Ethnopharmacological characteristics of Piper betle from Indonesian-Asian region and prospects of its use in biomedical purposes

Rationale. Piper betle of the family of Piperaceae, (P. betle) is a liana growing in the tropics of the Indonesian-Asian region, has long been actively used in folk medicine as a source of remedies for a variety of health problems. At the same time, the methods and purposes of using P. betle in folk medicine vary from region to region, and the effectiveness of its impact on human remains fully underestimated.

The aim of the study. To systematize and analyze modern literature data on the pharmacological potential of the medicinal plant Piper betle, growing in the countries of Madagascar, India, Bali and China of the Indonesian-Asian region.

Materials and methods. The search and analysis of data were carried out in international and regional databases (PubMed, Scopus, Web of Science, Science Direct, and Google Scholar) for the period from 1996 to 2025.

Results. The analysis of scientific literature data showed that the target fragment of metabolome (TFM) of Peper betle is characterized by a complex composition of biologically active compounds (BAS), which varies significantly from region to region. BAS of the TFM of this plant are responsible for various types of pharmacological activity, which justifies its use in traditional medicine and growing interest to the medical scientific community. It was found that within the range of P. betle growth, the chemical composition of TFM varies in terms of the content of alkaloids, terpenes, phenolic compounds, including flavonoids and volatile components.

Conclusion. P. betle is a promising object for further research in the field of phytopharmacology and reproductive medicine. Obviously, in-depth preclinical and clinical studies are needed to confirm the identified effects based on literature sources. At the same time, the collected literature data can contribute to future research in the field of pharmacology in order to create new promising drugs.

1. Sagar WH, Amol MA, Bhaurao K, Head K. Piper betle a herbal plant: A review. Int J Food Sci and Nutr. 2025; 10(1):27–35. URL: https://www.foodsciencejournal.com/assets/archives/2025/vol10issue1/10006.pdf. [date of access: 01.12.2024].

2. Pradhan D, Suri KA, Pradhan DK, Biswasroy P. Golden heart of the nature: Piper betle L. J Pharmacogn Phytochem. 2013; 1: 147–167. URL: https://www.phytojournal.com/archives/2013/vol1issue6/PartA/19.pdf [date of access: ].

3. Das S, Parida R, Sandeep S, Nayak S, Mohanty S. Biotechnological intervention in Betel vine (Piper betle L.): A review on recent advances and future prospects. Asian Pac J Trop Med. 2016; 9(10): 938–946. doi: 10.1016/j.apjtm.2016.07.029

4. Taukoorah U, Lall N, Mahomoodally F Piper betle L. (Betel quid) shows bacteriostatic, additive, and synergistic antimicrobial action when combined with conventional antibiotics. S. Afr. J. Bot. 2016; 105: 133–140. doi: 10.1016/j.sajb.2016.01.006

5. Chandra V, Yadav P, Verma NK, Khan WU. General neuropharmacological studies of Piper betel leaves on mice. Int. J. of Health Sci. 2022; 6(S1): 13087-99. doi: 10.53730/ijhs.v6nS1.8284

6. Bari MdS, Khandokar L, Yaque E, Romano B, Capasso R, Seidel V, et al. Ethnomedicinal uses, phytochemistry, and biological activities of plants of the genus Gynura. J Ethnopharmacol. 2021; 271: 113834. doi: 10.1016/j.jep.2021.113834

7. Tutu AKS, Guddun SSK, Kumari P, Dey SKD. An overview of Betel vine (Piper Betle L.): Nutritional, pharmacological and economical promising natural reservoir. Adv, Hortic, Sci. 2022; 36(1): 63–80. doi: 10.36253/ahsc-12290

8. Gupta RK, Guha P, Srivastav PP. Phytochemical and biological studies of Betel leaf (Piper betle L.): Review on paradigm and its potential benefits in human health. Acta Ecologica Sinica. 2023; 43(5): 721–732. doi: 10.1016/j.chnaes.2022.09.006

9. Guha P, Jain RK. Status report on production, processing and marketing of Betel leaf (Piper betle L.). Agricultural and Food Engineering Department, IIT, Kharagpur, India. 1997: 15–22.

10. Garg SC, Jain RR. Volatile constituents of the essential oil of Piper betel L. (Cultiver Sagar Bangla). Indian. J. Chem., Sect. B Organ. Chem. 1996; 35: 874–875.

