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KAVA

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Kava is an extract of the roots of Piper methysticum, a species of pepper plant that is found in Polynesia, Melanesia, and Micronesia.

Specific Substances

    1) Kava
    2) Kava kava
    3) Awa
    4) Ava
    5) Ava-ava
    6) Ava pepper
    7) Kava pepper
    8) Kava root
    9) Kawa
    10) Kawa Kawa
    11) Kew
    12) Sakau
    13) Tonga
    14) Wurzelstock
    15) Yangona
    16) Yaqona
    17) Intoxicating pepper
    18) Piper methysticum
    19) Piper methysticum Forst.
    20) Piper methysticum G. Forst.
    21) Rauschpfeffer
    22) CAS 500-64-1 (kawain)
    23) CAS 495-85-2 (methysticin)
    24) CAS 500-62-9 (yangonin)

Available Forms Sources

    A) FORMS
    1) Kava is available in the forms of roots, chips, extracts, tinctures, tablets, capsules, and powders (Fu et al, 2008; Norton & Ruze, 1994).
    2) The dried herb normally contains 3.5% kavalactones, although commercial products may contain as much as 70% kavalactones (Humberston et al, 2003). Kava contains six major kavalactones: kavain, dihydrokavain, methysticin, dihydromethysticin, yang-onin and demethoxyyangonin (Ernst, 2002).
    B) SOURCES
    1) Kava is derived from rhizome and roots of Piper methysticum, a member of the black pepper plant (family: Piperaceae), found in Polynesia, Melanesia, and Micronesia. Piper methysticum is a perennial shrub with woody, jointed stems and large dark green heart-shaped leaves, and generally grows to approximately 6-feet tall, forming dense thickets (Anke & Ramzan, 2004; Norton & Ruze, 1994).
    2) Traditionally, kava is made from the roots of Piper methysticum; however, other producers of kava may also include other parts of the plant including the stem peelings, aerial parts, and leaves (Anke & Ramzan, 2004). Two methods of extraction used to produce kava supplements include ethanolic and acetonic extraction (Ernst, 2002).
    C) USES
    1) Kava is commonly used in the Pacific islands as a beverage to induce relaxation where it is usually ingested before religious ceremonies (Heiligenstein & Guenther, 1998). It is marketed and sold commercially in industrialized countries as a sleeping aid and for treatment of anxiety disorders and depression (Stickel et al, 2003).
    2) Other reported uses of kava include: sedative, diuretic, anti-inflammatory, anticonvulsant, antifungal, aphrodisiac, and stimulant therapy. The resin from the kava root has been used as a local anesthetic and as a urinary antiseptic, and an analgesic mouthwash has been made to treat toothaches and canker sores (Chevalier, 1996; Heiligenstein & Guenther, 1998; Wong et al, 1998a; Anon, 1998a).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Kava is commonly used in the Pacific islands as a beverage to induce relaxation where it is usually ingested before religious ceremonies. It is marketed and sold commercially in industrialized countries as a sleeping aid and for the treatment of anxiety disorders and depression. It is available in the forms of roots, chips, extracts, tinctures, tablets, capsules, and powders. Kava has been banned in Germany, France, Switzerland, Australia, and Canada; however, it is still available in the United States.
    B) PHARMACOLOGY: Kava is derived from rhizome and roots of Piper methysticum (a perennial shrub), a member of the black pepper plant (family: Piperaceae), found in Polynesia, Melanesia, and Micronesia. The main active constituents in the root and rhizome of kava are a group of resinous compounds called the kavalactones, which include kavain (kawain), dihydrokavain, methysticin, and dihydromethysticin. Although a specific mechanism of action has not been established, it is speculated that the kavalactones may potentiate GABA receptors which may cause sedative effects. Another source suggested that kava may exert its effects by blocking voltage-gated sodium channels and by GABA receptor and dopamine receptor antagonism. In addition, it may have anticholinergic activity.
    C) TOXICOLOGY: Hepatotoxicity has been reported in patients taking both the traditional water-based kava extracts of the South Pacific and the medicinal solvent-based kava extracts of western countries, with flavokavain B as one of the possible causes. One study of aqueous, ethanolic, acetonic kava extracts and kava-herbs mixtures determined that hepatotoxicity was linked to the kava plant (eg, low quality of kava cultivars or kava plant-parts) rather than to chemical solvents (eg, ethanol, acetone) used. Two mechanisms of hepatotoxicity have been suggested: Induction of herb-drug interactions through modulation of metabolizing enzymes. Extracts of kava can significantly inhibit human cytochrome P450, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP4A9/11. Since many drugs are metabolized by these enzymes, kava can potentially affect drug metabolism. Another possible mechanism is formation of activated metabolites. Several metabolites (eg, kawain 11,12-quinone, 8,8-dihydrokawain 11,12-quinone) of kava can covalently bind to cellular DNA to form the kava-quinone methide derived DNA adducts, causing hepatotoxicity in humans.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH POISONING/EXPOSURE
    1) ACUTE: Nausea and vomiting, tachycardia, mild hypertension, diaphoresis, sedation, perioral paresthesia, extrapyramidal effects, visual disturbances, and ataxia have been reported in patients ingesting large amounts of kava. The CNS depressant effects may be enhanced when taken with other depressants such as benzodiazepines and ethanol.
    2) CHRONIC: Elevated liver enzymes, renal dysfunction, weight loss, gastritis, hematological abnormalities (leukopenia, thrombocytopenia), shortness of breath, disorientation, hallucinations, seborrheic dermatitis, and a characteristic rash with cracked and scaling skin have been reported in patients following long-term ingestion of large amounts of kava. Hepatotoxicity, including hepatitis, cirrhosis, and fulminant hepatic failure, has been reported with kava use. However in many of these cases, patients were also taking other medications with hepatotoxic potential. Thus, whether kava is the sole cause of hepatic injury remains controversial.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Laboratory Monitoring

