Hindawi

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
Betel nut is the dried seed of the fruit from the Areca palm,
which is cultivated particularly in South and Southeast Asian
countries. According to the statistics, India, Malaysia, and
Bangladesh have the world’s largest annual production in the
world. Meanwhile, betel nut is an important traditional
Chinese medicine (TCM), which has been used since an-
tiquity [1]. It is estimated [2] that about more than 600
million people chew and eat betel nut. In addition to its
medicinal use, there is a widespread abuse of addiction of
betel nut, which is considered the fourth most used
stimulant.
2. Chemical Composition
So far, a variety of chemicals have been identified from betel
nut, including alkaloids, tannins, flavonoids, triterpenoids,
steroids, and fatty acids [3].
2.1. Alkaloids. The alkaloids in betel nut are the main
active ingredients in research currently, while arecoline
(methyl 1-methyl-3,6-dihydro-2H-pyridine-5-carboxylate)
is considered the most important alkaloid in betel nut. It is
the main active ingredient and also the major toxic com-
pound. The total alkaloid content of betel nut is estimated
between 0.3% and 0.7%. The alkaloids also include arecai-
dine, arecoline, arecolidine, guvacoline, guvacine, areca-
tannin A1, arecatannin A2, isoguvacine, homoarecoline,
nicotine, and dichroine [4]. Recently [5], there are two new
alkaloids, acatechu A and acatechu B (as shown in Figure 1),
which are separated from betel nut and obtained their
structures, and the study of the component in betel nut like
alkaloids is still deepening.
Arecoline is a pyridine-type alkaloid which can quickly
cross the blood-brain barrier and that depends on its
chemical structure [6], which lacks quaternary ammonium
ions compared with methacholine and has higher lip-
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
and then to processing and placement, the content of
arecoline changed accordingly. The general trend is that the
content will decrease after the peak of ripeness [7].
2.2. Tannins. Tannin is the major component which makes
betel nut bitter and astringent. Proanthocyanidins are the
main tannin component of betel nut, including catechins,
arecatannin, and proanthocyanidin A and B [8, 9].
2.3. Flavonoids. Flavonoids [9], with various biological ac-
tivities such as antibacterial and antitumor, are also isolated
from betel nut. The main classes of flavonoids in betel nut are
isorhamnetin, chrysoeriol, luteolin, quercetin, glycyrrhizin,
jacareubin, flavan-3-ol, flavan-3,4-diols, 4′,5-dihydroxyl-
3′,5′,7-trimethoxyflavone, and 5,7,4′-trihydroxy-3′,5′-
dimethoxydihydroflavone [10, 11].
2.4. Triterpenoids and Steroids. Betel nut also contains tri-
terpenoids compounds, including isotic acid and its deriv-
atives and 3β-acetylursolic acid in betel nut, as well as
aromatic alcohol, aromatic methyl ether, fernenol, aroin,
cyclic altonil, and cycloartenol [12]. He et al. extracted
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].
2.5. Fatty Acids. It is normal to use supercritical fluid ex-
traction (SFE) to distill fatty acids and use GC/MS to analyze
volatile components in betel nut [14]. According to the
study, there are lauric acid, nutmeg acid, palmitic acid,
stearic acid, oleic acid, hexadanic acid, and (E,E)-2,4-dec-
adienaldehyde from the betel nut peel [15].
2.6. Other Chemical Compounds. Studies of the betel nut
composition yet contain multiple categories of compounds,
for instance, He et al. [13] found chrysophanic acid and
physcione. The polysaccharide in the betel nut is about
18.7%, mainly galactose and sucrose, and plays a main
antioxidant role in betel nut. Besides, resveratrol [16], erulaic
acid, ferulic acid, hervanonic acid, and deoxymethyl-io-
dinated lutein acrylic acid were also isolated from betel nut
seeds. Table 1 shows that the ingredients of betel nut.
3. Pharmacological Effects
3.1. Digestive System Effects. Salehi and his colleagues [18]
summarized the digestive system effects of betel nut, for
example, insect repellents, digestive function enhancers,
treatment of diarrhea, constipation, antiheartburn, ulcers,
and dyspepsia, and also treat gastrointestinal inflammation,
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-
crease of human saliva secretion, sweating, and excitement
and gastrointestinal peristalsis, and help to improve human
digestive function [19].
O OH
OCH3
O
O
N
OH O O
O O
HO NH2
OH HO OH
OH OH
acatechu A acatechu B
Figure 1: Chemical structures of acatechu A and B.