11. Bajpai V, Sharma D, Kumar B, Madhusudanan KP. Profiling of Piper betle L. in cultivars by direct analysis in real time mass spectrometric technique. Biomed Chromatogr. 2010; 24(12): 1283–1286. doi: 10.1002/bmc.1437

12. Syahidah A, Saad CR, Gassan MD, Rukayadi Y, Novarian MH, Kamarudin MS. Phytochemical analysis, identification and quantification of antibacterial active compounds in Betel leaves, Piper betle methanolic extract. Pak. J. Bio. Sci. 2017; 20(2): 70–81. doi: 10.3923/pjbs.2017.70.81

13. Mohottalage S, Tabacchi R, Guerin PM. Components from Sri Lankan Piper betle L. leaf oil and their analogues showing toxicity against the housefly, Musca domestica. Flavour Fragr. J. 2007; 22: 130–138. doi: 10.1002/ffj.1770

14. Sengupta R, Banik JK. A review on Betel leaf (PAN). IJPSR. 2013; 4(12): 4519-4524. doi: 10.13040/IJPSR.0975-8232.4(12).4519-24

15. Azahar NI, Mokhtar NM, Arifin MA. Piper betle: A review on its bioactive compounds, pharmacological properties, and extraction process. IOP Conf Ser Mater Sci Eng. 2020; 991(1): 012044. doi: 10.1088/1757-899X/991/1/012044

16. Nayaka NMDMW, Sasadara MMV, Sanjaya DA, Yuda PESKY, Dewi NLKAA, Cahyaingsih E and Hartati R. Piper betle (L): Recent review of antibacterial and antifungal properties, safety profiles, and commercial applications. Molecules. 2021; 26(8): 2321. doi: 10.3390/molecules26082321

17. Prabhu K, Sudharsan P, Ganesh KP, Chitra B, Janani C. Impact of Piper betle L. bioactive compounds in larvicidal activity against Culex quinquefasciatus. J. Nat. Pestic. Res. 2022; 2: 100-113. doi: 10.1016/j.napere.2022.100013

18. Mustafa RA, Hamid AA, Mohamed S, Bakar FA. Total phenolic compounds, flavonoids, and radical scavenging activity of 21 selected tropical plants. J. Food Sci. 2010; 75(1): 28-35. doi: 10.1111/j.1750-3841.2009.01401.x

19. Bajpai K, Sharma D, Kumar B, Madhusudanan KP. Profiling of Piper betle Linn. Cultivars by direct analysis in real time mass spectrometric technique. Biomed Chromatogr. 2010; 24(12): 12-83-1286. doi: 10.1002/bmc.1437

20. Carsono N, Tumilaar SG, Kurnia D, Latipudin D, Satari MH. A review of bioactive compounds and antioxidant activity properties of Piper species. Molecules. 2022; 27(19): 6774. doi: 10.3390/molecules27196774

21. Wardani L, Ompusunggu GB, Wirawati KT, Yanti KRD. Recent advances and applications in the antibacterial activity of Piper betle leaf extract. Pharm. Rep. 2025; 4(1): 87. doi: 10.51511/pr.87

22. Anggara Nenohai J, Rosyida I, Agustina I, Yanti Vitarisma I, Marfuah S. Essential oils of green Betel leaf (Piper Betle L.) and red Betel leaf (Piper Crocatum Rulz and Pav): Comprehensive overview of components, component structure, hybridization, addition, biological activities and their benefits. J. Kim. Mul. 2024; 22(1): 11–23. URL: https://jurnal.kimia.fmipa.unmul.ac.id/index.php/JKM/article/download/1262/1021/ [date of access: ].

23. Ali A, Chong CH, Mah SH, Abdullah LC, Choong TSY, Chua BL. Impact of storage conditions on the stability of predominant phenolic constituents and antioxidant activity of dried Piper betle extracts. Molecules. 2018; 23(2) : 484. doi: 10.3390/molecules23020484

24. Hao CY, Fan R, Qin XW, Hu LS, Tan LH, Xu F, et al. Characterization of volatile compounds in ten Piper species cultivated in Hainan Island, South China. Int. J. Food Prop. 2018; 1; 21(1): 633–44. doi: 10.1080/10942912.2018.1446147

25. Chagas MDSS, Behrens MD, Moragas-Tellis CJ, Penedo GXM, Silva AR, Gonçalves-de-Albuquerque CF. Flavonols and flavones as potential anti-inflammatory, antioxidant, and antibacterial compounds. Oxid. Med. Cell Longev. 2022; 9966750. doi: 10.1155/2022/9966750

26. Rekha VPB, Kollipara M, Gupta BRSS, Bharath Y, Pulicherla KK. A review on Piper betle L.: nature’s promising medicinal reservoir. Am. J. Ethnomed. 2014; 1(5): 276-289.