    A) Serum kava lactone levels are not clinically useful and are not readily available.
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Monitor hepatic enzymes and renal function tests in symptomatic patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with vomiting or diarrhea.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Severe toxicity is not expected after an overdose of kava.
    C) DECONTAMINATION
    1) PREHOSPITAL: Most cases of toxicity reported have involved chronic ingestion of kava. Gastrointestinal decontamination is generally not recommended.
    2) HOSPITAL: Most cases of toxicity reported have involved chronic ingestion of kava. GI decontamination is generally not required. Consider activated charcoal if coingestants with significant toxicity are involved.
    D) AIRWAY MANAGEMENTS
    1) Should not be required in these cases.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) Hemodialysis is generally not required.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance and gastrointestinal function. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, hepatotoxicity, dehydration, and electrolyte abnormalities.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PHARMACOKINETICS
    1) KAWAIN: Tmax: 1.4 and 1.8 hours. Kavalactones (alpha-pyrones) are lipid soluble with low absorption in the gastrointestinal tract and rapid absorption in the gut. The kavalactones are more rapidly absorbed when given orally as a root extract than when given as single compounds, and the bioavailability of the lactones is 3 to 5 times higher for the extracts than when given as single substances. Hepato cytochrome P450 enzymes are required for the clearance of kavalactones by the liver.
    I) DIFFERENTIAL DIAGNOSIS
    1) Includes agents that cause hepatotoxicity.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established. Kava toxicity is primarily from chronic use; however, acute toxicity has also been reported. Differences in kavalactones content in kava preparations, the duration of use, and individual variation are likely to play a role in toxicity. Kavalactones doses up to 2571 mg daily have been used with traditional aqueous kava beverages. Heavy consumption of kava by the aboriginal community (310 to 440 grams/week as a beverage) has resulted in malnutrition, weight loss, elevated liver enzyme, renal dysfunction, discolored sclerae, and an ichthyosiform rash. Extrapyramidal effects (dyskinesia and dystonia) occurred approximately 1 to 4 hours after ingesting 100 mg of kava extract. DOSES: The recommended dosage of kava is dependent upon the concentrations of the kavalactones, the active constituents of kava. AUSTRALIAN REGULATORY LIMITATION: A maximum of 125 mg of kavalactones per tablet or capsule and a maximum of 250 mg of kavalactones daily derived from water-based kava extracts.
    B) In older studies, the following doses were recommended for anxiety: standardized preparations: 100 to 200 mg daily of kavalactones in divided doses or as a single dose at bedtime. Dried rhizome: 1.5 to 3 grams daily of kavalactones in divided doses. Alcoholic preparation of 1:2 extract: 3 to 6 mL daily of kavalactones in divided doses, with no more than 20 to 40 mL per week.