3.2. Antiparasitic and Antibacterial Effects. Some of the
examples are antimalaria, treatment of leprosy, and anti-
bacteria. Chusri et al. [20] investigated the biological activity
of traditional herbal formulas to heal wounds and found that
ethanol extracts containing betel nut and other four herbs
can play an antibacterial role including against Staphylo-
coccus aureus (SA), methicillin-resistant Staphylococcus
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
effects of Areca nut extract (ANE) on coccidiosis, which
showed that ANE could make the food consumption of rats
and the mucosal damage improved. It explains that the betel
nut has a certain extent anticoccidial activity and beneficial
effect on tissue damage caused by coccidiosis.
3.3. Nervous System Effects. Betel nut can act on the nervous
system and has the effects of antiaging, improving learning
and memory. Arecoline has an acetylcholine-like effect,
which can activate M receptors, thus stimulating the
parasympathetic nerves. At the same time, arecoline also has
an inhibitory effect on gamma-aminobutyric acid (GABA),
which can bring delight and excitement. After arecoline
enters the oral cavity, it will have a mild systemic choline
effect [22]. Ono et al. [23] established an AD model in aged
rats and gave them 10 mg/kg arecoline for 6 consecutive
days. Experimental results found that this can improve the
cognitive performance of elderly rats, which shows that
arecoline has a certain pharmacological activity in im-
proving some symptoms of Alzheimer’s disease (AD).
Furthermore, the research results of Asthana [24] showed
that arecoline has a certain pharmacological effect on en-
hancing the memory of AD patients.
3.4. Cardiovascular Effects. It can be used as an antihy-
pertensive and diuretic. Some studies believe that betel nut is
an herbal medicine with antihypertensive and blood lipid-
lowering activities. Chewing betel nut will cause accelerated
heartbeat, temperature rising, and heavy sweating within a
certain period of time, promoting blood circulation. The
research of Inokuchi [25] is suggested that the extract of
betel nut has good hypotensive activity.
3.5. Other Effects. Some researchers have begun to study the
active ingredients in betel nut that inhibit α-glucosidase [26].
Arecoline is considered a natural α-glucosidase inhibitor to
treat postprandial hyperglycemia in diabetic patients. In
Evidence-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]
concluded by a systematic review that the neurological and
pharmacological mechanisms behind BQD may be related to
brain’s reward, cognitive and impulsive system intercon-
nection. Arecoline increases the level of brain serotonin and
norepinephrine, showing that it can prevent the decom-
position of neurotransmitters and improve dopamine (DA)
and 5-HT levels in the brain.
4.3. Reproductive Toxicity. Recently, Wu [35] found that
betel nut and arecoline had reproductive toxicity on male
rats, including the decline of sperm amount, azoosperma-
tism, and sperm morphological abnormalities, which lead to
sperm function impaired. There is possibility that the extract
of betel nut disturbs the sperm and human male repro-
ductive ability. Yuan [36] reported that betel nut extract
reduced the effect on human sperm motility, of which the
effect of arecoline is the most remarkable. Another study
[37] showed that the ethanol extract of betel nut had an effect
on the weight of ovaries of female rats, which significantly
increased the possibility of abortion. In general, betel nut
contains components that may lead to human reproductive
toxicity.
4.4. Cytotoxicity and Genotoxicity. Lin et al. [38] confirmed
the effects of arecoline on the epigenome and evaluated the
mRNA expression of histone methyltransferase, acetyl-
transferase, and demethylase in K-562 cells exposed to
arecoline. In fact, arecoline makes the expression of related
genes (M) that catalyze histone methylation, acetylation, and
demethylation is altered. While, H3K9 methylation involves
maintaining the stability of chromosomal structural and
inactivation of autosomal gene expression. Available data
indicate that arecoline-induced epigenic changes play a part
in chemically mediated mechanisms of cytotoxicity and
genotoxicity. Arecoline can induce DNA chain disruption,
chromosome distortion, and sister chromatid exchange,
affect DNA repair, and cause oxidative stress, and its me-
tabolites, arecaidine and arecoline-N-oxide, are also ge-
netically toxic [39] (Table 2).
Shih’s [40] study on the cytotoxicity of arecoline showed
that arecoline increases cytochrome C release and activates
the cysteine aspartate-specific protease related signaling
pathway, inducing neuronal cell death. Inhibition of cell
proliferation after arecoline addition may be caused by cell
death induced by cytotoxicity of arecoline. In addition, Yen
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-
forming cell apoptosis.
4.5. Carcinogenicity. Arecoline, an important ingredient in
betel nut, has been regarded as a possible carcinogen for
human beings by the International Cancer Research Insti-
tute [42]. IARC set betel nut as “Group2Bcarcinogens,”
which means “may be carcinogenic to humans.” It was also
observed that arecoline increased the incidence of tumors,
such as inducing malignant tumors of the esophagus and
tongue in animal experiments [39].
