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Home , Arecoline, Betel, Paan

Betel Induced Psychosis

{ Julia Shakh, BA, MD Case . 16 y/o (Shan) Burmese female, recent immigrant from Thai refugee camp, with no past psychiatric history.

. Family concerned about recent onset (2-3 weeks) behavioral changes, with the only stressor appearing to be Global Regents Examinations.

. She presented in a grossly disorganized fashion, which, due to her accent and simple use of English, initially appeared to be a significant language barrier.

. Patient and her family speak a Burmese dialect (Karan), which is seldom available by translator phone. Her brother helped interpret; an official interpreter sent by agency happened to be her neighbor and family friend, and was not fluent in the Karen dialect the patient’s family spoke. There was significant difficulty translating. . Patient is a good student, but otherwise struggling to adapt to school and life in the US; struggling with making friends. . Since failing her Global Regents examination in English (her only failed subject) her behavior changed. She began staying up all night to study more intensely. . She had been refusing to eat, citing lack of appetite. . She had been having difficulty sleeping, often staying up all night and leaving the house at 5 AM and returning shortly before sundown. . Family reported that this usually obedient child became defiant and oppositional, becoming aggressive when family tried to prevent her from leaving the home in the middle of the night. . She had cut her own hair prior to presentation. . She had been frequenting the Buddhist temple at night, and was asked to refrain from coming by at night. . She has been having command auditory hallucinations (identified as her deceased father), telling her to go swimming in an industrialized (and polluted) waterway near her house, which she would do (without disrobing) in her street clothing.

. Family report that the patient is the “glue” of the household. Her mother and siblings all work outside the home, and she is responsible for keeping the house tidy, cooking meals, and even wakes at 5AM to prepare breakfast for her family before everyone leaves for work. Family report that she has been neglecting her housework and has been “spitting” in her room such that it is a disgusting mess.

. Family adamant that the patient does not “do ”, ten panel urine toxicology is negative for substances of abuse. MSE

. Very petite and appearing very young for her age (10). Wearing a hospital gown, and wrapped in a hospital blanket.

. Oriented only to herself. Not attentive, engrossed in a drawing she colored in, dripping water on it and smearing it on the table.

.

. Grossly disorganized and unable to answer basic questions, volunteering a word salad and smiling sweetly in response.

. She is not easily redirected, and cooperating very minimally with interview and care on the unit. Past History

. Patient has no past psychiatric history.

. Patient and family deny any pertinent surgical or medical history, that she had developed appropriately as a child, and had never been hospitalized. They add that the patient has not been following with any physician, aside from mandatory immigration health screenings two years prior to presentation.

. Her father is deceased from complications of chronic use. She has an older (eldest) brother living in , who is currently in incarcerated for an unknown offense. He is said to have had similar symptoms as our patient in the past. He chronically uses Thai Stick. THAI STICK Social History

. Patient is of Shan (Burmese) descent. She was born in a refugee camp in Thailand, where she lived with her parents and (older) siblings. She was born to married parents, was the byproduct of a healthy pregnancy. Her family speaks Karen, and Thai (with the exception of her mother). . Her father passed away several years ago, prior to immigration to the US. His passing affected her disproportionately, as she had been the closest to her father (and had been the only daughter). . She completed the 10th grade. She had always been a high achieving student until coming to the US, where her teaching material was taught in Burmese, but tested in English. She had difficulty assimilating and acculturating, had difficulty learning the English language, and despite being quite friendly and social, was having difficulty making friends at school. She lamented that even the Burmese and Burmese-American children did not think she was “cool” enough to make friends. . Family continue to insist that the patient does not use any drugs or psychotropic substances, and that she is a “good girl” who upholds traditional values.

What may cause tooth staining?...

 Certain foods (curry/ , , )

 Habitual chewing of nut or

 Tobacco

 Medications (doxycycline)

 Chromogenic bacteria And further questioning revealed…

. That her mother was at one time heavy betel nut user (as was her deceased father).

. Conflict over cessation of the use of betel, which was discouraged by a Thai Ministry of Health campaign, nearly caused the patient’s parents to divorce.

. The patient herself began using betel at an early age, and had been using it heavily (around the clock vs occasionally after socially important/ holiday meals) the weeks preceding her hospitalization.