Clinical Effects

Summary Of Exposure

    A) USES: Kava is commonly used in the Pacific islands as a beverage to induce relaxation where it is usually ingested before religious ceremonies. It is marketed and sold commercially in industrialized countries as a sleeping aid and for the treatment of anxiety disorders and depression. It is available in the forms of roots, chips, extracts, tinctures, tablets, capsules, and powders. Kava has been banned in Germany, France, Switzerland, Australia, and Canada; however, it is still available in the United States.
    B) PHARMACOLOGY: Kava is derived from rhizome and roots of Piper methysticum (a perennial shrub), a member of the black pepper plant (family: Piperaceae), found in Polynesia, Melanesia, and Micronesia. The main active constituents in the root and rhizome of kava are a group of resinous compounds called the kavalactones, which include kavain (kawain), dihydrokavain, methysticin, and dihydromethysticin. Although a specific mechanism of action has not been established, it is speculated that the kavalactones may potentiate GABA receptors which may cause sedative effects. Another source suggested that kava may exert its effects by blocking voltage-gated sodium channels and by GABA receptor and dopamine receptor antagonism. In addition, it may have anticholinergic activity.
    C) TOXICOLOGY: Hepatotoxicity has been reported in patients taking both the traditional water-based kava extracts of the South Pacific and the medicinal solvent-based kava extracts of western countries, with flavokavain B as one of the possible causes. One study of aqueous, ethanolic, acetonic kava extracts and kava-herbs mixtures determined that hepatotoxicity was linked to the kava plant (eg, low quality of kava cultivars or kava plant-parts) rather than to chemical solvents (eg, ethanol, acetone) used. Two mechanisms of hepatotoxicity have been suggested: Induction of herb-drug interactions through modulation of metabolizing enzymes. Extracts of kava can significantly inhibit human cytochrome P450, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP4A9/11. Since many drugs are metabolized by these enzymes, kava can potentially affect drug metabolism. Another possible mechanism is formation of activated metabolites. Several metabolites (eg, kawain 11,12-quinone, 8,8-dihydrokawain 11,12-quinone) of kava can covalently bind to cellular DNA to form the kava-quinone methide derived DNA adducts, causing hepatotoxicity in humans.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH POISONING/EXPOSURE
    1) ACUTE: Nausea and vomiting, tachycardia, mild hypertension, diaphoresis, sedation, perioral paresthesia, extrapyramidal effects, visual disturbances, and ataxia have been reported in patients ingesting large amounts of kava. The CNS depressant effects may be enhanced when taken with other depressants such as benzodiazepines and ethanol.
    2) CHRONIC: Elevated liver enzymes, renal dysfunction, weight loss, gastritis, hematological abnormalities (leukopenia, thrombocytopenia), shortness of breath, disorientation, hallucinations, seborrheic dermatitis, and a characteristic rash with cracked and scaling skin have been reported in patients following long-term ingestion of large amounts of kava. Hepatotoxicity, including hepatitis, cirrhosis, and fulminant hepatic failure, has been reported with kava use. However in many of these cases, patients were also taking other medications with hepatotoxic potential. Thus, whether kava is the sole cause of hepatic injury remains controversial.

