Betel quid, health, and addiction

Introduction

Areca is a widely used addictive substance that is a recognized carcinogen. Areca comes from the fruit of the Areca catechu palm tree, and often inaccurately referred to as betel nut. Typically areca is combined with the leaf of a betel vine, slaked lime, and other ingredients to form a quid that is chewed. While the traditional use of betel quid has a history dating back thousands of years in many cultures, in the last century it has become progressively more common for tobacco to be combined with betel quid, compounding both the health liability and addictive properties. We discuss need for public health programs and the development of cessation treatments. Pharmacotherapies are likely to need to address both nicotine dependence and specific physical cues familiar to betel quid users.

Preparations of areca

The fruits of the areca palm (Areca catechu) are used in various preparations by an estimated 600 million people (C. H. Lee et al., 2014) on a regular basis. The stones of the areca fruits, usually mistakenly identified as nuts, are generally not consumed, at least not for nutrition, but chewed along with other ingredients in forms that are both psychoactive and addictive (C. H. Lee et al., 2018). One of the most common preparations involves the use of a leaf from the betel vine (Piper betle), coated with slaked lime, to make a packet with areca and other ingredients referred to as a betel quid (Rooney, 1993). About 50% of the time, adult users add tobacco to their quids (Gupta and Warnakulasuriya, 2002; Niaz et al., 2017).

Areca addiction

Betel quid use (areca with or without tobacco) is an orphan addiction (Little and Papke, 2015), little studied and poorly understood. But there is an ever-growing appreciation for the global health impact of this form of drug addiction (Mehrtash et al., 2017; Niaz, et al., 2017). The majority of the betel quid users are stuck in a cycle of use and dependence while aware that they put their health at risk. As western societies have in recent decades been trying to deal with tobacco use, Asian countries are now beginning to enact new public policies to deal with the public health and individual cost of betel use (Garg, Chaturvedi, & Gupta, 2014; Gupta and Warnakulasuriya, 2002; Mehrtash, et al., 2017). There is a growing appreciation of the need for education campaigns and oral health screening in betel quid-using communities (Kao and Lim, 2015; Mehrtash, et al., 2017); however, as with smoking, the comorbid health issues are best addressed by prevention of betel quid addiction and cessation programs that prevent disease by helping people escape the addictions. Unfortunately, for those already using betel quid, individual awareness of a health risk is generally not sufficient motivation for a person to quit an addiction (Herzog et al., 2014; Little et al., 2014a). Furthermore, the availability of efficacious treatments is limited, thereby providing a reason for developing targeted cessation therapies.

Addiction therapies

Although nicotine has been recognized as an addictive substance for many years (Benowitz, 1988; Robinson and Pritchard, 1992; Stolerman and Jarvis, 1995), little progress has been made in developing successful pharmacotherapies for oral tobacco cessation, and even for smoking cessation rates of abstinence are modest at best. Existing smoking cessation therapies, including nicotine replacements and partial agonists like varenicline and cytisine, have at best a 20% success rate (Picciotto and Kenny, 2013; Picciotto and Mineur, 2014). To date, the best treatments for smokeless tobacco cessation are educational and behavioral, offered during health/dental clinic visits or through telephone counseling (Gupta et al., 1986; NCI, 2014). Other studies conducted in India have demonstrated anti-tobacco community education programs (Anantha et al., 1995) and worksite (Sorensen et al., 2017) and school-based teacher (Sorensen et al., 2013) tobacco control interventions are effective methods for reducing tobacco use. Research on areca specific cessation interventions is extremely sparse. Moss and colleagues (Moss, Kawamoto, Pokhrel, Paulino, & Herzog, 2015) pilot-tested an areca cessation intervention that was modeled after smoking cessation programs. An updated version of this cessation program currently is being assessed in a randomized clinical trial.

Special considerations for areca addiction

Only recently has areca addiction been approached with the same methodology and behavioral scales as used in the tobacco research field (Herzog, et al., 2014; C. H. Lee, et al., 2014; C. H. Lee, et al., 2018; Little et al., 2014b; Warnakulasuriya, Chaturvedi, & Gupta, 2015); however, aside from the identification of nicotine-like activity in arecoline, little is known about the fundamentally addictive activities in areca (Papke, Horenstein, & Stokes, 2015). Due to the production of copious amounts of blood-red saliva, the muscarinic effects of arecoline are obvious even to a casual observer of betel quid users. Muscarine is the prototypical activator of the acetylcholine receptors stimulated by the parasympathetic nervous system. These receptors control all the various aspects of the “rest and digest” spectrum of parasympathetic effects that include lacrimation and gastro-intestinal motility, along with salivation. There are many muscarinic receptors expressed throughout the brain as well (Pauly, Stitzel, Marks, & Collins, 1989), which are known to be important for cognitive function (Terry and Buccafusco, 2003). While scopolamine, a muscarinic antagonist, can produce a cognitive impairment (Peele and Baron, 1988; Woodruff-Pak and Hinchliffe, 1997) and has been classified as a hallucinogen (Graff, 1969; Jalali, Afshari, & Babaei, 2014), there are no reports of muscarine or other muscarinic agonists causing drug-seeking behavior. Muscarine was first isolated from Amanita muscaria in 1869 (Fraser, 1957). Interestingly, although Amanita muscaria is considered a sacred mushroom by some Siberian tribes (M. R. Lee, Dukan, & Milne, 2018), it was only discovered much later that the essential psychoactive component in Amanita muscaria is not muscarine but muscimol (Konig-Bersin, Waser, Langemann, & Lichtensteiger, 1970), an activator of GABA receptors in the brain. It remains to be seen whether areca also might contain other unknown important psychoactive agents.

