A man taking alprazolam became semicomatose a few days afterstarting to take kava,which was suggested to be due to additivesedation. The pharmacokinetics of midazolam were unaffected bykava.
Clinical evidence,mechanism, importance and management
A 54-year-old man taking alprazolam,cimetidine and terazosin was hospitalised in a lethargic and disorientated state 3 days after starting to take kava, which he had bought from a local health food store. He denied having overdosed with any of these drugs. The patient became alert again after several hrs (See reference number 1). The reason for what happened is not known, but suggested explanation is that kava :7.8pt; font-weight:normal; color:#000000″>α-pyrones might have had additive sedative effects with those of alprazolam (See reference number 1,2). This is an isolated case and its general importance is not known.
In a study in 6 subjects who regularly took 7 to 27 g of kavalactones weekly as an aqueous kava extract, there was no change in metabolism of a single 8mg oral dose of midazolam before or after they stopped kava for 30 days (See reference number 3). Similar results were found in a study in 12 healthy subjects given kava kava root extract 1 g twice daily for 28 days before receiving a single 8mg dose of oral midazolam (See reference number 4). In contrast to some in vitro data, these studies show that kava has no effect on cytochrome P450 isoenzyme CYP3A4, of which midazolam is a probe substrate (See reference number 4). It is possible that kava levels achieved clinically are insufficient to affect CYP3A4. The findings of these studies suggest that it is unlikely that kava will alter pharmacokinetics of other substrates of CYP3A4 (see table 1 below,, for a list).
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| Table 1 Drugs affecting or metabolised by isoenzyme CYP3A4 | the cytochrome P450 | |
|---|---|---|
| Inhibitors | Aprepitant Azoles Itraconazole Ketoconazole Voriconazole Cimetidine Delavirdine Diltiazem Grapefruit juice Imatinib | Macrolides Clarithromycin Erythromycin Troleandomycin Nefazodone Nicardipine Protease inhibitors SSRIs Fluoxetine Verapamil |