Areca nut (AN) and betel quid (BQ) products have been highly scrutinized by the scientific community in the last decade due to their classification by the International Agency for Research on Cancer as a group 1 carcinogen. However, neither the size of the user demographic nor the production levels of the product have varied greatly since the announcement, demonstrating that large demographics remain susceptible to oral cancer. Researching the demographic groups and their preferred AN or BQ products has helped provide an overview of the problem globally, from the diversity of products used to the users' demographic variation, including ethnicity, age group, wealth levels, and other factors. However, there is still a considerable lack of available sources related to AN or BQ usage in China, which is the region with the second-highest number of AN or BQ users. Recent studies of the chemical composition of AN or BQ products from different regions or with different preparation methods have reported varied chemical compositions. This is a novel view of the product because chemical components found to be carcinogenic, such as alkaloid arecoline, decreased under certain processes. Thus, different innovative approaches could be considered for AN or BQ research as use of these products has great historical, cultural, and social significance and there is a potential to be less harmful to humans.

In 2003, the International Agency for Research on Cancer (IARC) concluded through its investigation of the available research that the areca nut (AN), also known as betel nut, as well as the betel quid (BQ), with or without the presence of tobacco, were deemed to be carcinogenic to humans.[1] Since this announcement, there has been increased understanding that AN or BQ have carcinogenic properties, and as a result, there has been increased development of new research approaches. Specifically, novel omic technologies have allowed further detailed work, providing evidence that sufficiently supports the perspective for the carcinogenicity of AN or BQ in humans, which is caused by several different biological interactions.[1] The categorization by the IARC has identified AN/BQ products to be dangerous, but the IARC has also observed large gaps in the knowledge required to support the strategies and policies needed to minimize usage risks within the global population.[2]

From a traditional and cultural perspective, AN and BQ have a long history of usage in Asia and the Pacific regions due to their use for cultural, medicinal, and ceremonial purposes.[3] With their euphoric properties and gain in temporary alertness, use of the products has allowed them to be the fourth most addictive substance globally, following only nicotine, ethanol, and caffeine.[4] BQ is a formulation that consists of the betel leaf from the Piper betle L. vine, areca nut from an Areca catechu tree, calcium chloride, and often tobacco, as well.[5] Depending on local preferences, other substances are also added to provide different flavorings and experiences.[1]

Chewable ANs require preprocessing, and these procedures can vary greatly across different regions and population groups. This consequently creates wide variations in the relative concentrations of chemical constituents within the nuts. Also, AN can be added to BQ or consumed at different ripeness stages, depending on the desired texture and taste, which can ultimately alter the relative proportions of the active chemical components of the AN used. For example, studies showed that unripe AN contains higher polyphenol content compared to the ripened nut.[6] The chemical composition of AN consists of carbohydrates, fats, proteins, polyphenols, alkaloids, and other minerals, with a total of 873 metabolites that were analyzed by ultra-performance liquid chromatography-tandem mass spectroscopy in the ground AN preparation.[7]

Table 1 summaries the procedures for processing chewable ANs. Although most of the previous analyses were done based on Indian and Taiwanese results, studies revealed Chinese-processed ANs contain a significantly different ratio of constituents. Recent advances in technology provide a higher resolution for such matters. Thus, in this narrative review article, we describe how new technologies reveal that processed ANs contain different chemical compositions and summarize those differences while identifying existing knowledge gaps. Importantly, this narrative review, for the first time, to our knowledge, incorporates publications in Chinese that have been absent in the international literature reviews on the subject.

Table 1

Common areca or betel products denoting their ingredients and processing methods

Common areca or betel products denoting their ingredients and processing methods
Common areca or betel products denoting their ingredients and processing methods

To investigate this topic, a narrative review approach was chosen because the aim of this article was to provide a broad perspective and explore the general debates and developments. This approach was used, rather than a systematic review approach because the latter focuses on unique and specific queries, using explicit methodology.[14]

Data for this study were carried out through PubMed and the University of British Columbia Library collection, with keywords used in combination, including areca, areca nut, betel, betel quid, gutka, pan masala, income, low income, middle income, culture, demographic, use, and innovations. Country and region names were also used to aid the search. These include India, China, Indonesia, Myanmar, Bangladesh, Southeast Asia, Pacific islands, Oceania, and Taiwan. Papers were restricted to having a publication date spanning 10 years (2012–2022) to reflect the newest and most sensitive analytical approaches, whereas two older publications were used as points of reference.[1,15] To focus on the larger user groups observed during the research, which are those from countries and regions located in Asia and Oceania, we chose to exclude immigrants and locals residing in developed countries such as the United States and Europe.

