acid
3-Acetylursolic acid,
Terpenoids 4.2. Central Nervous Toxicity and Addiction. Adriane [31]
Arborinol
Arborinol methyl ether found that when the neuroleptic drugs combine with betel
Fernenol nut, the extra propyramidal effect will be aggravated, and the
Arundoin combination of betel nut with trifluorothiotons and pro-
Cycloartenol pylene cycling can cause stiffness, mild dyskinesia, and
5, 8-Epidioxiergosta-6 mandibular tremor. Combination with fluorosis can cause
Steroids Beta-sitosterol tremor, stiffness, and sensory abnormalities, and combi-
22-Dien-3-ol nation with prednisone and salbutiamine can cause asthma.
Stigmasta-4-en-3-one Arecoline, a potentially addictive component of betel
2-Lauroleic acid nut, is an oxidative inhibitor that suppresses monoamine
Arachidic acid oxidase A(MAO-A). Thus, it can prevent the decomposition
Cis-4-dodecenoic acid
of neurotransmitters, increasing the concentration of do-
Fatty acids Cis-9, cis-12-linoleic acid
Myristic acid pamine and serotonin in the brain, thereby bringing eu-
Oleic acid phoria and happiness [32].Consequently, many betel nut
Palmitic acid chewers occur withdrawal symptoms after a long-term
Vanillin consumption of betel nut, which is as difficult to quit
Alpha-terpineol completely as tobacco. Withdrawal syndrome is character-
Benzyl alcohol ized by mood swings, anxiety, irritation, inattention, sleep
Capric acid disorders, and increased appetite. According to the statistics,
Others
Caproic acid there are a large number of betel nut consumers around the
Resveratrol world which has the betel quid dependence (BQD). Win-
Quinic acid stock et al. [33] reported that part of the subjects had a
Dicoumarin withdrawal reaction after stopping the betel nut chewing,4 Evidence-Based Complementary and Alternative Medicine
with an average dependence severity of 7.3. Ko et al. [34] such as inducing malignant tumors of the esophagus and
concluded by a systematic review that the neurological and tongue in animal experiments [39].
pharmacological mechanisms behind BQD may be related to
brain’s reward, cognitive and impulsive system intercon-
4.5.1. Oral Carcinogenesis. In recent years, an increasing
nection. Arecoline increases the level of brain serotonin and
amount of data indicate that the habit of betel nut chewing is
norepinephrine, showing that it can prevent the decom-
harmful to human oral health, even caused oral cancer,
position of neurotransmitters and improve dopamine (DA)
resulting in death or severe facial distortion [43] (as shown in
and 5-HT levels in the brain.
Figure 2). It has been shown that the appearance of oral cancer
is closely related to unhealthy oral habits, including betel nut
4.3. Reproductive Toxicity. Recently, Wu [35] found that chewing [44]. There are a series of studies that have found that
betel nut and arecoline had reproductive toxicity on male oral cancer is due to carcinogenic agents such as arecoline,
rats, including the decline of sperm amount, azoosperma- active oxygen, and nitrosamines, which are highly related to
tism, and sperm morphological abnormalities, which lead to human toxicology [45]. In experiments on the interaction
sperm function impaired. There is possibility that the extract between those of are coline and human fibroblasts, the re-
of betel nut disturbs the sperm and human male repro- searchers confirmed that alkaloids of betel nut stimulate col-
ductive ability. Yuan [36] reported that betel nut extract lagen synthesis, of which the effects of arecaidine are
reduced the effect on human sperm motility, of which the remarkable and in a concentration-dependent manner.
effect of arecoline is the most remarkable. Another study Chewing betel nut can induce oral leukoplakia and oral
[37] showed that the ethanol extract of betel nut had an effect submucosal fibrosis (OSF), while OSF is an oral cancer
on the weight of ovaries of female rats, which significantly (OC) precancerous state. Currently, Murti et al. [46]
increased the possibility of abortion. In general, betel nut considered that the consumption of betel nut is the re-
contains components that may lead to human reproductive markable cause of OSF through ecological observations and
toxicity. case reports. The habit of chewing betel nut may cause oral
precancerous lesions such as OSF with the possibility of
malignant transformation [47]. When arecoline was ad-
4.4. Cytotoxicity and Genotoxicity. Lin et al. [38] confirmed ministered in drinking water to GPT delta rats, the fre-
the effects of arecoline on the epigenome and evaluated the quency of oral tissue mutations which were detected is at
mRNA expression of histone methyltransferase, acetyl- 2.5 times that of the untreated, showing a unique mutation
transferase, and demethylase in K-562 cells exposed to spectrum. It is suggested that arecoline produces muta-
arecoline. In fact, arecoline makes the expression of related tionally induced damage in the oral tissues of rats [48].
genes (M) that catalyze histone methylation, acetylation, and Moreover, N-nitrogenous derivatives of arecoline are a
demethylation is altered. While, H3K9 methylation involves significant carcinogenic factor, which tends to oral squa-
maintaining the stability of chromosomal structural and mous hyperplasia in mice [49]. Wang et al. [50] examined
inactivation of autosomal gene expression. Available data the RT-PCR and found that after removing HIF1A-AS1
indicate that arecoline-induced epigenic changes play a part gene segment, the arecoline-stimulated migration capacity
in chemically mediated mechanisms of cytotoxicity and in buccal mucosal fibroblasts (BMFs) was obstructed. Their
genotoxicity. Arecoline can induce DNA chain disruption, results showed that arecoline may result to relatively
chromosome distortion, and sister chromatid exchange, overexpress in OSF tissues compared to normal tissue
affect DNA repair, and cause oxidative stress, and its me- counterparts and can activate BMFs, which may be one of
tabolites, arecaidine and arecoline-N-oxide, are also ge- the pathogenic pathways of OSF. Lin et al. [51] found that
netically toxic [39] (Table 2). OSF associated with chewing betel nut increases the chance
Shih’s [40] study on the cytotoxicity of arecoline showed of multiple oral cancers greatly. It is vital to prevent OSF
that arecoline increases cytochrome C release and activates and stop chewing betel nut for reducing the morbidity of
the cysteine aspartate-specific protease related signaling OC. A recent meta-analysis of Yang et al. [52] found that
pathway, inducing neuronal cell death. Inhibition of cell the prognosis of patients with betel nut chewing habits was
proliferation after arecoline addition may be caused by cell poorer than those not. Therefore, long-term betel nut users
death induced by cytotoxicity of arecoline. In addition, Yen should be aware of the potential risk of cancer.
