Kava (also known as kava-kava, kawa kawa, ava ava, awa awa, yati, yagona, and yangona), is the name given by Pacific islanders both to a shrub belonging to the pepper family and the psychoactive beverage made from the rhizome.
Kava is native to Oceania but has been cultivated since 3’000 years ago throughout the regions of Micronesia, Polynesia, and Melanesia for medicinal purposes and ceremonial and social events. [1]
Kava’s enduring traditional use makes it a plant of great historical and traditional significance.
In Pacific cultures, this plant is considered sacred and its beverage is served when welcoming guests, celebrating childbirth, during marriages, as well as at funerals. Indeed, the Kava beverage has been compared to the use of wine in Western countries.
Furthermore, thanks to its psychoactive properties, it is used to reach a higher consciousness level during religious ceremonies. [1], [2]
Traditional Kava Effects
Traditionally, kava has also been used to induce physiological and psychological relaxation, as well as for the treatment of several diseases related to the genitourinary tract, such as chronic gonorrhea and menstrual problems, having an antiseptic effect on the urine. [1]
After Kava reached Europe, it gained a lot of popularity as an herbal medicine to treat anxiety and it is marketed as a dietary supplement in the U.S. to relieve stress, improve sleep and memory, and regulate mood. However, in Germany, in 2002 Kava’s use was banned due to its potential hepatotoxicity.
Unlike the well-documented neurological benefits, Kava’s toxic effects are still under debate. Undoubtedly there is a lack of standardization which makes the diversity of kava products a major challenge and produces an unmet need for quality initiatives [2].
Botany and Phytochemistry
The Latin name for Kava is Piper methysticum, meaning intoxicating pepper. Indeed, Kava is a shrubby plant belonging to the family of Piperaceaem, measuring from one over to four meters in height.
It is a hard, slow-growing perennial composed of main monopodial stems and lateral sympodial stems. These lateral branches grow from the young parts of the stem and, as they age, they die and fall away.
When the plant reaches maturity, it assumes the shape of a bouquet of ligneous stems clustered together at their base. There are over 150 cultivars of P. methysticum and they show a very high variation of habit: some of them are composed of a few stems with very long internodes, and some of them have short internodes. Some others present a much higher number of stems. Kava reproduces by stem propagation, due to the scarce incidence of female flowers and thus unproductive fruit pollination [2], [3].
The main active components of Kava are called kavalactones (or kavapyrones) and flavokavains that have analogous pharmacological activity and biosynthetic pathways.
The most abundant kavalactones are:
- (+)-kavain (1.8%);
- (+)-methysticin (1.2%);
- desmethoxyyangonin (1%);
- yangonin (1%);
- (+)-dihydrokavain (0.6%);
- (+)-dihydromethysticin (0.5%).
Also, all the flavokavains — divided into Flavokavains A, B, and C [1].
These components are usually extracted from the roots and the rhizome of the plant since their concentration decreases in the aerial parts of the plant. Moreover, the cytotoxic alkaloid pipermethysticin has recently been isolated from the aerial part of P. methysticum [2], [4].
Traditional Means of Kava Administration
Traditionally, Kava’s fresh rhizome is chewed and spit into a bowl, where it is mixed with cold water or coconut water and then strained through a natural fiber and served as a hot juice [1].
In Western societies, other extraction solvents rather than water have been used to maximize kavalactones’ yield and improve the anxiolytic power of the remedy, decreasing the possibility of other less controllable side effects.
Both kavalactones and flavokavains extraction yields are maximized using organic solvents such as acetone (> 80%) and 96% ethanol.
However, several studies prove that glutathione (GSH) might be a key component in reducing Kava’s side effects by binding irreversibly to kavalactones through a lactone ring-opening Micheal-type reaction. Contrarily to the other components, GSH’s higher extraction yields are obtained with ethanol concentrations lower than 50% [5].
Neurochemical activity
As previously anticipated, the diversity of Kava extracts relies on so many variables that, even though many studies have been conducted on the plant, it is difficult to systematize them.
Indeed, Kava is assumed both as a recreational drug and as a medicine. Not only does the dosage vary among these two uses, but also the control of the cultivar and the extraction solvent, which is water when Kava is used as a recreational beverage, and organic when used as a medical preparation.