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) CONJUNCTIVAL DISCOLORATION: Chronic consumption of kava may cause redness and discoloration of the conjunctiva (Mathews et al, 1988).
    2) VISUAL CHANGES: Acute ingestion of 500 mL of kava beverage resulted in visual function changes, including reduced near-point of accommodation and convergence, an increase in pupil diameter, and oculomotor balance disturbances (Bone, 1994; Anon, 1996). The visual changes occurred approximately 30 to 40 minutes after kava ingestion.
    3) CASE REPORT: Saccade (eye movement) function was investigated in a group (n=11) of acutely intoxicated indigenous kava drinkers. The intoxicated participants all drank kava from a communal bowl shared equally (approximately 16.4 grams/hour for a total consumption of 205 grams) within the 24 hours prior to testing. The control group (n=17) consisted of regular kava users who had not consumed kava in the week prior to testing. The intoxicated subjects showed blepharospasm and saccadic visual changes (dysmetria and slowing of visually guided saccades). Symptoms improved once the kava was cleared from the body (Cairney et al, 2003).
    4) SACCADE: Another study examined saccade and cognitive function in current kava users, ex-kava users, and non-kava users, and found no difference between these groups (Cairney et al, 2003a).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Tachycardia (105 bpm) and milder hypertension developed in a 37-year-old man following an acute ingestion of an herbal tea containing kava. The patient admitted to drinking several cups of the herbal tea that tasted "too strong" (Perez & Holmes, 2005).
    B) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) A 37-year-old man developed mild hypertension (BP 137/86 mmHg) and tachycardia following acute ingestion of an herbal tea containing kava. The patient admitted to drinking several cups of the herbal tea, and that it tasted "too strong" (Perez & Holmes, 2005).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH POISONING/EXPOSURE
    a) Shortness of breath may occur with long-term kava ingestion (Mathews et al, 1988; Anon, 1988).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) Marked sedation may occur following ingestion of large doses of kava (Bone, 1994).
    b) CASE REPORT: Cognitive and saccade (eye movement) function were investigated in a group (n=11) of acutely intoxicated indigenous kava drinkers. The intoxicated participants all drank kava from a communal bowl shared equally (approximately 16.4 grams/hour for a total consumption of 205 grams) within the 24 hours prior to testing. The control group (n=17) consisted of regular kava users who had not consumed kava in the week prior to testing. The intoxicated subjects showed ataxia, tremors, sedation, blepharospasm and saccadic visual changes. Performance of complex cognitive functions was not impaired (Cairney et al, 2003).
    c) SACCADE: Another study examined saccade and cognitive function in current kava users, ex-kava users and non-kava users, and found no difference between these groups (Cairney et al, 2003a).
    B) PARESTHESIA
    1) WITH POISONING/EXPOSURE
    a) Kava may cause a local anesthetic effect described as numbness of the mouth and tongue (Singh, 1992; Anon, 1996; Anon, 1998).
    C) ABNORMAL GAIT
    1) WITH POISONING/EXPOSURE
    a) Kava ingestion may cause gait instability and ataxia due to motor control impairment (Chanwai, 2000; Norton & Ruze, 1994; Ruze, 1990; Bone, 1994).
    b) CASE REPORT: A 37-year-old man presented to the ED with nausea, diaphoresis, vomiting, leg weakness, and dizziness. Physical examination revealed that the patient had a decreased level of consciousness, his gait was unsteady and ataxic, and his speech was slurred. After 4 hours of observation in the ED, the patient's ataxia resolved and his mental status improved. The patient admitted to ingesting an herbal tea containing kava prior to the onset of symptoms. Seven hours after presentation to the ED, he was discharged without sequelae (Perez & Holmes, 2005).
    D) PARALYSIS
    1) WITH POISONING/EXPOSURE
    a) Temporary paralysis may occur following high-dose administration of kava (Anon, 1998a; Bone, 1994).
    E) HYPOREFLEXIA
    1) WITH THERAPEUTIC USE
    a) Kava may cause hyporeflexia (Norton & Ruze, 1994).
    F) EXTRAPYRAMIDAL DISEASE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 45-year-old woman presented with severe extrapyramidal effects, including rigid akinesia, resting and intentional tremor, and akathisia following chronic ingestion of St. John's wort and kava-kava. The patient recovered following intravenous administration of biperiden. It was suggested that kava-kava's antidopaminergic and anti-GABA-ergic actions may have been responsible for the extrapyramidal effects (Ballesteros et al, 2001).