27. Ngamsurach P, Praipipat P. Antibacterial activities against Staphylococcus aureus and Escherichia coli of extracted Piper betle leaf materials by disc diffusion assay and batch experiments. RSC Adv. 2022; 12(40): 26435– 26454. doi: 10.1039/d2ra04611c

28. Ali I, Khan FG, Suri KA, Gupta BD, Satti NK, Dutt P, Afrin F, et al. In vitro antifungal activity of hydroxychavicol isolated from Piper betle L. Ann. Clin. Microbiol. Antimicrob. 2010; 9: 7. doi: 10.1186/1476-0711-9-7

29. Lao RCC, Yabes AM, Tobias-Altura M, Panganiban LCR, Makalinao IR. In vitro antibacterial and antibiofilm activities of Piper betle L. ethanolic leaf extract on Staphylococcus aureus ATCC 29213. Acta Med. Philipp. 2023; 57(12): 53–60. doi: 10.47895/amp.vi0.6412

30. Jantorn P, Tipmanee V, Wanna W, Prapasarakul N, Visutthi M, Sotthibandhu DS. Potential natural antimicrobial and antibiofilm properties of Piper betle L. against Staphylococcus pseudintermedius and methicillin-resistant strains. J. Ethnopharmacol. 2023; 317: 116820. doi: 10.1016/j.jep.2023.116820

31. Pecková R, Doležal K, Sak B, Květoňová D, Kváč M, Petřík I, et al. Effect of selected Indonesian plants on Giardia intestinalis in an experimental in vitro model. BMC Complement. Med. Ther. 2025; 25(1): 1-8. doi: 10.1186/s12906-025-04755-8

32. Gundala S, Yang C, Mukkavilli R, Paranjpe R, Brahmbhatt M, Pannu V, et al. Hydroxychavicol, a Betel leaf component, inhibits prostate cancer through ROS-driven DNA damage and apoptosis. Toxicol. Appl. Pharmaco.l 2014; 280(1): 86–96. doi: 10.1016/j.taap.2014.07.012

33. Pin K, Chuan AL, Rashih AA, Mazura MP, Fadzureena J, Vimala S, Rasadah MA. Antioxidant and anti-inflammatory activities of extracts of Betel leaves (Piper betle) from solvents with different polarities. J. Trop. For. Sci. 2010; 22(4): 448-455. URL: https://www.jstor.org/stable/23616901. [date of access: 01.12.2024].

34. Lubis M, Syahfitri W. Antifertility Effect of Sirih leaf (Piper betle L.) ethanol extract on male Wistar Rats spermatogenesis: Efek Antifertilitas Ekstrak Etanol Daun Sirih (Piper betle L.) Pada Spermatogenesis Tikus Wistar Jantan. Jurnal Farmasi Galenika (Galenika Journal of Pharmacy) (e-Journal). 2023; 9(1): 110–8. doi: 10.22487/j24428744.2023.v9.i1.16029

35. Biswal S. Phytochemical analysis and a study on the antiestrogenic antifertility effect of leaves of Piper betel in female albino rat. Anc. Sci. Life. 2014; 34(1): 16–22. doi: 10.4103/0257-7941.150770

36. Ratul A, Rokeya B, Tusher H. Elucidation of phytochemicals and antidiabetic activity of methanolic extract of Piper betle Leaves on nSTZ-induced Type 2 diabetic Model. Eur. J. Med. Health Sci. 2025; 7(1): 428-41. doi: 10.34104/ejmhs.025.04280441

37. Sen S, Chakrabort R. (Eds.) Herbal Medicine in India 2020. Springer Singapore. doi: 10.1007/978-981-13-7248-3

38. Gupta RK, Guha P. Effect of ages on yield and quality of essential oil of betel leaf (Piper betle L.): Antioxidant activity, GC-MS and SEM analysis. Food and Humanity. 2023; 1: 1494–1502. doi: 10.1016/j.foohum.2023.10.017

39. Alam B, Akter F, Parvin N, Pia RS, Akter S, Chowdhury J, et al. Antioxidant, analgesic and anti-inflammatory activities of the methanolic extract of Piper betle leaves. AJP. 2013; 3(2): 112–125. doi: 10.22038/ajp.2013.16

40. Dasgupta N, De B. Antioxidant activity of Piper betle L. leaf extract in vitro. Food Chem. 2004; 88(2): 219–224. doi: 10.1016/j.foodchem.2004.01.036

41. Nguyen NH, Nhi TTY, Nhi NTV, Cuc TTT, Tuan PM, Nguyen DH. Comparative study of the silver nanoparticle synthesis ability and antibacterial activity of the Piper Betle L. and Piper Sarmentosum Roxb extracts. J. Nanomaterials. 2021; 5: 1-9. doi: 10.1155/2021/5518389

42. Peddapalli H, Boggula N, Ramya D, Rashi KN, Rao PV. Therapeutic potential of Piper betle: an amazing nature’s medicinal reservoir. Chem. Res. J. 2020; 5: 62-75.