. The “spitting” her mother had been annoyed and concerned about, was the red staining alkalinized saliva which is a byproduct of betel chewing. It is considered impolite and offensive to do so indoors. “Burmese Toba(s)cco”

. It was quite difficult to question the patient about her use of Betel, as she continued to be disorganized and grossly psychotic, with episodes of acute agitation. . It was several weeks before we were able to talk about her habits, and even then there was a significant language barrier, as she did not know the word “betel”. . Eventual identification and clarification of her habit involved searching the various words/slang used for betel in various Burmese dialects, and matching this word to her use. . She was also asked to describe the common use of this substance, which is easily available here in the US, as it is not a controlled substance. . There are various ways to use Betel, and modern methods now include addition of tobacco and flavoring agents that make its use attractive to youth. Hospital Course

. The patient is started on Zyprexa. Her hospital course is prolonged, and initially she draws very little benefit from the medication. She requires multiple PRN medications for agitation, aggression, bizarre and disorganized behaviors. She has a preoccupation with water; she tries to abscond from the unit, pleading to be discharged.

. Neuroimaging obtained is unimpressive. Labs are normal. Vital signs were not available until the last week of her hospitalization, due to agitation and non-cooperation.

. Patient began to improve into her fourth week in the hospital, and was discharged home. She and her family were counseled to avoid betel use.

So, what is “Betel Nut”

. An estimated 600 million people around the world chew betel quids, which, after tobacco, alcohol, and drinks, makes them the fourth most commonly used psychoactive substance internationally. . It is the nut of , the Areca Palm. . The is the source of a psychoactive called . Arecoline is a powerful muscarinic and nicotinic receptor . . In TCM and it is utilized as a powerful antihelminthic, and used to alleviate toothache. Betel Leaf . betle is the leaf of a tropical belonging to the family, which also includes pepper and . . Piper betle flower or leaf contains aromatic phenolic compounds which have been found to stimulate the release of catecholamines in vitro. . Used in Ayurveda and TCM to treat headache. Also utilized as a breath freshener, and mouth antiseptic. . Widely used in cooking, and believed to have a high nutritious value by many, and regarded as a medicinal herb. Why Chew? Who Chews? What may be found in a betel quid? . Areca nut

. Betel leaf

. Lime

. Catechu (aka Catha) (extract of acacia tree bark used variously as a food additive, astringent, , and dye)

. Tobacco

. flavorings Lime ()

• Ca (OH)2 is a food additive, most commonly used to preserve/pickle foods. It is responsible for the bright red saliva coloration associated with Betel quid chewing.

• Utilized to facilitate hydroxylation of active compounds into more readily absorbed alkaloid forms, particularly for sublingual absorption.

• Often made from incineration of coral, even seashells.

• Very caustic, and often causes mucosal chemical burns, which with persistent and chronic use cause mucosa to become fibrotic and pre-cancerous. Said to be the predominant in Betel Quid. “Taiwanese ”

 https://www.youtube.com/watch?v=DyKI6UgI 1Jk : “Matters of Betel and Areca”:

• “Matters of Betel and Areca”: said to be a phrase that is synonymous with love and weddings.

• This is due to the large part Areca and betel leaves have in Buddhist ceremonies (used as offerings), thus also marking their ceremonial importance in weddings.

• A wedding cannot occur without the presence of Areca and Betel, and many elaborate arrangements of Areca and Betel leaves are made for weddings. Vietnam

. Although less common today, marriages were typically arranged in Vietnam. For a traditional wedding, it is customary for the groom’s family to visit the bride’s home with a gift of Betel nuts, and officially ask permission to receive the bride.

. After introductions, socializing, and the groom’s and bride’s parents chewing betel and discussing arrangements, the wedding would finally be confirmed and announced.

. Betel chewing is an important social pastime, and clearly, in the case of arranged marriages, provides a way to make a stressful event more pleasant. Tan and Lang

Tan and Lang were (twin) brothers. Lang was in love with a beautiful young woman named Lu, who was the most beautiful woman in the village, and also was in love with Lang. Lang, however, was not allowed to marry until his older brother Tan did so. When it was time for Tan to marry, he chose Lu, and Lu, because she could not tell the brothers apart from a distance, agreed to do so. Lu eventually realized she married the wrong brother, but accepted this, as Tan looked just like Lang and was good natured. The couple went to live on their own. Lang came along. Tan gave less and less attention to his brother, making him sad. One day, Lang returned from the fields first, as he was quite tired. Lu came out to affectionately greet him, thinking he was Tan, and although Lang tried to identify himself it was too late. Tan came home and saw Lang and Lu holding hands, and became angry and sad. Lang felt guilty, and left the house. He came to rest at a river where he felt tired, fell asleep, and never woke up. He turned into a limestone slab. Tan was worried about his brother’s absence, and went looking for him. He too, came to the same spot on the river, where he laid down to rest, and never woke up. In his place sprung up an Areca Palm. Lu, heartbroken and worried for her husband, also came to search for him. She came to the same fateful spot by the river, where she leaned against the Areca tree and limestone slab, and felt a familiar warmth. Lu cried until she was fatigued, and also fell asleep and did not wake up. In her place sprung up a betel leaf and enveloped the areca tree and limestone slab with its leaves. Thus the story represents the faithful love between brothers and a husband and wife. King Hung shortly after, passed by this same site by the river, and after hearing the story and its symbolism, proclaimed that all marriages are officiated with the combination of areca nut, betel leaf, and lime, to symbolize faithful love. () • Usually consists of betel leaf, areca nut, lime, tobacco, catechu, , sweet pickle, seeds (mukhwas), and other flavorings. • Paan is frequently chewed after meals, and is believed to freshen breath. • There are different kinds of Paan; those not containing tobacco or areca, often called “sweet Paan” are eaten as a snack or desert after meals and are not spat out after chewing. • There are hundreds of varieties of Paan; a Paan maker is called a Paanwala https://www.youtube.com/wat • Also known to be detrimental ch?v=-y4B-ZEEioo to health and to cause oral cancers, like other betel formulations. India () • Gutka does not contain the Betel leaf.