For Chinese manuscripts, research was performed using Google Scholar, Baidu Xueshu, and CNKI, inclusive of Chinese keywords [betel nut or AN], [edible betel nuts], [processing], [research], [agriculture], [industry]. The keywords [China] and [Taiwan] were used for location specification.

AN and BQ usage has been reported in many countries and regions but is found predominantly within Asia and Oceania, which include, but are not limited to, India, China, Indonesia, Myanmar, Bangladesh, Thailand, Malaysia, Sri Lanka, Bhutan, Nepal, Cambodia, Papua New Guinea, and several Pacific Islands.[2,13] These countries and regions could largely be considered to be low- and medium-income (LMIC) countries, and specifically for India, the large demographic diversity across various Indian provinces and territories allows a study of the socioeconomic and environmental effect of the use of AN or BQ on a large population scale.[16]

Most current large cohort studies were done in India because this was the only available resource at the time. However, China also contains a significantly large demographic of AN or BQ users observable from the country's production of ANs, ranking second after India at 11% of global AN production in 2014. There were up to 100 million estimated AN users across China by 2016, a number that is estimated to grow 25% yearly.[3,17] Despite the large user base, to our knowledge there are no available national level cohort studies relating to AN or BQ product usage, but provincial studies and small reports were found in Chinese. For example, a study conducted in 2011 found that 38.4% of the population in Hunan province (population of 67 million) chews an average of 23.6 grams of AN products daily.[18] However, such studies are opportunistic and do not fall within a wider national program of observational population cohorts.

AN usage in China for cultural and medicinal reasons dates back millennia. The first report of the traditional Chinese medicine (TCM) properties of ANs dates to the Three Kingdoms period of China (220–280 AD), approximately 1800 years ago, and appears in the Chinese monograph for medicine yaolu.[19] Use of ANs for TCM has been continuous since, and as recently as 2015, the Chinese Pharmacopoeia contains up to 60 different formulations containing ANs.[20] These formulations are prescribed for promoting digestion or treatment of abdominal pain, acting as a mainstay component of TCM. It is known as one of the four major medicinal products in southern China.[21] Currently, the southern part of China, especially Hainan and Hunan provinces, along with India, are the main production and consumption areas for ANs. The product formulations in each country are summarized below.

The investigation of the effects of AN or BQ on each demographic can be extremely challenging, especially due to the different formulations of BQ that are used by different ethnic groups, age groups, and even individuals living in the same area. There are, however, different types of AN or BQ products that relate to the ripeness of the nut and the section of the nut, as well as the preparation methods of the products.[22]

India and Indonesia

AN or BQ products tend to involve wrapping betel leaf with ripened ANs.[10] Examples of products found in India include pan (betel leaf wrap containing sliced AN, lime, catechu, and other spices, with or without tobacco), pan masala or gutka (crushed AN mixture containing slaked lime, catechu, and tobacco), and zarda (dried and boiled tobacco leaves, AN, slaked lime, fragrance, spice, and flavors).[10] Other processing methods used in India are sun-drying, peeling, dehusking, boiling, and mixing in spices, essence, sweetening, and other substances, that are specific for each AN-derived product.[22] Also, AN can be added to BQ or consumed at different ripeness stages, affecting the internal components of the AN and BQ when consumed.[1] The product formulations in Indonesia typically use ingredients similar to those found in India, such as AN, betel leaf, and slaked lime. Tobacco is often not added to the BQ outright, but it is commonly used after the AN product has been chewed for a short time.[23]

