Written by: Simon Ido | MSc
Forwarded by; Prof. Shoseyov Oded. Estimated reading time 4 min, 21 seconds
Last update, Sep, 2021
Piper methysticum, Kava
Piper methysticum, otherwise known as Kava, is a tradi- tional plant native to Pacific societies utilized for cen- turies for its soothing effects. Kava has psychoac- tive properties when consumed and is classified as a narcotic.
Kava’s active components consist mainly of kavalactones, which are phenolic polyketides with anxiolytic and analgesic properties supported by over 3000 years of traditional use and recent clinical trials. These effects are achieved through modulation of GABA activity via alteration of lipid membrane structure and sodium channel function, monoamine oxidase B in- hibition, and noradrenaline and dopamine re-uptake inhibition. Kava’s components also act on the cannabinoid receptors. More specifically, yangonin is the only kavalactone to bind to the CB1 receptor. Yangonin is also a potent dopamine antagonist, and is thought to aid in limiting the euphoric actions of the kavalactones at higher concentrations.
Current evidence supports the use of kava for mild, generalized anxiety[5, 9, 10] in both animal and early clinical trials. These placebo-controlled trials show im- provements in neurotic, premenopausal, and chronic forms of anxiety with key themes of reductions in stress, calming effects, and improvements in sleep.
Kava was withdrawn from European markets in 2002 due to concerns over hepatotoxicity, however recent re- search has shown that liver damage can be caused usu- ally only in extremely high doses and alongside consump- tion with alcohol or other drugs via modulation of the cytochrome P450 system (CYP). Water-based con- sumption methods are considered safer than ethanolic extracts, which is supported by traditional methods of use.
MODE OF ACTION
Kavalactones are structurally related to liphophilic lac- tones, and have been characterized since the second half of the 19th century. The six major kavalactones, ac- counting for 96% of kava’s lipid extract fraction, are dehydrokavain, dihydrokavain, yangonin, kavain, dihy- dromethysticin and methysticin. Minor constituents include other kavalactones, chalcones, piperidine alka- loids, and essential oils.
The mode of action for which kavalactones affect the body has been fairly well-studied in vitro. One study showed a fast action on voltage-dependent sodium chan- nels, which contributes to the local anaesthetic and an- ticonvulsive properties of kava. However, it is thought that GABAA, dopamine D2, opioid, and histamine re- ceptor interactions are responsible for kava’s anxiolytic, muscle relaxant, and sleep-inducing effects.
These interactions include reduced excitatory neuro- transmitter release due to blockade of calcium ion chan- nels, enhanced ligand binding (no direct binding as is seen with benzodiazepenes) to gamma-aminobutyric acid (GABA) type A receptors, reversible inhibition of monoamine oxidase B, and reduced neuronal reuptake of noradrenaline (norepinephrine) and dopamine. In an- imal models, it was seen that kavalactones did not bind to GABAA receptors – however, the kavalactones were still able to activate GABAergic effects.
Another study examined yangonin, which is a kavalac- tone that was found to be an agonist to the CB1 receptor in vitro. This has implications that kava affects the en- docannabinoid system as one of its modes of action, and also somewhat describes its anxiolytic effects as cannabi- noid antagonists have previously been studied for their anxiolytic properties.
While fears over kava’s hepatotoxic attributes have been found to be related primarily to excessive dosage and use with alcohol, it is considered largely safe to con- sume, especially if consumed via a water-extraction. There are however also potential drug interactions via modulation of the CYP450 system or P-glycoprotein pump. Frequent and heavy use of kava is discour- aged and can have some detrimental side effects such as dermopathy and lower lymphocyte counts. However, infrequent and social use of kava seems to be fairly safe and effective[4, 9].
The pharmacological effects of kava has been shown in multiple studies to be statistically significant in reducing anxiety[5, 9, 10].
These studies and literature searches are early clinical trials, where the patients take about 1-2 months to see an improved anxiolytic effect over the placebo. These placebo-controlled trials also show improvements in neu- rotic, premenopausal, and chronic forms of anxiety with key themes of reductions in stress, calming effects, and improvements in sleep.
Kava also has sleep inducing effects which is thought to be caused by changes of the activity of 5- HT neurons, while its relaxing effects are attributed to activation of the mesolimbic dopaminergic neurons.
In clinical considerations, studies highlight the impor- tance of high-quality herbal material and high standards of manufacturing.
There have been some reported side effects from Kava, mostly in the form of nausea and gastrointenstinal discomfort[1, 9, 10].
Kava has been traditionally an essential component of many Pacific Island societies, traditionally used during religious and and cultural ceremonies as a psychoactive and used in social settings as an inebriate beverage that elicits relaxation[6, 9].
As described above, kava can be used in a social set- ting as a water-based extraction (tea) for its relaxing properties.
It can also be recommended by clinicians for use in general anxiety disorder[1, 9, 10].
 S. S. Baum, R. Hill, and H. Rommelspacher. Ef- fect of kava extract and individual kavapyrones on neurotransmitter levels in the nucleus accumbens of rats. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 22(7):1105–1120, 1998.
 A. R. Bilia, L. Scalise, M. C. Bergonzi, and
F. F. Vincieri. Analysis of kavalactones from piper methysticum (kava-kava). Journal of Chromatog- raphy B, 812(1):203–214, 2004. Biomedically Rele- vant Plant Components: Active Principles and Tox- icants.
 D. Dinh, U. Simmen, K. Berger Beuter, B. Beuter,
K. Lundstrom, and W. Schaffner. Interaction of var- ious piper methysticum cultivars with cns receptors in vitro.
 E. Ernst. A re-evaluation of kava (piper methys- ticum). British Journal of Clinical Pharmacology, 64(4):415–417, 2007.
 M. Feltenstein, C. Lambdin, M. Ganzera, H. Ran- jith, W. Dharmaratne, N. P. D. Nanayakkara, I. A. Khan, and K. J. Sufka. Anxiolytic properties of piper methysticum extract samples and fractions in the chick social–separation–stress procedure. Phy- totherapy Research, 17(3):210–216, 2003.
 V. Lebot and J. Lèvesque. The origin and distri- bution of kava (piper methysticum forst. f., piper- aceae): A phytochemical approach. Allertonia, 5(2):223–281, 1989.
 A. Ligresti, R. Villano, M. Allarà, I. Ujváry, and
V. Di Marzo. Kavalactones and the endocannabi- noid system: The plant-derived yangonin is a novel cb1 receptor ligand. Pharmacological Research, 66(2):163–169, 2012.
 T. Pluskal, M. Torrens-Spence, T. Fallon,
A. De Abreu, C. Shi, and J. Weng. The biosynthetic origin of psychoactive kavalactones in kava. Nature Plants, 5(8):867, 878.
 J. Sarris, E. LaPorte, and I. Schweitzer. Kava: A comprehensive review of efficacy, safety, and psychopharmacology. Australian & New Zealand Journal of Psychiatry, 45(1):27–35, 2011. PMID: 21073405.
 Y. Singh and N. Singh. Therapeutic potential of kava in the treatment of anxiety disorders.