
General features: The English name is Piper betle but colloquially called Betel leaf (BL) which in Bengali or Hindi is named Paan. In Sanskrit, it is referred to be Tambool. The plant is a dioecious (unisexual) evergreen vine. The leaves are glossy heart-shaped and white catkins. It is cultivated only for the leaves which are consumed for chewing with betel/areca nuts in order to freshen the mouth. The term ‘betel’ originates from the Southern Indian Malayalam language. The plant belongs to the Piperaceae family of Piper genus and is native to Southeast Asia India, Bangladesh, the Philippines, Malaysia, and the nations of Indochina regions. In addition to those places, BL is even distributed to almost all of the South Pacific and Indian Oceanic islands. The perennial creeper is approximately 7 – 8 ft tall growing attractive heart-shaped leaves 3 – 5 inches in diameter and 6 – 7 inches in length that are edible by nature. The plant usually grows within 3 – 6 months under partial shade and prefers well-drained rich soil. The leaves have a spicy taste by character. Besides chewing with betel/areca nut it is also used in many Southeast Asian cooking including salads. In Thailand, young tender leaves are used to wrap for making numerous favorite snacks filled with versatile assortments e.g., peanuts, shrimps, shallots mixed with lime, and chopped ginger. Soaking the leaves in sugar water for a few hours alters the flavor, adding subtle pleasantness to the wrapped food. Owing to the attractiveness, leaves are often used for the sake of food arrangement on a platter. The small white flower spikes grown to be tiny fruits are also edible. Other than being used as food, BL is also employed as a traditional medicine in many Asian countries [1]. Ordinarily, in India, there are a few varieties of BL which are basically named according to regions of origin and their tastes vary e.g. Kolkata, Banarasi, Maghi, Bangla, etc. In neighboring Bangladesh, most of the BL-producing regions are Dinajpur, Rangpur, Chittagong, Faridpur, Jessore, Narayangonj, Barisal, and Sylhet. A large section of harvested BL is exported to the Middle East, Pakistan, and Myanmar despite the huge domestic consumption at home.
History and mythology of Betel leaf: In India BL/Paan is deeply associated with the social culture dating back to almost 400 BC. As mentioned in the antiquated Indian apothecary, Ayurvedas have aptly described its medicinal values. Marco Polo, the 13th-century European traveler documented the practice of chewing BL wrapping with areca/betel nut among the kings and nobles of India after the meal to freshen the mouth and feel satiety. As indicated in traditional Chinese medicine, BL is frequently used to treat several physiological disorders since it can act as a detoxifying, antioxidizing, and antimutating agent. Recent studies reveal that leaf extract or some of the extracted fractions by aqueous or organic solvents exhibit a significant number of medicinal roles while acting as antidiabetic, anti-inflammatory, immunomodulatory, anti-ulcerative, hepatoprotective, anticancer, anti-infective, and cardiovascular problems, etc. Additionally, the leaves also have a beneficial role in oral hygiene [2]. Chewing BL alone does not produce any harmful or toxic effects. On the contrary, it may lower the risk of mammary cancer/tumor [3].
In India and some parts of Southeast Asia, BL / Paan has immense cultural significance, particularly in the event of socialization. It is a post-dinner snack that is enjoyed by the guests after the meal during the course of social engagements or mingling. Besides that, Paan leaves are an essential part of Hindu weddings all over India. Hindu mythology says that Paan has been originated during the event of “Samudra Manthan” as “Tamboolan” which is the holy trinity of Gods. Paan leaves signify sincerity and prosperity at the commencement of a relationship and subsequently seek blessings of the elders in a providential manner, particularly in times of tying the knot for eternity. In the course of the event, the bride is brought before the groom while covering her face with two Paan leaves. Afterward removing them, she looks at the groom; the very look is considered to be auspicious and destined to be blessed. It is famously said; ‘the newly wedded couple is compatible to one another like a Paan leaf divided in half’. This traditional event of using Paan leaves symbolizes happiness, fertility, as well as prosperity therefore included in all Indian weddings and rituals. In addition, its use has been particularly noticed during the worship of Gods and in all Hindu rituals. Along with the whole Areca nut, the combination symbolizes loyalty and the firm pledge of the couple to each other. It has been customarily introduced in every Hindu religious and wedding ritual. The unique arrangement of Paan leaves is also a crucial part of sixteen adornments (Solah Sringar) ordained for a married woman. Further, chewing with areca nut and catechu gum with a touch of slaked lime produces an attractive red color to the lips. Additionally, Paan leaves also act as an aphrodisiac, reasonably necessary for the newlyweds.