• It can and often does contain tobacco and flavoring agents, and of course Areca palm nut.

• Contents are often ground or finely cut, and a pinch of the mixture is placed into the buccal fold. This also makes it easy for those who have lost their teeth, to continue their Areca habit.

• In recent years, water scarcity and climate change have made it less lucrative and even cost prohibitive to grow Betel leaves on the .

• As a result Gutka has grown to be quite popular, as it is more cost effective. Physiological effects

. Produces a sense of well-being, , heightened alertness, sweating, salivation, a hot sensation in the body and increased capacity to work. Betel chewing also leads to habituation, and withdrawal.

. However, the mechanisms underlying these effects remain poorly understood. Arecoline, the major alkaloid of Areca nut, has been extensively studied, and several effects of betel chewing are thought to be related to the actions of this parasympathomimetic constituent.

. However, betel chewing may produce complex reactions and interactions. In the presence of lime, arecoline and guvacoline in Areca nut are hydrolyzed into and guvacine, respectively, which are strong inhibitors of GABA uptake.

. Piper betle flower or leaf contains aromatic phenolic compounds which have been found to stimulate the release of catecholamines in vitro. Thus, betel chewing may affect parasympathetic, GABAnergic and sympathetic functions. . Betel chewing produces an increase in heart rate, blood pressure, sweating and body temperature.

. In addition, EEG shows widespread cortical desynchronization indicating a state of arousal. In autonomic function tests, both the sympathetic skin response and RR interval variation are affected. Betel chewing also increases plasma concentrations of and epinephrine.

. These studies suggest that betel chewing mainly affects the central and autonomic nervous systems. Future studies should investigate both the acute and chronic effects of betel chewing. Such studies may further elucidate the psychoactive mechanisms responsible for the undiminished popularity of betel chewing since antiquity. Toxic Psychosis

. Areca Nut Psychosis was first described in Papua in 1977 by Burton-Bradley, and was associated with high intake as part of a ceremony with traditional healers.

. It has been used in Melanesia to induce intoxication and altered states of consciousness.

. An acute toxic psychosis featured by auditory hallucinations, grandiosity, persecutory delusions has rarely been observed in heavy habitual users. It is more commonly observed in individuals who are naïve to the substance who consume a large amount, or individuals who are heavy users (after a period of non-use), who consume large amounts in one instance, for example, for a ceremony.

. Acute psychosis with betel use is more likely in those who are predisposed to mental illness. Betel and Schizophrenia

. The muscarinic hypothesis of schizophrenia postulates that the muscarinic ACh system plays a crucial role in the pathology and treatment of schizophrenia. Data from clinical, postmortem, neuroimaging, and preclinical and clinical pharmacology studies support this hypothesis.

. Postmortem and neuroimaging studies have shown a decreased number of M1 and M4 muscarinic ACh receptors in persons with schizophrenia in several key areas, including caudate and putamen, hippocampus, anterior and posterior cingulate cortex, and prefrontal cortex.

. Similar changes were not found in persons with bipolar disorder or major depression. The levels of M2 and M4 muscarinic ACh receptors were unchanged in schizophrenia. These findings are supported by a single- photon emission CT (SPECT) study that found a significant decrease in vivo in the availability of muscarinic receptors in the cortex and basal ganglia in patients with schizophrenia compared with healthy controls. . In a preliminary study conducted in the North Colombo Teaching Hospital, , we observed that a higher proportion of patients with schizophrenia chewed betel compared with control subjects. The frequency of chewing betel was also higher among the patients with schizophrenia. A recent study from ( Sullivan et al, 2000) has shown that betel chewing may in fact have a beneficial effect on patients with schizophrenia in terms of reducing both positive and negative symptoms. They postulate that the action of the betel nut alkaloid, arecoline, may provide an explanation.