Furthermore, the location in which the Areca catechu grows can also affect the chemical composition of the nut. A study performed by Sari et al[24] determined that AN bought from West Papua and West Kalimantan of Indonesia contained the highest detectable phenolics compared with AN from Banda Aceh and North Sumatra.[24] The alkaloid content analysis of the four main alkaloids attributed to addictiveness and carcinogenicity (guvacine, arecaidine, guvacoline, arecoline) by liquid chromatography–tandem mass spectroscopy (LC-MS/MS) found arecaidine to be 5- to 10-fold higher in pan masala and gutka products as compared with a dry AN.[25] However, there is no systematic comparative LC-MS/MS analysis across the different areas of India and Indonesia, thus such comparisons remain limited. Apart from this significant difference, a substantial difference in total alkaloid concentration was also observed in the different brands of pan masala and gutka.[25] Furthermore, areca seeds contained high concentrations of flavonoids and phenolics, which, with their strong antioxidant properties, can lead to the development of cancer.[22] The latter study also found that ripe ANs contained higher amounts of the phenolic tannin compared to unripe areca, contrary to the study previously outlined in IARC's monograph[15], indicating that unidentified content variabilities could exist among areca plant varieties and their seeds.[22,26]

Pacific Islands

Pacific islanders have a preference for unripened AN products, which is also the preference of users from Taiwan and a very few areas in China.[13,22] The Pacific island region consists of the three US-affiliated Pacific islands (USAPI), Guam, American Samoa, and the Commonwealth of the Northern Mariana Islands, along with the Republic of Palau, Federated States of Micronesia, and Republic of the Marshall Islands, which are not affiliated with the United States. A regional study suggested that 20% of USAPI adults consume AN or BQ daily, but these numbers also vary among islands, as does the method of consumption.[26]

Compared to India or China, the processing of ANs in these Pacific islands is relatively simple, with limited processing and with preference for either the immature and soft ugam (red) variety or the hard mature white (changnga) variety of AN.[26] Most Pacific islanders have their locally specific combinations. However, there is no high-performance liquid chromatography (HPLC) data available for these nuts and products, and most of the current policies are based on data obtained from older analytical technologies and a few observational studies.

China

In comparison, consumers in China have preference for areca husk products processed from unripened ANs.[21] China has relatively complex processing steps for making chewable ANs, which are most often without tobacco.[27] Processing methods of the AN in China typically include choosing seeds, washing, soaking, baking, slicing, removing the cores, marinating, and packaging, which allows the nut to be sold as a mass-produced and standardized product.[27]

Different processing methods have been researched and developed by Chinese researchers over the last 10 years in areas related to AN or BQ food processing. This research has been driven by changing tastes in the consumer population (i.e., requesting a wide variety of choice/flavors), changing demographic of consumers (i.e., younger individuals using ANs for recreational use), and competition with the existing providers. Indicative of this innovative explosion is the fact that between 2012 and 2022 there have been 539 publications (found on Baidu Xueshu with the keywords [in Chinese] “process manufacturing” and “edible betel nut”; list provided in Supplemental Table 1, available online), consisting entirely of papers on food chemistry, engineering, processing, and analytical chemistry. Furthermore, 288 of these 539 publications contain information relating to patents, demonstrating the industry's desire to improve their product(s).

Recent studies using HPLC, which is a robust and high-resolution tool, revealed that newly developed processing methods can significantly change some of the constituents inside the nuts.[11,27,28] Notably, some of these findings report a decrease in the harmful oncogenic substances mentioned previously. Specifically, through the processing methods of cooking, soaking, and marinating to produce the final product sold, HPLC results observed polyphenol and alkaloid content lowered by more than 50% as compared with the dried AN.[28] Compared to the fresh AN, however, polyphenol and guvacoline content increased by 1.6-fold and 4.1-fold, respectively, whereas the arecaidine, guvacine, and arecoline contents decreased by 34%, 33%, and 45%, respectively, in the final product.[28] When processed AN extract was administered to Kunming mice, changes in body mass, immune response, and inflammation markers over a 4-week period was observed,[29] indicating a reduction in the harmful components as compared with previous similar experiments on mice. The AN industry thus expresses a hope that researching the effect of innovative processing approaches could help to provide a better tasting and safer product in terms of carcinogenicity.[27] Another such indication of variation was reported by Yuan et al,[30] who noticed variance among Chinese AN products, depending on the method of processing or the inclusion and exclusion of certain parts of the nut. Therefore, systematic approaches using HPLC-based technologies are needed to systematically assess the relative chemical compositions in treated ANs because their different treatments can help provide a clearer understanding of the carcinogenicity of the consumed nut product. These chemical analyses would also need to be linked to population cohort evidence so that an understanding of the quantified use and effect of processing treatments and their alternatives can be fully understood and explored.