Concerning the Hindu epic Ramayana, it has been stated that during exile in the forest, Lord Rama chewed betel leaves / Paan to control his hunger. The story further proceeds that once Goddess Sita offered a garland made of Paan to Lord Hanuman as a sign of appreciation since he covered a risky journey to convey the message of Lord Rama to her. Following that event, the tradition of offering Paan to Lord Hanuman was started. In other great Hindu epic, Mahabharata, Paan, also plays a significant role. The story perpetuates that after his victory over an evil enemy, the great warrior Arjuna asked the priests to conduct ‘Yagnya’, which is ostentatiously named “Rajaugya Yagnya”. Since Paan’s leaves are badly needed for the event and find no availability, out of desperation Arjuna arrives at the kingdom of Snakes – “Nag Lok”. He begged Nag Rani (meaning snake Queen) for Paan leaves. From that mythological point of view, Paan is known as Nag-Velli or Nagarbel in most of the southern states of India [4].
The word Paan originally evolved from the Sanskrit language ‘Parna’ meaning ‘leaf’. It is appraised to be a pious product throughout India. They are offered to greet people at home signifying the friendship and wishing good fortune, especially in the southern and eastern Indian states. In eastern India like Assam, Paan is offered right after the meal as a respect to the invited guests. In northern India and possibly all over the country the holy pitcher colloquially named “Kalasha” / “Ghot” is always adorned with five Paan leaves placed underneath a green coconut. The arrangement is kept before the icon of God or Goddess during the Puja (worship) which is normally seen during the Durga Puja or Diwali ceremonies. It is a belief that placing Paan leaves makes water in the pitcher ‘holy’ and afterward spraying on the people will remove away any sins. It is already known for a long time to serve as traditional folk medicine since Paan is good for the digestive system [5]. It has also been recommended by ancient Indian medicine writers that betel leaves should be taken early in the morning, after meals, and at bedtime. As indicated by Shusrutasamhita, (an ancient Sanskrit text on medicine and surgery, a part of Ayurveda) betel leaf is aromatic, stimulant, carminative, and astringent. Chewing the leaf will sweeten the breath, improve voice, and remove foulness of mouth. `
During the period of Sultanate, Ibn Battuta (1304 – 1369 AD) mentioned the use of BL / Paan which he noticed being chewed with or without the areca nut to freshen the mouth after the meal. Chewing Paan leaves alone produces freshness in the mouth and also helps digestion. Abul-Fazl ibn Mubarak (1551 – 1602 AD) a Persian scholar and one of the nine jewels of Emperor Akbar’s court in India who wrote “Akbarnama” (an official history of the emperor’s regime) also mentioned the use of betel leaf or Paan all over the Indian subcontinent. He also identified different ways to consume it in various regions. Further, as per the taste, he identified the category “Maghi” produced near Agra and Bihar which are thin and offer the most pleasant tastes. Afterward, Niccolo Manucci (1638 – 1717 AD), a Venetian traveler, writer, and historian, worked in the court of the Mughal Emperor Shajahan and wrote many facts regarding the use of betel leaf / Paan. He also mentioned that ladies used to chew the leaves with the touch of lime and areca nuts almost throughout the day. The lips stained with a deep red color were noticed to enhance the beauty. In Moghul court offering Paan to the noble guests was a strict norm. Often numerous fragrant substances were added to gain extra pleasure, which was relished by the royal visitors of the court. According to Manucci, it was distinctively a royal affair. Manucci also observed that Hindu deities were also offered Paan and whole areca nuts during the worship or Puja [6].