In regard to the psychoactive properties of areca, survey data of betel quid users in Yangon (Papke et al., this issue) offer at best contradictory results with nearly equal numbers of the respondents identifying it as a CNS stimulant (like coffee) or a CNS depressant (like alcohol). In any case, such data are confounded by the concomitant presence of tobacco in the betel quids used by most of the survey subjects. The high levels of nicotine in most of the betel quids used by the study subjects would strongly implicate that nicotine dependence must be an important factor contributing to their addiction and that nicotine replacement therapy might be helpful for them to manage craving and withdrawal that could occur during a cessation attempt (Hatsukami, Jensen, Allen, Grillo, & Bliss, 1996).

Although cessation attempts could be aided with nicotine replacement therapies that reduce withdrawal symptoms such as might be provided by nicotine gum, there are other aspects of betel quid-taking experience which would be better addressed with a more focused therapy. We have identified effects of areca compounds on several types of brain receptors and transporters (Papke unpublished). However, the muscarinic activity of arecoline stands out, with one consistent effect experienced by the betel quid users being the copious production of saliva. Although the muscarinic activity itself would not cause addiction, the stimulation of saliva would be a consistent cue (Bevins and Palmatier, 2004) associated with whatever addictive activities areca might possess, as well as a conditioned response to the delivery of nicotine. Moreover, it has been demonstrated that nicotine effectively enhances the salience of other cues (Perkins, Karelitz, & Boldry, 2017). These cues can perpetuate the drug-use behavior.

These observations suggest that, while a replacement therapy like nicotine gum alone might be unsatisfying to a betel quid user, a similar product augmented with a an alternative safe muscarinic agent might be useful for helping betel quid users to quit. Pilocarpine is the most commonly used muscarinic agonist for therapeutic applications. It is used to improve salivary function in patients recovering from head and neck cancers and suffering from radiation-induced xerostomia (Cheng et al., 2016). While it is used in pill form for that indication, it is also available as eye drops for topical application to treat glaucoma (Liebmann and Lee, 2017). A nicotine gum, spiked with pilocarpine would have an immediate effect similar to betel quid of stimulating salivation, while the release of nicotine could decrease cravings and withdrawal related to nicotine dependence and facilitate cessation of betel quid chewing.

The magnitude of the problem

Betel quid was once considered by Europeans as a quaint and somewhat curious custom and by South Asians as a societal norm. Nowadays, it is largely unknown by Americans outside of the substantial communities of immigrants from the Indian subcontinent, Southeast Asia, and Western Pacific Islands. Based on data from the U.S. census, there are a total of approximately 9 million first generation immigrants in the U.S. from countries where areca product use is high. Additionally, areca use is prevalent in the U.S. territory of Guam (population of 168,000), and the U.S- affiliated Commonwealth of the Northern Mariana Islands (population 54,000). As with other cultural traditions, this use may be passed on to second, third, and even further generations, especially in tightly knit social communities, such as those of the Indian-Gujarati immigrants. It is reasonable to estimate the total number of people in the U.S. who have a cultural tradition of areca product use to be close to 20 million, and based on the limited survey data available (Changrani, Gany, Cruz, Kerr, & Katz, 2006; Murphy and Herzog, 2015), more than 1 million people in the US may be current users, with elevated risks for oral disease and cancers (Auluck, Hislop, Poh, Zhang, & Rosin, 2009). In some cases, the use of areca products may spread to other populations. For example, in Hawaii, where Micronesian students of a betel-using culture mix with the general student population, 2% of the high school students identified themselves as current users of betel nut (Pobutsky and Neri, 2012) although Micronesians constitute only 1% of the total population.

Summary

In conclusion, betel quid is addictive and results in serious adverse health consequences. There is a need to educate the public and health professional of its addictive effects and provide treatments for cessation. As with tobacco, it is likely that interventions that combine behavioral counseling and pharmaceutical cessation aids will yield optimal results. However, there is a great need to determine the underlying biological and psychosocial basis for this addiction and to develop treatments that are not only effective but also culturally sensitive.