It is clear that: (1) the carcinogenicity classification of AN and related products has not had an effect on their consumption over the last 2 decades; (2) there is a very fragmented landscape of consumption across the main geographical areas of India, Indonesia, China, and the Pacific islands; and (3) there is a rapid pace of innovation in terms of product preparation and mass production in China, resulting in many new formulations (in addition to TCM usage), which remain underinvestigated.

Although the use of LC-MS/MS methods reveal variations between different nuts and processing approaches, thus affecting the relative chemical substance concentrations of the final products, evidence remains sparse and incomplete. The recent Chinese studies involving chemical constituent research of different processing methods and formulations may provide a systematic baseline for such future comparisons. Such knowledge may inform the formulations or processing that the AN and BQ industrial sector needs in order to limit the harm their product does to its users. This knowledge gap is further exacerbated because most of the AN or BQ usage is within LMIC groups that are still developing their research capacity and funding, often lacking the means to perform systematic research and/or population cohort studies. The knowledge gap is also amplified by the lack of related articles published by Chinese scientific groups in international scientific publications. It would thus be beneficial for the countries that have large numbers of AN or BQ users, such as India and China, to embark on long-term, sustainable research initiatives in the field and to work together by compiling associated findings and identifying biomarkers that relate to processing and quality control. This knowledge would inform both the industrial sector and the relevant public health authorities and regulating bodies.

Regarding suggestions for potential health benefits, it is suggested that the traditional medicinal usage of AN or BQ provides anti-inflammatory, antiparasitic, antihypertensive, and antidepressant functions.[7,31] Betel leaf extracts are suggested to inhibit the growth of microbes and several fungal species.[32] Specifically, betel leaf has many phytochemical constituents that, when studied independently, are known to provide applications in anti-inflammatory (germacrene-D), antimicrobial (germacrene-B, gluobulol), antiseptic (eugenol), anticancer (alpha-cadinene), and antimutagenic (hydroxychavicol) research.[32] Furthermore, data have shown that arecoline helped reduce the development of multinucleated osteoclasts and promoted osteoblastogenesis and bone mineralization through upregulation of genes involved in the expression of RUNX2, ALP, and Col1.[31] With up to 1800 years of AN and betel leaf usage in TCM, and with multiple medicinal recipes recorded in various legacy TCM monographs, AN usage has been documented for the treatment of several gastrointestinal and parasitic diseases.[19,33] Thus, the potential health benefits remain an aspect that has not been thoroughly evaluated and documented by recent technological advancements in research.[19] Further clinical research should be led by the TCM community to confirm the presence of these medicinal properties of the areca plant and to provide a modern lens for the knowledge base regarding the four major medicinal plants from south China.[20,33]

The practice of AN or BQ usage is hard to control at an individual level due to the high addiction rate and dependency on the product by its users. Yet, theoretically, potential therapeutic properties might be obtainable if used as a standardized supplement at lower dosages.[34] Hence, this product might provide alternative beneficial formulations in specific and well-stratified patient cases and, as such, provide a sustainable future path for the industry. Further studies of AN and BQ products and the effect of different methods of processing can also provide a pathway for product providers to limit the toxicity of their products for long-term users as a precursor for longer term public health measures.

AN and BQ products were classified as group 1 carcinogens; however, the use of these products has not been reduced globally, and major knowledge gaps remain. Recent studies involving chromatography methods, paired with analytical methods such as mass spectroscopy, have provided indications for a much larger variation in the chemical composition(s) of the products than those originally considered. Many of the observed differences result from modifications in formulations and processing methods, from how and where the plants were grown, and from the consumption with additives. These differences are also strongly associated with the formulation of various products sold locally in different regions, reflecting local customs and traditions in the commercial products sold internationally.

There is limited understanding of both the current AN or BQ user demographic in China and the different preparation methodologies. However, there has been a recent explosion of innovation relating to the manufacturing and mass production process as documented within the Chinese scientific community. It would be beneficial for more studies to be conducted regarding China and AN or BQ and to allow translations of relevant research so that it can be accessed globally to improve the international exposure of research published from within China. In this way, major gaps in knowledge will begin to be addressed in a systematic and analytical manner.

Supplemental Material

Supplemental materials are available online with the article.

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Source of Support: This study was supported by grants from the National Natural Science Foundation of China (82030099).

Conflict of Interest: None.

Disclaimer: Where authors are identified as personnel of the International Agency for Research on Cancer/WHO, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/WHO.

This work is published under a CC-BY-NC-ND 4.0 International License.

Supplementary data