    b) CASE SERIES: Four patients experienced extrapyramidal effects, including dyskinesia and dystonia, after ingestions of 100 to 150 mg of kava extract. Two of the four patients developed the extrapyramidal effects 1.5 to 4 hours after ingestion of the first dose of kava extract. The patients recovered following intravenous administration of biperiden 2.5 to 5 mg and discontinuation of the kava extract (Schelosky et al, 1995).
    G) CHOREOATHETOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 27-year-old man presented with choreoathetosis on three different occasions, following ingestion of large amounts of kava. The choreoathetosis severely affected his limbs, trunk, neck, and facial musculature, with marked athetosis of the tongue. On each occasion, symptoms resolved within 12 hours after administration of intravenous diazepam (Spillane et al, 1997).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) Nausea was reported in three of 24 subjects following ingestion of 500 mL of kava extract (Prescott et al, 1993).
    b) CASE REPORT: A 37-year-old man presented with nausea and vomiting following an acute ingestion of an herbal tea containing kava (Perez & Holmes, 2005).
    B) GASTRITIS
    1) WITH POISONING/EXPOSURE
    a) Chronic kava ingestion was reported to be associated with the development of gastritis; the incidence of gastritis was reported to increase with co-ingestion of alcohol (Ngirasowei & Malani, 1998).
    C) WEIGHT LOSS FINDING
    1) WITH POISONING/EXPOSURE
    a) Chronic ingestions of kava, 310 to 440 grams of kava per week as a beverage, has been associated with the development of malnutrition and weight loss (decreased body mass index) (Ballesteros et al, 2001; Mathews et al, 1988; Anon, 1998).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ABNORMAL LIVER FUNCTION
    1) WITH POISONING/EXPOSURE
    a) Elevated liver enzymes may occur following chronic ingestion of kava, in large quantities (Chanwai, 2000; Heiligenstein & Guenther, 1998; Spillane et al, 1997). One study found that elevated gamma glutamyl transferases (GGT) and alkaline phosphatase (ALP) levels were reversible and return to baseline following a 1 to 2 week abstinence from kava (Clough et al, 2003).
    b) In a cohort study of heavy kava drinkers (n=27), gamma glutamyl transferases (GGT) were increased in 23 of 27 subjects, along with minimally elevated aminotransferases in 8 of 27 subjects. It was concluded that this finding might reflect an induction of CYP450 enzymes more than direct liver injury (Russmann et al, 2003).
    B) TOXIC HEPATITIS
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: Two cases of hepatitis associated with consumption of traditional aqueous kava extract were reported in 59-year-old and 55-year-old females. Both patients presented with jaundice, elevated liver aminotransferases (ALT and AST) and elevated total bilirubin. Case 1 also reported a prolonged thromboplastin time and eosinophilia. Symptoms developed 4 to 5 weeks after starting to drink kava. Laboratory values normalized within 3 months of stopping kava consumption (Russmann et al, 2003).
    1) Although hepatitis has been reported with traditional kava use, fulminant hepatic failure has not been reported in countries where consumption levels are significantly higher than the recommended therapeutic dose in kava herbal products (Cairney et al, 2003).
    2) One theory is that some manufacturers use a different processing method and different parts of the plant when compared to traditional preparations, resulting in a product that may result in hepatotoxicity (Clough et al, 2003).
    b) CASE REPORT: A 42-year-old man developed toxic hepatitis after drinking 2 to 3 L of traditional kava beverages during Samoan ceremonies. He presented 3 weeks post-ingestion with weakness, loss of appetite, jaundice, and markedly elevated liver enzymes (AST 1602 Units/L, ALT 2841 Units/L) and bilirubin (peak of 31 mg/dL). Abdominal ultrasound revealed a hyperechoic liver structure with normal biliary ducts and a multilayer aspect of the gallbladder. Liver histology was compatible with toxic liver injury (an infiltration of the portal fields with lymphocytes and eosinophilic granulocytes, necrosis of single or clustered hepatocytes, and swollen Kupffer cells). Following supportive care, his condition improved, and he was discharged 19 days after presentation (Christl et al, 2009).
    C) HEPATIC FAILURE
    1) WITH POISONING/EXPOSURE
    a) Hepatitis, cirrhosis, and liver failure (with at least one patient requiring liver transplantation) have been associated with the ingestion of products containing herbal extracts of kava in Germany, and Switzerland (Taylor, 2001).
