Reviewed: Sarris J, Stough C, Teschke R, Wahid ZT, Bousman CA, Murray G, Savage KM, Mouatt P, Ng C, and Schweitzer I. Kava for the treatment of generalized anxiety disorder RCT: analysis of adverse reactions, liver function, addiction, and sexual effects. Phytother Res. January 2013; [epub ahead of print]. doi: 10.1002/ptr.4916.

Empirical observations and clinical trial evidence suggest that preparations made from the root of kava (Piper methysticum, Piperaceae) are efficacious in the treatment of anxiety; however, cases of hepatotoxicity associated with kava use have led to its withdrawal or restricted use in many Western countries. Considering that kava has anxiolytic effects, questions arise as to whether kava is addictive, has adverse sexual side effects, or has withdrawal effects that might be similar to pharmaceutical anxiolytic drugs such as the benzodiazepines (drugs with an anti-anxiety effect). Uncertainty regarding the cause of the liver toxicity centers on poor-quality raw material, plant cultivars, and extraction solvents. Hence the purpose of this randomized, double-blind, placebo-controlled study was to evaluate adverse events (AEs), withdrawal/addiction effects, and liver function effects associated with kava use in patients with generalized anxiety disorder (GAD). Also, genetic polymorphism (when more than one different phenotype exists in the same species) of the liver enzyme cytochrome P450 2D6 (CYP2D6), which metabolizes compounds in kava, was evaluated to determine whether subjects who were poor or extensive metabolizers have different AEs using water-extracted kava from noble cultivars (that is, kava cultivars with higher levels of kavain and lower levels of dihydromethysticin).¹

Patients (n=58; aged 18-65 years) with DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4^th Edition) diagnosed with GAD were recruited from the Greater Melbourne area in Victoria, Australia, via mass media. Patients were excluded if they had any of the following conditions: major depressive disorder or elevated depressive symptomatology (greater than 17 on the Montgomery-Asberg Depression Rating Scale); a DSM-IV diagnosis of a psychotic or bipolar disorder; significant suicidal ideation in the previous six months; current use of antidepressants, mood stabilizers, antipsychotics, opioid analgesics, or St. John’s wort (Hypericum perforatum, Clusiaceae); diagnosed hepatobiliary disease/inflammation; substance abuse or dependency disorder in the previous six months; a previous adverse reaction to kava or benzodiazepines; kava or benzodiazepine use in the previous 12 months; or abnormal baseline liver function. The study began with a one-week run-in phase to identify placebo responders. Any subject who showed a 50% improvement on the Hamilton Anxiety Scale (HAM-A) score during this placebo phase was excluded from the study.

For six weeks, patients received placebo or an aqueous kava extract with the equivalent of 120 mg of kavalactones/day, which was titrated to 240 mg/day in patients showing no response at three weeks. The kava was formulated from pressed, dried, aqueous peeled rootstock of kava (Medi-Herb, Integria Healthcare; Eight Mile Plains, Queensland, Australia). The kava extract was independently analyzed at Southern Cross University at Lismore, Australia, and was determined to contain various kavalactones: dihydrokavain (15.5 mg, 26%), kavain (12.5 mg, 21%), dihydromethysticin (11 mg, 18%) methysticin (8.5 mg, 14%), yangonin (8 mg, 13%), and desmethoxygangonin (5mg, 8%); the alkaloid pipermethystine, which has been implicated in some kava extracts associated with cases of liver dysfunction, was not detected.

At weeks two and seven, AEs were assessed via questionnaire, and blood was drawn for liver function tests and to determine polymorphisms.

No significant AEs were reported. One case of dermatitis and one case of minor stomach upset were associated with kava intake. Withdrawal was assessed by treating all patients with placebo for one week at study end. There was no significant increase in AEs in either treatment group. Addiction was assessed by evaluating the number of patients who said that they wanted an increase in dose. Both treatment groups had the same number of patients who wanted to increase the dosage. There were no significant differences from baseline in liver function tests, and no patients developed clinical signs of hepatic abnormality. However, gamma-glutamyl transpeptidase (GGT) showed a trend toward elevation in kava-treated patients compared with those who took placebo at week seven (P=0.08). This finding may be due to an outlier; one patient (an extensive CYP2D6 metabolizer) had isolated increases in GGT and alanine aminotransferase (ALT) that both returned to baseline levels after the study. However, intermediate or extensive CYP2D6 metabolizer status had no significant impact on the type or frequency of AEs or abnormal liver function tests. Kava did not diminish sexual performance or enjoyment in men or women. However, there was a trend for kava-treated men to have more difficulty reaching orgasm (P=0.067). Kava-treated women had a significant increase in sex drive (P=0.04).

The authors conclude that water-extracted kava from noble cultivars has no deleterious effects on sexual function and pleasure, has no addictive qualities or withdrawal issues, and is safe for patients with GAD when taken for six weeks. The researchers also wrote that patients with GAD would require treatment for longer than six weeks, so a larger, longer-term study is needed to confirm the findings. Nonetheless, this study contributes to the growing body of evidence that water-soluble, standardized formulations of kava from noble cultivars are safe. The authors conclude that these data may assist in the reintroduction of kava in restricted markets. This study uses a medicinal dose of kava, and the results cannot be extrapolated to traditional recreational use with higher doses of kavalactones.

—Heather S. Oliff, PhD

Reference

1.         Sarris J, Stough C, Bousman CA, Wahid ZT, Murray G, Teschke R, Savage KM, Dowell A, Ng C, Schweitzer I. Kava in the treatment of generalized anxiety disorder: a double-blind, randomized, placebo-controlled study. J Clin Psychopharmacol. 2013;33(5):1-6.