Phytochemical components: The phytochemical composition of BL / Paan shows that the leaf extract contains a considerable number of biologically active compounds. Their concentration depends on the nature of plants, season, and climate. Pharmacologically, Paan provides antiplatelet, anti-inflammatory, immunomodulatory, gastroprotective, and antidiabetic effects. The major items are chavibetol, safrole, and in many cases chavicol, eugenol, isoeugenol, germacrene D, piperol – A, piperol – B, hydroxychavicol, and caryophyllene [7,8]. The stems contain several phytosterols like β – sitosterol, β – dauscosterol, and stigmasterol. Concerning the alkaloids, there exists piperine, pellitorine, piperdardine, and guineensine. It also contains lignan e.g., pinoresinol, and several other bioactive components. Additionally, there is also the presence of oleanolic acid, dehydropipernonaline, piperolein-B, Bornyl cis-4-hydroxycinnamate, and Bornyl p-Coumarate [9]. The roots of BL plant have several unique compounds e.g., aristololactam A – II, a new phenylpropane, 4 – allyl resorcinol, and diketosteroid stigmast-4ene-3,6-dione. The essential oil of BL constitutes mainly phenol and terpenes. Interestingly, the level of phenolic components changes according to the gender of plants. In male plants, the level is three times higher. The level of thiocyanates also differs considerably, twice in male compared to female plants. Higher phenolic content provides better-tasting leaves [10,11]. The enjoyable pungent aromatic taste of BL is due to its phenolic content. The studies using aqueous or methanolic extract of BL indicate the presence of flavonoids, alkaloids, tannins, sterols, phenols, saponins, terpenoids, and their glycosides. The bitter-tasting components in BL are terpenoids and their acetates, including chavibetol, chavicol, cadinene, and 1,8 cineole [11].
The fresh leaves contain 85 % moisture, 3.1 % protein, 0.8 % fat, 6.1 % carbohydrate, 2.3 % fiber, 230 mg calcium, 40 mg phosphorus, 7.0 mg Iron, and 3.4 µg iodine. In addition, they have large amounts of potassium nitrate 0.42 %. The identified sugars are glucose, fructose, maltose, and sucrose. The reducing sugar levels vary from 0.38 – 1.46 %. The enzymes present are catalase and diastase. According to traditional folk medicine, the leaves have anticancer potential [12]. Recent studies on five different varieties of BL/Paan named Bangla, Misti, Khasi, Sanchi, and Bari show about 101 volatile compounds that are almost double in number, 50 than the previously reported ones [13]. Betel leaves contain 0.15 – 0.20 % essential oil which are categorized to be monoterpenes, sesquiterpenes, phenylpropanoids, and aldehydes. The levels of essential oil are largely dependent on botanical origin, age, and harvesting time. They are also differentially distributed in different categories. For example, the Sagar Bangla cultivar contains chavicol which is absent in Magahi [14].

| Compounds | % of constituents |
| Chavibetol | 53.1 |
| Caryophyllene | 3.71 |
| Chavibetol acetate | 15.5 |
| Allyl pyrocatechol diacetate | 0.71 |
| Chavibetol methyl ether | 0.48 |
| Campene | 0.48 |
| Pinene | 0.21 |
| Eugenol | 0.32 |
| Limonene | 0.14 |
| α- pinene | 0.21 |
| 1,8 cineol | 0.04 |
| Allylpyrocatechol monoacetate | 0.23 |
| Safrole | 0.11 |
Ethnomedicinal uses: The therapeutic effects of BL alone or in combination with others have been skillfully mentioned in Ayurvedas around 1400 BC. The ancient Vedic literature, Atharveda (~ 3000 BC) described the useful role of BL / Paan against a large number of diseases. The Vedic name of betel leaves, Saptasira mentioned Kamasutra (Ancient Indian text written in Sanskrit on sexuality, eroticism, and emotional fulfillment of life) composed by Vatsayan, the saint describing the facts about its aphrodisiac actions. In both Ayurvedic and Unani systems of medicine, BL is employed as an appetite stimulant, vermifuge, astringent, anthelmintic, breath freshener, carminative, cardiac tonic, dentifrice, preventing diuretic emmenagogues, laxative, enhancing menstruation, nerve tonic, and treatment of the urinary disorder. It has been noticed that people in Nepal chew betel leaf or mix leaf juice with hot water, honey, or milk as a mild stimulant, to cure intestinal worms, and remove bad breath. It also improves digestion, treats nervous pain, eases urination, as an analgesic, and reduces cough and cold [15].