    b) CASE REPORT: A 14-year-old girl developed fulminant hepatic failure requiring liver transplantation following ingestion of a kava-containing product (200 mg/day) for 4 months. A workup for alternative causes of liver failure was negative. The patient's liver biopsy prior to transplant showed hepatocellular necrosis consistent with chemical hepatitis. The product also contained St. John's wort which may have potentiated the hepatotoxic effects of kava (Humberston et al, 2003).
    D) HEPATIC NECROSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 39-year-old woman presented with a history of elevated liver enzymes (ALT of 796 Units/L and GGTP of 112 Units/L). She gave a history of chronic ingestion of kava pyrones, 60 mg, and the occasional ingestion of St. John's wort. One week after discontinuation of all medications, the GGTP normalized (49 Units/L). Two weeks after rechallenge with kava, her liver enzymes became elevated. A liver biopsy revealed acute necrotizing hepatitis. Kava was again discontinued and the patient's liver enzymes returned to normal within 4 months (Strahl et al, 1998).
    b) In a retrospective review of published (n=7) and unpublished (n=29) cases of kava-associated hepatic toxicity reported to the German Federal Institute for Drugs and Medical Devices (BfArM) between 1990 and 2002, the most frequent liver injury was hepatic necrosis (n=16). Cholestatic hepatitis (n=7) and lobular hepatitis (n=1) were also reported. In 3 cases, an association with kava was considered certain as the cause of liver injury. In the remaining 33 patients, kava was determined to be the probable cause (n=21) or played a causal role (n=12) in the observed liver damage. Fulminant hepatic failure was reported in 9 patients, 3 of whom eventually died. Of the 9 patients with fulminant hepatic failure, 8 underwent liver transplantation, with 2 of the deaths occurring from postsurgical infectious complications (Stickel et al, 2003).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL RENAL FUNCTION
    1) WITH POISONING/EXPOSURE
    a) Renal dysfunction, including hematuria and proteinuria, may occur following long-term ingestion of large amounts of kava (Mathews et al, 1988; Anon, 1998).
    B) RETENTION OF URINE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 61-year-old man developed acute urinary retention after drinking 1 L of kava. Following supportive care, he improved without further sequelae (Leung, 2004).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH POISONING/EXPOSURE
    a) Chronic kava ingestion has been associated with the development of lymphopenia (Anon, 1998).
    B) THROMBOCYTOPENIC DISORDER
    1) WITH POISONING/EXPOSURE
    a) Decreased platelet volume has been associated with chronic kava ingestion (Anon, 1998).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH POISONING/EXPOSURE
    a) A generalized red, dry, and scaly rash may develop with long-term ingestion of large amounts of kava and is reversible upon discontinuation of kava (Chanwai, 2000; Wong et al, 1998a; Norton & Ruze, 1994; Mathews et al, 1988; Anon, 1998b).
    b) One study reported the development of an ichthyosiform rash, with scales appearing on the neck and torso and the dorsum of hands, arms, and legs of patients, following chronic ingestion of kava. It was speculated that kava produced a vitamin B deficiency that resulted in the scaling, but administration of nicotinamide did not resolve the rash (Ruze, 1990).
    B) SEBORRHEA
    1) WITH POISONING/EXPOSURE
    a) Seborrheic dermatitis occurred in two patients following long-term ingestion of kava extract. One of the two patients experienced itching after several hours of sunlight exposure. Both patients developed erythematous plaques on the face, chest, and back. Patch testing with kava extract was positive in one patient, while the other patient showed significant proliferation of peripheral blood lymphocytes(Jappe et al, 1998).
    C) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 37-year-old man developed diaphoresis following acute ingestion of an herbal tea containing kava (Perez & Holmes, 2005).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of this agent during pregnancy.
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of this agent during lactation.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Serum kava lactone levels are not clinically useful and are not readily available.
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Monitor hepatic enzymes and renal function tests in symptomatic patients.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Serum kava levels are not clinically useful and are not readily available.
    2) Monitor renal function tests and hepatic enzymes in symptomatic patients.
    B) HEMATOLOGIC
    1) Monitor CBC's following significant exposure. Kava use has been associated with lymphopenia and decreased platelet volume.
    4.1.3) URINE
    A) URINALYSIS
    1) Monitor urinalysis in patients with significant exposure. Heavy consumption of kava has been associated with hematuria and proteinuria.