4.5.1. Oral Carcinogenesis. In recent years, an increasing
amount of data indicate that the habit of betel nut chewing is
harmful to human oral health, even caused oral cancer,
resulting in death or severe facial distortion [43] (as shown in
Figure 2). It has been shown that the appearance of oral cancer
is closely related to unhealthy oral habits, including betel nut
chewing [44]. There are a series of studies that have found that
oral cancer is due to carcinogenic agents such as arecoline,
active oxygen, and nitrosamines, which are highly related to
human toxicology [45]. In experiments on the interaction
between those of are coline and human fibroblasts, the re-
searchers confirmed that alkaloids of betel nut stimulate col-
lagen synthesis, of which the effects of arecaidine are
remarkable and in a concentration-dependent manner.
Chewing betel nut can induce oral leukoplakia and oral
submucosal fibrosis (OSF), while OSF is an oral cancer
(OC) precancerous state. Currently, Murti et al. [46]
considered that the consumption of betel nut is the re-
markable cause of OSF through ecological observations and
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-
ministered in drinking water to GPT delta rats, the fre-
quency of oral tissue mutations which were detected is at
2.5 times that of the untreated, showing a unique mutation
spectrum. It is suggested that arecoline produces muta-
tionally induced damage in the oral tissues of rats [48].
Moreover, N-nitrogenous derivatives of arecoline are a
significant carcinogenic factor, which tends to oral squa-
mous hyperplasia in mice [49]. Wang et al. [50] examined
the RT-PCR and found that after removing HIF1A-AS1
gene segment, the arecoline-stimulated migration capacity
in buccal mucosal fibroblasts (BMFs) was obstructed. Their
results showed that arecoline may result to relatively
overexpress in OSF tissues compared to normal tissue
counterparts and can activate BMFs, which may be one of
the pathogenic pathways of OSF. Lin et al. [51] found that
OSF associated with chewing betel nut increases the chance
of multiple oral cancers greatly. It is vital to prevent OSF
and stop chewing betel nut for reducing the morbidity of
OC. A recent meta-analysis of Yang et al. [52] found that
the prognosis of patients with betel nut chewing habits was
poorer than those not. Therefore, long-term betel nut users
should be aware of the potential risk of cancer.
4.5.2. Risk of Other Cancers. Besides oral cancer that attracts
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
betel nut with liver cirrhosis (LC) and hepatocellular cancer
(HCC). It was remarkable that betel nut caused the risk of LC
and HCC increased by 4.25 times among subjects that still
chew betel nut and caused the risk of infection with hepatitis
B or hepatitis C. In fact, betel quid chewing has an increased
synergistic effect on the risks associated with hepatitis B and
Evidence-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-
mune risk caused by hepatitis C. Hence, it might be said that
chewing betel nut will induce liver cirrhosis and hepato-
cellular cancer. According to reports [54], there is an as-
sociation between betel nut chewing and esophageal cancer,
which can significantly increase the risk of cancers.
4.6. Nephrotoxicity. Wang et al. [55] researched many
chronic kidney disease (CKD) patients and non-CKD pa-
tients and analyzed the effect of betel nut chewing on ne-
phropathy. It showed that the betel chewer had a higher risk
of CKD than others, which can speculate that chewing betel
nut has nephrotoxicity and associated with CKD occurrence.
5. Conclusion
Through a series of studies, this review summarized the
chemical composition of betel nut and pharmacology and
research progress in clinical application of betel nut. Edible
betel nut is more toxic, staying longer in the mouth, and using
it for a long time is more likely to cause dependence than
medicinal betel nut. The medicinal betel nut is generally weak
in toxicity, with a small dosage and little harm to the human
body. The difference between the two is mainly in the way of
use. As one of the most effective components of betel nut,
arecoline has pharmacological activities such as antibacterial
and anthelmintic effects, reducing postprandial hyperglycemia
and improving Alzheimer’s disease. However, the harmful and
side effects of betel nut cannot be ignored, including cyto-
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
related to betel quid dependence (BQD) in consumers and
improper promotion and guidance of enterprise. After clari-
fying the toxicology mechanism and potential risks of areco-
line, the public should try to stay away from these substances.
It is necessary to develop adjuvant therapeutic drugs
for betel nut withdrawal syndrome of potential BQD
cessation drugs. In areas like Taiwan, such dependence
quit institutions have emerged. Furthermore, chewing
betel nut is not the only carcinogenic factor; thus, the use
of products, like electronic cigarettes, containing areco-
line should also be eliminated. In conclusion, the pro-
portion of betel nut as chewing snacks should be
depressed gradually. The increased investment in research
of betel nut effects is vital for future work, and betel nut
will play a more positive role in pharmacological and
medical fields through guidance and supervision rather
than becoming an unregulated addictive substance.
6 Evidence-Based Complementary and Alternative Medicine
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Acknowledgments
This work was financially supported by the National Key
R&D Program of China (2019YFC1711000).
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