Pharmacological effects: The chemical composition of BL shows the presence of versatile bioactive components that obviously exert several pharmacological actions on human health. Below are the few effects that seem important to reveal.
Anticancer / Antitumor / Antiproliferative effect – The antitumor action of BL was first reported while using BL extract on benzo[a] pyrene-induced tumors in buccal pouches of hamsters. The results show that BL can prevent tumor production. Numerous studies have indicated that BL extract can inhibit preneoplastic and neoplastic changes. It is also active in doing partial and complete suppression of tumors during short-term and long-term treatment. The ethanolic, methanolic, ethylacetate, or hexane extract can control dose-dependently the proliferation of breast cancer cell line MCF-7, IC50 ~ 65 – 130 µg / ml. It also suppresses cell migration at a dose of ~ 25µg / ml [15]. Further, oral feeding of BL extract significantly inhibits the growth of human prostate cancer (PC3) xenografts implanted in nude mice. In the case of Hep-2 cells the aqueous extract shows potent cytotoxic behavior, IC50 ~ 96.25 µg / ml. At high doses, leaf extract can also inhibit the emergence of tumors. Investigations show that several phyto-ingredients present in extract e.g., hydroxychavicol, α – tocopherol, eugenol, and β – carotene can prevent benzo[a]-pyrene-induced neoplasia in the forestomach of male Swiss mice. The extract of BL or its constituents is also capable of decreasing the number of papillomas; the highest capacity is provided by α-tocopherol and β-carotene. The studies in vitro using BL extract having the presence of hydroxychavicol on several pancreatic cancer cell lines like MIA PaCa-2, PANC-1, L929, INT407, NIH-3T3, Vero, and HEK293 show inhibition of cell proliferation, epithelial-to-mesenchymal transition, invasion, and migration through gene repression, induced DNA damage resulting in mitotic catastrophe leading to apoptosis via JNK and caspase-mediated pathway [16]. Among many of the anticancer / antitumor-promoting agents of fresh green BL / Paan, hydroxychavicol has been identified to be the significant one [17].
Anti-inflammatory/analgesic/antinociceptive effects – Theanti-inflammatory actions of ethanol-extracted BL has been studied by following arthritic model using Freund’s adjuvant-induced rats. The study reveals that the antiinflammatory and antiarthritic effect is dose-dependent and occurs due to the downregulation of Nitric oxide (NO) production [18]. Further experiments showed that BL extract can inhibit hyaluronidase (HYA), xanthine oxidase (XOD), and lipoxygenase (LOX), particularly more effective toward XOD and LOX exhibiting its antiarthritic and antiinflammatory efficacy. The in vitro anti-inflammatory activity of methanolic extract has been measured using the cell line RAW 264.7 exposed to E. coli lipopolysaccharide (LPS). The inhibitory experiments were also performed using leaf essential oils by detecting metalloproteinase -2 (MMP-2) and metalloproteinase – 9 (MMP-9) following the gelatin zymogen method in vitro. About 85 % inhibition has been noticed [19]. The analgesic effect has been tested on rats by monitoring the carrageenan-induced hind paw edema model using a hot plate, formalin test also by following the writhing tests. The leaf extract inhibits all and the effect is dose-dependent [20]. The antinociceptive effect has been studied using hot and cold-water extract at various doses using tail flick, hot plate, and formalin test models on cross-bred albino mice. The cold-water extract shows the maximum efficiency, and the effect is mediated by opioid-mediated pathways although some of the analgesics work by modulating TRPM8 / TRPA1 channels [21].