43. Sikdar B, Mukherjee S, Bhattacharya R, Raj A, Roy A, Banerjee D, et al. The anti-quorum sensing and biofilm inhibitory potential of Piper betle L. leaf extract and prediction of the roles of the potent phytocompounds. Microb. Pathog. 2024; 195: 106864. doi: 10.1016/j.micpath.2024.106864

44. Arambewela LSR, Arawwawala LDAM, Kumaratunga KG, Dissanayake DS, Ratnasooriya WD, Kumarasingha SP. Investigations on Piper betle grown in Sri Lanka. Pharmacogn. Rev. 2011; 5(10): 159-163. doi: 10.4103/0973-7847.91111

45. Valle JR, Puzon DL, Juliana JJM, Cabrera EC, Rivera WL. Thin layer chromatography-bioautography and gas chromatography-mass of antimicrobial leaf extracts from Philippine Piper betle L. against multidrug-resistant bacteria. Evid. Based Complementary Altern. Med. 2016; 2016: 4976791. doi: 10.1155/2016/4976791

46. San TT, Wang Y-H, Hu D-B, Yang J, Zhang D-D, Xia M-Y, et al. A new sesquineolignan and four new neolignans isolated from the leaves of Piper betle, a traditional medicinal plant in Myanmar. Bioorg. Med. Chem. Lett. 2020; 31: 127682. doi: 10.1016/j.bmcl.2020.127682

47. Wirasuta IMAG, Srinadi IGAM, Dwidasmara IBG, Ardiyanti NLPP, Trisnadewi IGAA, Paramita NLPV. Authentication of Piper betle L. folium and quantification of their antifungal-activity. J. Tradit. Complement. Med. 2016; 7(3): 288–295. doi: 10.1016/j.jtcme.2016.08.006

48. Seo J, Lee U, Seo S, Wibowo AE, Pongtuluran OB, Lee K, Han SB, Cho S. Anti-inflammatory and antioxidant activities of methanol extract of Piper betle Linn. (Piper betle L.) leaves and stems by inhibiting NF-κB/MAPK/Nrf2 signaling pathways in RAW 264.7 macrophages. Biomed. Pharmacother. 2022; 155: 113734. doi: 10.1016/j.biopha.2022.113734

49. Xiao C-Y, Sun Z-L, Huang J, Li R-S, He J-M, Gibbons S, et al. Neolignans from Piper betle have synergistic activity against antibiotic-resistant Staphylococcus aureus. J. Org. Chem. 2021; 86(16): 11072–11085. doi: 10.1021/acs.joc.0c02682

50. Tuan PM, Ngan NT. Exploring the volatileo compounds, pigments, phenolics and in vitro bioactivities of Betel Leaves from Vietnam. TJNPR. 2024; 30; 8(5): 7166– 7122. doi: 10.26538/tjnpr/v8i5.18

51. Shah SK, Jhade DN. Evaluation of antifertility potential of Piper betle (Petiole) on female Wistar rats “rising approaches of herbal contraception’’. Biochem. Biophys. Rep. 2018; 15: 97–102. doi: 10.1016/j.bbrep.2018.08.001

52. Sonphakdi T, Tani A, Payaka A, Ungcharoenwiwat P. Antibacterial and toxicity studies of phytochemicals from Piper betle leaf extract. J. King Saud. Univ. Sci. 2024; 36(10): 103430. doi: 10.1016/j.jksus.2024.103430

53. Tutu AKS, Guddun SSK, Kumari P, Dey SKD. An overview of Betel vine (Piper betle L.): Nutritional, pharmacological and economical promising natural reservoir. Adv. Horticul. Sci. 2022; 36(1): 63-80. doi: 10.36253/ahsc-12290

54. Charirak P, Prajantasan R, Premprayoon K, Srikacha N, Ratananikom K. In vitro antibacterial activity and mode of action of Piper betle extracts against soft rot disease-causing bacteria. Scientifica (Cairo) 2023; 2023: e5806841. doi: 10.1155/2023/5806841

55. Biswas P, Anand U, Saha SC, Kant N, Mishra T, Masih H, et al. Betelvine (Piper betle L.): A comprehensive insight into its ethnopharmacology, phytochemistry, and pharmacological, biomedical and therapeutic attributes. .J Cell Mol. Med. 2022; 26(11): 3083–119. doi: 10.1111/jcmm.17323