Methods

    A) CHROMATOGRAPHY
    1) A gas chromatographic-mass spectrometric method, with methane chemical ionization, was used to identify the metabolites of kava lactones, in human urine, following kava ingestion (Duffield et al, 1989).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, hepatotoxicity, dehydration, and electrolyte abnormalities.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance and gastrointestinal function. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Serum kava lactone levels are not clinically useful and are not readily available.
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Monitor hepatic enzymes and renal function tests in symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Most cases of toxicity reported have involved chronic ingestion of kava. Gastrointestinal decontamination is generally not recommended.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY: Most cases of toxicity reported have involved chronic ingestion of kava. GI decontamination is generally not required. Consider activated charcoal if coingestants with significant toxicity are involved.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Serum kava lactone levels are not clinically useful and are not readily available.
    2) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    3) Monitor hepatic enzymes and renal function tests in symptomatic patients.

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established. Kava toxicity is primarily from chronic use; however, acute toxicity has also been reported. Differences in kavalactones content in kava preparations, the duration of use, and individual variation are likely to play a role in toxicity. Kavalactones doses up to 2571 mg daily have been used with traditional aqueous kava beverages. Heavy consumption of kava by the aboriginal community (310 to 440 grams/week as a beverage) has resulted in malnutrition, weight loss, elevated liver enzyme, renal dysfunction, discolored sclerae, and an ichthyosiform rash. Extrapyramidal effects (dyskinesia and dystonia) occurred approximately 1 to 4 hours after ingesting 100 mg of kava extract. DOSES: The recommended dosage of kava is dependent upon the concentrations of the kavalactones, the active constituents of kava. AUSTRALIAN REGULATORY LIMITATION: A maximum of 125 mg of kavalactones per tablet or capsule and a maximum of 250 mg of kavalactones daily derived from water-based kava extracts.
    B) In older studies, the following doses were recommended for anxiety: standardized preparations: 100 to 200 mg daily of kavalactones in divided doses or as a single dose at bedtime. Dried rhizome: 1.5 to 3 grams daily of kavalactones in divided doses. Alcoholic preparation of 1:2 extract: 3 to 6 mL daily of kavalactones in divided doses, with no more than 20 to 40 mL per week.

Therapeutic Dose

    7.2.1) ADULT
    A) The recommended dosage of kava is dependent upon the concentrations of the kavalactones, the active constituents of kava.
    B) AUSTRALIAN REGULATORY LIMITATION: A maximum of 125 mg of kavalactones per tablet or capsule and a maximum of 250 mg of kavalactones daily derived from water-based kava extracts (Teschke & Schulze, 2010).
    C) In older studies, the following doses were recommended for anxiety:
    1) Standardized preparations: 100 to 200 mg daily of kavalactones in divided doses or as a single dose at bedtime (Bone, 1994; Wong et al, 1998).
    2) Dried rhizome: 1.5 to 3 grams daily of kavalactones in divided doses (Bone, 1994).
    3) Alcoholic preparation of 1:2 extract: 3 to 6 mL daily of kavalactones in divided doses, with no more than 20 to 40 mL per week (Bone, 1994).