Effect on Acetylcholine esterase and Neurological Disorders – The aqueous, ethanol, or methanol extract of BL can potently inhibit both acetylcholine (AChE) and butyrylcholine esterase (BChE). The most efficiently acting identifiable components are hydroxychavicol and chlorogenic acid. Hydroxychavicol is seen to be more potent (IC50 = 21.23 ± 0.33 μg/ml) than chlorogenic acid (IC50 =45.55 ± 1.89 μg/ml) but the 1:1 mixture shows the highest potency. The inhibition of AChE and BchE is an immensely important event for enhancing brain activity preventing neurodegenerative disorders like Alzheimer’s disease, dementia, impaired cognitive function, or memory loss among elderly people. Experiments on Wister rats while administering aqueous extract of BL show exceedingly promising results in the case of AlCl3 induced Alzheimer’s disease model. Several other experiments including this one indicates that BL extract could be a potential therapeutic source to prevent the progression of Alzheimer’s or other forms of dementia and neurological problems [22].
Cardioprotective effect – The cardioprotective effect has been studied in rats by inducing myocardial infarction using Isoproterenol (ISP) at larger doses. In that situation, oral administration of hydroalcoholic extract of BL can potently modulate systolic, diastolic, and mean arterial pressure including several parameters related to ventricular functions like contractility (+LV dp/dt) and relaxation (LV dp/dt), and heart rate. The extract also reinstates the level of catalase, glutathione peroxidase, glutathione, and superoxide dismutase. It also lowers the leakage of creatine phosphokinase-MB isoenzyme of LDH and reduces lipid peroxidation in the heart indicating the protection against ISP-induced myocardial infarction. Further, BL is seen to prevent oxidative cardiac cell injury noticed during in vitro experiments using rat cardiac cell line, H9c2 incubated with hydrogen peroxide. In this experiment, ethylacetate extract lowers the oxidative stress reducing intracellular reactive oxygen species (ROS), simultaneously improving cellular defense at 10 µg / ml concentration. The major active compound identified is eugenol which provides protection against any cardiac damage [23].
Anti-platelet aggregating effect – Several phyto-components have been identified that exhibit anti-aggregating effects on human platelets. They are β – sitosterol, ursonic acid, and 3β-acetyl Ursolic acid.

The in vitro study shows that all three items inhibit platelet aggregation induced by arachidonic acid (AA), platelet activation factor (PAF), and adenosine diphosphate (ADP). On the other hand, aqueous extract of BL prevents aggregation of rabbit plasma platelets induced by AA and collagen (IC50 ~ 207 and 335 µg / ml). The overall experiments indicate that BL extract contains ingredients that inhibit platelet aggregation by eliminating ROS or preventing thromboxane B2 generation [24].
Antidiabetic effect – The antidiabetic effect of BL extract has been tested in normoglycemic and streptozotocin-induced or Alloxan-treated diabetic rats following oral administration. The extract shows significant lowering of blood glucose levels in a dose-dependent manner. In the course of glucose tolerance tests, extract reduces the effect of external glucose loads. The antidiabetic activity of hot water extract could not inhibit glucose absorption in the small intestine. The extracts are non-toxic and well tolerated even in the case of prolonged consumption. No side effect has been noticed concerning hepatotoxicity or nephrotoxicity [25].
Antioxidant effect – Reactive oxygen species (ROS) generation is one of the significant markers of any disease pathology. Antioxidants act as protectors since many chronic and degenerative diseases are evolved or triggered by ROS production. Using 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay of the ethanolic extracts of three varieties of BL / Paan, Bangla, Sweet, and Mysore has shown that Bangla one possesses the highest antioxidant properties which can be correlated with its total phenolic content as well as reducing-capacity of the extracts. Isolation and identification of the Bangla leaf extract show mainly the presence of chavibetol (CHV), allyl-pyrocatechol (APC), or their glucosides. Although the chemical profile is quite the same the levels of CHV and APC are seen considerably less in Mysore and Sweet ones. The most effective component is observed to be CHV compared to APC regarding the antioxidant behavior to scavenge the generated free radicals or ROS. APC prevents Fe+2-induced lipid peroxidation of liposomes and rat brain homogenates and also γ- ray-induced damage of pBR322 plasmid DNA than CHV which shows better ability to scavenge O–2 radicals and hydrogen peroxide [26]. The methanol extract of Bangla Paan can inhibit glucose-induced glycation, thiol group modification, and carbonyl formation during studies by in vitro BSA-glucose model [27].