et al. [41] found that arecoline can inhibit AMPK, the AMP-
dependent protein kinase, through inducing intracellular
reactive oxygen substances, and it is responsible for per- 4.5.2. Risk of Other Cancers. Besides oral cancer that attracts
forming cell apoptosis. public attention, arecoline may also be a contributing factor
to esophageal, liver, lung, and other diseases. For example,
Wu et al. [53] explored the association between chewing
4.5. Carcinogenicity. Arecoline, an important ingredient in betel nut with liver cirrhosis (LC) and hepatocellular cancer
betel nut, has been regarded as a possible carcinogen for (HCC). It was remarkable that betel nut caused the risk of LC
human beings by the International Cancer Research Insti- and HCC increased by 4.25 times among subjects that still
tute [42]. IARC set betel nut as “Group2Bcarcinogens,” chew betel nut and caused the risk of infection with hepatitis
which means “may be carcinogenic to humans.” It was also B or hepatitis C. In fact, betel quid chewing has an increased
observed that arecoline increased the incidence of tumors, synergistic effect on the risks associated with hepatitis B andEvidence-Based Complementary and Alternative Medicine 5
Table 2: Summary of DNA damage by arecoline and its metabolites [39], (+) for positive results and (–) for negative results.
Compound DNA breaks Unscheduled DNA synthesis
(+) Mice kidney cells (+) Early spermatid stages of Swiss albino mice cells
(+) Human oral cells (+) Hep-2 cells
Arecoline (+) Hep-2 cells (−) Human gingival keratinocytes
(+) 293 cells
(−) Rat liver clone 9 cells
(+) Rat liver clone 9 cells
(+) Human oral cells
Arecoline-N-oxide
(+) Immunodeficient NOD/SCID
mice
Arecaidine (+) Human oral cells
3-(N-Nitrosomethylamino)
(+) Human oral cells
propionaldehyde
Oral Leukoplakia
Oral Submucous Fibrosis
Limited Mouth Opening
Lymphadenectasis
Figure 2: Oral diseases associated with betel nut.
hepatitis C, yet stopping chewing BQ can reduce the im- use. As one of the most effective components of betel nut,
mune risk caused by hepatitis C. Hence, it might be said that arecoline has pharmacological activities such as antibacterial
chewing betel nut will induce liver cirrhosis and hepato- and anthelmintic effects, reducing postprandial hyperglycemia
cellular cancer. According to reports [54], there is an as- and improving Alzheimer’s disease. However, the harmful and
sociation between betel nut chewing and esophageal cancer, side effects of betel nut cannot be ignored, including cyto-
which can significantly increase the risk of cancers. toxicity and genetic toxicity, carcinogenicity (especially oral
cancer), OSF, and addiction dependence. There are still a large
number of people who are diagnosed with oral cancer, which is
4.6. Nephrotoxicity. Wang et al. [55] researched many related to betel quid dependence (BQD) in consumers and
chronic kidney disease (CKD) patients and non-CKD pa- improper promotion and guidance of enterprise. After clari-
tients and analyzed the effect of betel nut chewing on ne- fying the toxicology mechanism and potential risks of areco-
phropathy. It showed that the betel chewer had a higher risk line, the public should try to stay away from these substances.
of CKD than others, which can speculate that chewing betel It is necessary to develop adjuvant therapeutic drugs
nut has nephrotoxicity and associated with CKD occurrence. for betel nut withdrawal syndrome of potential BQD
cessation drugs. In areas like Taiwan, such dependence
5. Conclusion quit institutions have emerged. Furthermore, chewing
betel nut is not the only carcinogenic factor; thus, the use
Through a series of studies, this review summarized the of products, like electronic cigarettes, containing areco-
chemical composition of betel nut and pharmacology and line should also be eliminated. In conclusion, the pro-
research progress in clinical application of betel nut. Edible portion of betel nut as chewing snacks should be
betel nut is more toxic, staying longer in the mouth, and using depressed gradually. The increased investment in research
it for a long time is more likely to cause dependence than of betel nut effects is vital for future work, and betel nut
medicinal betel nut. The medicinal betel nut is generally weak will play a more positive role in pharmacological and
in toxicity, with a small dosage and little harm to the human medical fields through guidance and supervision rather
body. The difference between the two is mainly in the way of than becoming an unregulated addictive substance.6 Evidence-Based Complementary and Alternative Medicine
Conflicts of Interest [14] Q. U. Li-Jie, W. J. Liu, X. J. Qian, and A. D. Sun, “GC-MS
analysis of essential oil of betel extracted by supercritical CO_
The authors declare that they have no conflicts of interest. 2 extraction,” Science and Technology of Food Industry, vol. 8,
no. 3, 2012.
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H. Yoshimura, “Studies on crude drugs effective on visceral
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