Kava Pharmacology

Kava Pharmacology - from Nutritional and Herbal Therapies for Children and Adolescents p.236

Pharmacodynamics

Kava contains dozens, if not hundreds, of constituents. Psychoactive ingredients are presumed to be the many kavapyrones and kavalactones, including kavain, dihydrokavain, yangonin, methysticin, and dihydromethysticin (Spinella, 2001). Kavain and dihydrokavain are presumed to be the most permeable to the blood–brain barrier.
Kavalactones facilitate the functioning of GABA A receptors, in a manner that is similar to benzodiazepines, but kavalactones do not appear to bind to benzodiazepine receptors. The overall effect involves positive allosteric modulation of chloride channels, increasing the influx of chloride and hyperpolarizing the cell. The increase in GABA activity may also be secondary to kavain’s suppression of thromboxane, which further enhances GABA activity. In addition, kavalactones inhibit calcium channels, and various kavalactones may do so additively, producing a reduction of calcium influx by as much as 70 percent. Thus, the psychoactive effect involves broad inhibition of neuronal firing. Several kavalactones have also been found to inhibit sodium channels, further contributing to the inhibitory effect (Spinella, 2001).
Kavalactones may have other psychoactive properties. Kavain and methysticin weakly block the reuptake of norepinephrine, but seem to have no effect on serotonin. The effect on dopamine is inconsistent, with levels rising in some parts of the brain and dropping in others (Spinella, 2001). Kavalactones may also reversibly block platelet MAO B enzymes, and this effect does not seem evident until at least 3 or 4 weeks of treatment (Uebelhack et al., 1998). This may be responsible for some of the latency of clinical response observed in research trials.

Pharmacokinetics

Kava lactones are rapidly absorbed in the small intestine and transported to the liver, where they undergo metabolism via the CYP 450 system of enzymes. Although the specific pathways have not yet been identified, 2D6 may be the primary pathway (see further discussion of adverse effects). Importantly, however, kava constituents seem to inhibit 1A2, 2C9, 2C19, 2D6, 3A4, and 4A9/11 enzymes, thus making the use of kava problematic with most prescription medications (Medical Economics, 2007). After the first pass effect, kava enters systemic circulation and is absorbed by various tissues in the body. Several kavalactones cross the blood–brain barrier, but may do so competitively, making it difficult to predict which ones are most psychoactive. Peak levels of kavalactones in the plasma occur about 2 hours after oral administration, and metabolites of kava are excreted in the urine, while unabsorbed portions are excreted in the feces (Anke & Ramzan, 2004).

Dosing

In research, typical dose for adults is 70–240 mg/day (0.8–2.8 mg/kg/day) of kava, or 60–120 mg/day (0.7–1.4 mg/kg/day) of a standardized preparation of 30 percent kavalactones (Lee et al., 2007). Dose with children and adolescents should start at the low end of the range and gradually titrate upwards, and clinicians should keep in mind that 4 weeks or more may be necessary before therapeutic effect is evident, and therefore a few weeks at each dose level may be needed before it will be apparent whether the dose is effective. The supplement may be administered in divided doses, although it is usually given in the evening.
Adverse Effects
Most regard kava to be safe and effective, especially in low doses, and that fears of adverse effects have caused many to use kava at doses that are unnecessarily low (Connor & Davidson, 2002). Mild reactions include gastrointestinal upset, dizziness, headache, and dermatological reactions, including ‘kava dermopathy’ after prolonged heavy use, a yellowing of the skin. Changes in vision, mydriasis, and disturbances in eye tracking have also been reported, as well as impaired motor reflexes and rare difficulties in motor coordination, including choreoathetosis, all of which reversed upon discontinuation (Medical Economics, 2007; Lee et al., 2007).
The greatest concern surrounds the risk of liver damage. Over 60 cases of hepatotoxicity have been reported around the world, and many of these required liver transplants (Currie & Clough, 2003), including a 14-year-old girl who had been taking kava supplements (at unspecified dose) for 3 months (Campo et al., 2002). Concern over hepatotoxicity has caused some countries to restrict the use of kava and require a prescription. In some cases, it is apparent that adulterants added to kava may have been responsible for the liver damage, and methods of extraction
may also be involved. In addition, some of those with liver damage have been found to exhibit low levels of endogenous CYP 2D6 enzyme (Currie & Clough), which may be responsible for most of kava’s metabolism. This is further confirmed by data that suggests that in many cultures, heavy use of kava (at doses hundreds of times greater than doses used during supplementation) reveal no history of hepatic damage (Currie & Clough). Waller (2002) performed a high-level review of all available data and concluded that serious adverse hepatic effects that can be traced to kava use are extremely rare, and involve very few individuals who may be hypersensitive to it or reveal an idiosyncratic reaction. Another published report estimated that of approximately 250 million daily doses of kava administered in the 1990s, only two individuals revealed hepatotoxicity secondary to kava, and in both cases the supplement was used far above the recommended dose (Schmidt & Nahrstedt, 2002). Consequently, most regard kava as safe when used at the doses recommended above, although patients who take kava should have their liver function monitored regularly, especially if the supplement will be used for more than 1 month.
The use of alcohol is contraindicated when kava supplementation is utilized. Kava and alcohol may have additive, if not synergistic, effects because they both increase GABA transmission and exert similar inhibitory effects. Even more importantly, both kava and alcohol induce liver enzymes, and the combination of the two may further predispose patients for liver damage. This is very important to consider in adolescents, since many teenagers tend to experiment with alcohol, especially if they also have a history of symptoms of anxiety (Albano et al., 2003).
Additional factors should also be considered. In some cases, patients who used kava started to exhibit symptoms of depression, especially with long-term use (Blumenthal, 2003). Generally, patients with a history of depression should avoid using kava. Because depression and anxiety often coexist, the supplement may not be appropriate for that group of patients.
Because of kava’s extensive inhibition of liver enzymes, the use of kava should be avoided with the vast majority of medications, including anticoagulants, antiplatelet medications, heparins, thrombotic agents, amantidine, muscle relaxants, and most psychoactive agents (antidepressants, anxiolytics, mood stabilizers, etc.). Patients need to remember that even over-the-counter medications should be avoided with kava. For example, acetaminophen (sold in the US as Tylenol), poses some risk of hepatotoxicity, especially when used regularly, and using kava with Tylenol may increase the risk of liver damage. Parents of patients who take kava must be advised against using any medications concurrently with the supplement unless the combination is cleared (and monitored) by a medical professional.
Use of kava is contraindicated during pregnancy. Female adolescents who take kava and are suspected of being sexually active must be advised of this risk, and should use contraception to prevent pregnancy. If oral contraceptives are used, since they are metabolized by a CYP 3A4 pathway that is inhibited by kava, their plasma levels may increase, potentially causing unpredictable results. Once again, medical professionals prescribing the contraceptives must be aware that kava will be used concurrently and must approve (and monitor) the combination.