Maximum Tolerated Exposure

    A) ADULT
    1) Kavalactones doses up to 2571 mg daily have been used with traditional aqueous kava beverages (Teschke & Schulze, 2010). Heavy consumption of kava by the aboriginal community (310 to 440 grams/week as a beverage) has resulted in malnutrition, weight loss, liver and renal dysfunction, discolored sclerae, and an ichthyosiform rash (Mathews et al, 1988; Anon, 1998).
    2) A man developed toxic hepatitis after drinking 2 to 3 L of traditional kava beverages during Samoan ceremonies over a period of 20 days. Following supportive care, his condition improved (Christl et al, 2009).
    3) Elevation of aminotransferases and total bilirubin developed in a 55-year-old woman after drinking 4 cups of traditional aqueous kava extract every night (approximately 18 grams of kavalactones per week) for 5 weeks (Russmann et al, 2003).
    4) Visual disturbances occurred 30 to 40 minutes after ingestion of 500 mL of kava beverage (Bone, 1994). Saccadic visual changes occurred in a group of intoxicated kava drinkers who had consumed approximately 205 grams of kava powder within 14 hours (Cairney et al, 2003).
    5) Extrapyramidal effects (dyskinesia and dystonia) occurred approximately 1 to 4 hours after ingesting 100 mg of kava extract (Schelosky et al, 1995).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) DIHYDROKAVAIN
    1) LD50- (ORAL)MOUSE:
    a) 920 mg/kg (Bone, 1994)
    B) DIHYDROMETHYSTICIN
    1) LD50- (ORAL)MOUSE:
    a) 1050 mg/kg (Bone, 1994)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The main active constituents in the root and rhizome of kava are a group of resinous compounds called the kavalactones, which include kavain (kawain), dihydrokavain, methysticin, and dihydromethysticin. Although a specific mechanism of action has not been established, it is speculated that the kava lactones may potentiate GABA receptors which may cause sedative effects (Anon, 1998a). Another source suggested that kava may exert its effects by blocking voltage-gated sodium channels and by GABA receptor and dopamine receptor antagonism. In addition, it may have anticholinergic activity (Leung, 2004).
    B) Racemic kavain, a kava lactone, may inhibit the cyclooxygenase activity which may result in antiplatelet effects and possibly analgesia (Anon, 1998).

Toxicologic Mechanism

    A) HEPATOTOXICITY: Hepatotoxicity has been reported in patients taking both the traditional water-based kava extracts of the South Pacific and the medicinal solvent-based kava extracts of western countries, with flavokavain B as one of the possible causes (Teschke & Schulze, 2010). In one study of kava hepatotoxicity, aqueous, ethanolic, acetonic kava extracts and kava-herbs mixtures from several locations around the world (Australia, US, Germany) were compared. It was determined that hepatotoxicity was linked to the kava plant (eg, low quality of kava cultivars or kava plant-parts) rather than to chemical solvents (eg, ethanol, acetone) (Teschke et al, 2009).
    B) Two mechanisms of hepatotoxicity have been suggested:
    1) INDUCTION OF HERB-DRUG INTERACTIONS through modulation of metabolizing enzymes (eg, hepatic cytochrome P450) by which the drug metabolism can be affected (Fu et al, 2008).
    a) Extracts of kava can significantly inhibit human cytochrome P450, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP4A9/11. Since many drugs are metabolized by these enzymes, kava can potentially affect drug metabolism. One study reported that kavalactones, dihydrokawain, and yangonin have COX-2 inhibitory activity. It is proposed that kava may cause hepatotoxicity mediated by inhibition of COX-2 enzyme activity (Fu et al, 2008).
    2) FORMATION OF ACTIVATED METABOLITES (Fu et al, 2008):
    a) Several metabolites (eg, kawain 11,12-quinone, 8,8-dihydrokawain 11,12-quinone) of kava can covalently bind to cellular DNA to form the kava-quinone methide derived DNA adducts, causing hepatotoxicity in humans (Fu et al, 2008).

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