. However, betel chewing is an important risk factor for oro-pharyngeal carcinoma, and contributes significantly to oral health-related morbidity and mortality ( Trivedy et al, 2002). Thus, the dual diagnosis of schizophrenia and betel chewing should not be missed, and services to address this problem should receive priority in many developing countries.

Dependence and Withdrawal . Cessation of arecoline will most commonly yield the following symptoms: mood swings, anxiety, irritability, reduced concentration, sleep disturbance, increased appetite.

. Withdrawal symptoms appear to differ, especially since consumption habits/methods appear to differ regionally. Withdrawal appears to be worse when Areca is combined with tobacco.

. In a small study by Weinstock et al (2000), 70% of users had failed to stop using arecoline due to withdrawal and tolerance; of these only two individuals were able to stop use, but only by starting cigarette smoking.

. A larger Taiwanese study demonstrated a 44% rate of dependence, with criteria for dependence defined as such: cravings during a period of abstinence, continued use despite illness or mouth ulcers/wounds, difficulty refraining from chewing in forbidden areas.

. It appears that the ability to quit areca nut chewing becomes more difficult Potential treatment of Addiction?

https://www.youtube.com/watch?v=QmbrbQk4K eY Pregnancy outcomes

. Among Bangladeshi pregnant women, 94% regularly chew betel nut, 9% smoke and 1% used alcohol. 31% are heavy chewers (>10 nuts/day).

. The principal reasons for pregnant women to chew are: to prevent morning sickness (28%), to prevent having a smelly mouth (26%), the habit of chewing (20%), being addicted (10%).

. Primigravidity, betel nut chewing and low BMI had a statistically significant impact on birth weight reduction of 467 g (p < 0.001), 238 g (p = 0.02) and 175 g (p = 0.005) respectively. Other studies quote an average of 500g birth weight reduction. . 80% of the women thought that chewing would not have any effect on the fetus.

. 51 infants in the study group developed mild neonatal jaundice compared with 79 in the control group. Possibly some substance in the betel chew is an inducer of glucuronyl transferase. The difference in the overall incidence of jaundice is significant (P0.001) Neonatal withdrawal . A female newborn presented with irritability and hypertonia 48 hours after a eutocic delivery at 38 weeks of gestation (APGAR at 1,5 and 10 minutes: 9,10,10). The infant was born to a healthy 38 year old mother who was an immigrant from and came to the obstetrics department for childbirth. . The mother reported no toxic habits and no visits to any obstetrician during gestation. . The infant’s weight was 3090g, length was 49 cm, and head circumference was 34cm. . testing on the mother was negative for opiates, , , , , and . . It was noticed that the mother’s oral mucosa, tongue, and teeth were stained reddish brown (and patient was further questioned and found to be a heavey user of betel). . The placenta was tested with GC, and found to have arecoline. . Neonatal abstinence syndrome was assessed every 3 hours by using the scoring system of Kaltenbach and Finnegan. An ultrasonographic stud of the brain through the anterior fontanelle was unrevealing. On the third day of life, treatment with phenobarbital was started because Finnegan scores were 8. The neonate showed no signs of neonatal abstinence by day of life # 5. Effects Detrimental to Health

Precancerous conditions . Oral precancerous lesions, including erythroplakia (a reddened patch in the mouth) and (a white patch on the mucous membranes in the mouth that cannot be wiped off). . (OSF), a precancerous lesion that stiffens the soft pink tissue that lines the inside of the mouth (i.e., oral mucosa).

Cancer . Oral cancers—predominantly carcinomas of the lip, mouth, tongue, and pharynx . Cancer of the esophagus Other health effects . Reproductive health outcomes such as increased risk of having a low birth-weight infant . addiction Gutka syndrome (Indian Cancer Society)

References Neuropathology of Drug and Substance Misuse Volume 3 J Biomed Sci. 2001 May-Jun;8(3):229-36. Effects of Betel chewing on the central and autonomic nervous systems.

Indian Journal of Cancer (Indian Cancer Society) Gutka or areca nut Chewer's syndrome, P Chaturvedi Head and Neck Service, Department of Surgical Oncology, Tata Memorial Hospital, Mumbai - 400 012, India

Betel Use and Schizophrenia K. A. L. A. Kuruppuarachchi, S. S. Williams The British Journal of Psychiatry May 2003, 182 (5) 455; DOI: 10.1192/bjp.182.5.455a

Betel nut chewing during pregnancy, Madang province, M. Senna, , , F. Baiwoga, J. Winmaia, I. Muellerb, S. Rogersonc, N. Senna, c http://monographs.iarc.fr/ENG/Monographs/vol85/mono85.pdf https://www.cdc.gov/tobacco/data_statistics/fact_sheets/smokeless/betel_quid/