Hepatoprotective effect – Using Wister rats, hepatoprotective effect has been verified by making ethanol-induced hepatotoxic injury also subsequently orally administering alcoholic extract of BL. The highest activity has been noticed for Bangla Paan at a dose of 300 mg / Kg Body wt that can lower Aspartate aminotransferase (AST), Thiobarbutyric acid reactive substance (TBARS), Alanine aminotransferase (ALT), and lipid hydroperoxides subsequently improving non-enzymatic antioxidants like glutathione (GSH), vitamin E, and vitamin C, also free radical destroying enzymes Catalase, Superoxide dismutase, and GSH peroxidase within liver and kidney of the animals [28]. Additionally, BL extract (200 mg / Kg body wt) improves the condition during D-galactosamine intoxication and subsequent generation of oxidative stress in Wister rats by enhancing the level of antioxidants [29]. The hepatoprotective effect is further confirmed by inducing liver fibrosis using Carbon tetrachloride (CCl4) plus corn oil injection in Wister rats. The extract alleviates fibrosis of the liver by inhibiting AST and ALT activities reducing glutathione S – transferase actions simultaneously lowering the expression of α-smooth muscle actin and enhancing the expression of matrix metalloproteinase – 2 induced by SOD and CAT and inhibiting, tissue inhibitor of metalloproteinase – 2. The study also reveals that leaf extract can significantly prevent any damage inflicted by CCl4 on the liver [15, 30].
Immunomodulatory effect – It has been known from a traditional medicinal point of view that BL possesses unique immunomodulatory properties. The effects of BL extract by methanol on lymphocyte proliferation, interferon – γ receptors, and nitric oxide (NO) production were measured in vitro. Additionally, in vivo experiments are designed to study cellular and humoral immune responses of mice immunized with ship red blood cells. BL potently suppresses phytohemagglutinin-stimulated peripheral blood lymphocyte proliferation in a dose-dependent manner. The decrease of antibody titre and simultaneous suppression of inflammation indicates the immunosuppressive action of BL extract on cellular and humoral response in mice. In a way, BL could be a good natural therapeutic agent to treat various immune diseases including an autoimmune one [31].
Effect on thyroid hormones – Experiments on male Swiss albino mice have shown that aqueous extract of fresh BL uniquely exhibits a dual role depending on its concentrations, concerning the thyroid levels in circulation also including lipid peroxidation, and activities of superoxide dismutase (SOD) and catalase (CAT). At very low doses (0.1 and 0.4 g / Kg/day for two weeks) BL lowers thyroxine (T4) but enhances triiodothyronine (T3) levels. On the contrary, at higher doses (0.8 and 2.0 g / Kg/day), the effect reverses. It increases lipid peroxidation but subsequently decreases SOD and CAT activities. It is thus established that BL exerts both stimulatory and inhibitory effects on thyroid function, especially in male mice [32].
Antiulcerogenic effect – The antiulcerogenic effect of BL extract by ethanol has been conducted on indomethacin-induced gastric injury in Sprague Dawley rats [33]. Oral administration of BL extract (200 mg / Kg body wt) for ten days provides significant protection against gastric lesions and simultaneously increases the activity of SOD and CAT. It also amplifies mucus levels, increases hexosamine and thiol groups whereas reduces the damaged oxidative lipid levels. The extract reduces ulcer index by 93.4 % and accelerates healing [34].
Miscellaneous other effects – It has been experimentally confirmed that Betel leaves exhibit numerous other pharmacological effects, highly beneficial for human health. Below are the examples of several of them.
A) Antibacterial effect; B) Anthelmintic effect; C) Antifungal effect; D) Insecticidal effect; E) Larvicidal effect; F) Anti atherogenic effect; G) Anti-hyperlipidemic effect; H) Anti-anxiety, Antistress, and Antidepression effect; I) Antifertility effect.
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