tives such as benzodiazapines but without the development of either physical or psychological depen-
dence [15,46].
From intensive chemical and pharmacological studies of kava root-rhizome extracts over the past
century, several key active constituents have been identified [12,46]. The pharmacological activity of this
plant appears to be associated with a family of styrylpyrones called kavapyrones (or kavalactones) that
have effects on several neurotransmitter systems including those involving glutamine, -aminobutyric
acid (GABA), dopamine, and serotonin [15]. Although the kavapyrones shown in Figure 7 represent the
predominant pharmacologically active components in kava root extracts, a total of 18 have been identi-
fied to date [47]. These remaining kavapyrones appear to be derivatives of either kawain, yangonin, or di-
hydromethysticin [12,47]. Although details of kavapyrone biosynthesis are still lacking, evidence from
other systems such as Equisetum arvensegametophytes suggests that styrylpyrones may arise from a
triketide produced by successive condensation of two malonyl CoA molecules with a phenylpropanoid
CoA ester (Ref. 48 and references therein). This is similar to reactions catalyzed by chalcone synthase ex-
cept that two rather than three successive condensations involving malonyl CoA are involved. Studies
have shown that kavapyrone levels in kava roots are influenced by environmental factors. In cultivated
kava plants, kavapyrone levels appear to increase with irrigation and mineral nutrient supplementation
and decrease with shading [49]. Moreover, varietal differences in kava also appear to have a role in de-
termining the overall level of kavapyrone production [49].
Interestingly, kava plants are sterile and plantation production involves propagation from stem cut-
tings [46]. From genetic studies, it has been suggested that kava represents a sterile relative of Piper wich-
mannii(native to New Guinea), which was distributed across the South Pacific islands with human mi-
gration and through somatic mutation became sterile (Ref. 49 and references therein). This sterilty of
kava, its limited growth habitat range (South Pacific tropics), the time required for growth before root har-
vest (about 8 years), and the high world demand have raised concerns about potential overharvesting. Al-
though attempts have been made to grow kava in tissue culture for propagation and possible in vitro phy-
tochemical production, little success has been achieved [50].
I. Valerian
Valerian (Valeriana officinalis) has had a long history of use as a relaxing sedative and as treatment for
insomnia [51]. For example, this use of valerian was noted in Dioscorides’ De Materia Medicawritten in
Roman times. During World War I, valerian was used as a treatment for shell shock [19]. Valerian is a
tall perennial growing in damp swampy areas that is native to Europe and temperate regions of Asia
[15,21,51]. The plant used traditionally for medicinal purposes is only one of 250 species in the genus Va-
leriana[15]. For use as a phytomedicinal, hot-water infusions (teas) or alcohol-water extracts (tinctures)
are generally produced from the roots of this plant [51].
The major compounds present in active valerian extracts are a series of sesquiterpenes and iridoids
(Figure 8). Major sesquiterpenes include valerenic acid and valeranone. The iridoids are present as a se-
ries of closely related epoxy-iridoid esters called the valeopotriates, the major compounds being valtrate,
isovaltrate, acevaltrate, and didrovaltrate [12,19,21]. Overall, the valeopotriate level in dried valerian
roots ranges from 0.4 to 2% [15,19,21]. The valeopotriates are labile compounds that break down under
conditions of moisture, heat, or acidity to liberate unsaturated aldehydes such as baldrinal and isovaleric
acid [12,51]. Production of isovaleric acid during the drying of valerian roots contributes to the unpleas-
ant odor of this plant material [15,19].
PHYTOMEDICINAL CHEMICAL PRODUCTION BY PLANTS 495
Figure 7 Examples of kavapyrones from Piper methysticum(kava). (Adapted from Ref. 12.)