Nevertheless, Kava has shown a wide range of biological activities including:
- Sedative,
- Mild local anesthetic,
- Analgesic,
- Anxiolytic and antistress,
- Antispasmodic,
- Anticonvulsant,
- Antithrombotic,
- Hypnotic,
- Skeletal muscle relaxant,
- Antifungal,
- Neuroprotective effects [6].
However, it has gained attention mainly because of its anxiolytic power. Anxiety disorders are probably the most common psychiatric disorders, having a lifetime prevalence of 15-20% of the global population.
Brief periods of anxiety are common in daily life, but anxiety is diagnosed as a psychiatric disorder when its intensity or duration reaches pathological proportions and its effects are debilitating to the individual.
Typical anxiolytic drugs are barbiturates and benzodiazepines, which have a positive effect on the release of Gamma-Aminobutyric Acid (GABA), a neurotransmitter that has an inhibitory activity on the central nervous system (CNS).
A Little More Details on Kavalaktones
Kava’s neurochemical activity is mainly due to the kavalactones, which are only slightly different in their mechanism of action. The major differences are related to the pharmacokinetic properties (absorption rate, distribution in the body, metabolism, and elimination) of the individual compounds, but not to their biochemical activity.
Kavalactones share with barbiturates and benzodiazepines the facilitation of GABAergic transmission, which best accounts for the anti-anxiety and sedative properties of Kava. In addition, kavalactones block voltage-gated cation channels, which also causes sedation. [4], [6]
The main difference between Kava and traditional anxiolytic is its ability to inhibit the reuptake of noradrenaline, which plays a crucial role in cognitive functions associated with the frontal lobes, [4] This activity produces an increase in alertness by stimulation of central adrenergic mechanisms and may enhance memory and have a positive effect on the allocation of attention and processing capacity.
Does Kava has side effects?
Kava seems to have no adverse impact on cognitive functions, which is one of the main side effects of benzodiazepines and barbiturates assumption. [6] Furthermore, Studies on healthy volunteers confirmed that the deep sleep phase was lengthened and the duration of REM sleep was not influenced. These effects were viewed as being favorable, in comparison with orthodox sedatives that depress both REM and deep sleep.
This is why Kava may be seen as a first-line treatment for anxiety disorders, thanks to these positive effects on cognition in comparison to conventional anxiolytics. [4]
Adverse effects and lack of standardization
The safety of Kava has not been questioned until quite recently. The only undisputed adverse effect is a skin rash induced by excessive Kava drinking, which has been termed “kava dermopathy”. Its knowledge has its roots in the past and South Pacific islanders know by experience that it can be reversed just by abstaining from drinking Kava until the skin conditions clear up [6].
Nevertheless, in Western countries, a few cases of necrotizing hepatitis have been reported that have been attributed to the Kava assumption. In particular, Kava use as an herbal anxiolytic drug was banned in Germany between 2002 and 2014. [2], [6]
Many hypotheses have been made to explain the hepatotoxic mechanism and scientists have been questioning whether it could have been due to the different composition of the extract (different kavalactones ratio), the “nobility” of the cultivar, or to the use of aerial parts of the plant that might contain toxic alkaloids [2]. However, the most accepted hypothesis doesn’t rely on any of these options.
The observation of the total absence of reports about the occurrence of hepatotoxic events among traditional users leads to think that Kava’s toxicity might be due to its extraction solvent.
Indeed, while in the South Pacific Kava is extracted with water, Western pharmacological preparations are often obtained with organic solvents.
Summary and Conclusion
As previously said, the amount of GSH in Kava extract is directly proportional to the water-to-organic solvent ratio. [5], [7] This molecule is responsible for the lactone ring opening of kavalactones and thus for their metabolism.
On the other hand, lactones are usually metabolized in the liver by the cytochrome P450 system. P450 inhibition or induction is an important factor leading to drug interactions since this family of enzymes is important for the degradation of toxins and pharmaceuticals.
Furthermore, P450s are most abundant in the liver and a few isoforms are responsible for 80% of the total hepatic metabolism. [7] A few of the Kava-induced hepatotoxic events were related to the depletion of these isoforms.
The absence of GSH in the Kava extract might induce an overload of the P450 system, particularly in subjects with a pre-existing GSH deficiency. [5]
Kava has demonstrated to have an elevated pharmacological potential primarily as an anxiolytic. However, to realize its clinical capacity at its maximum, scientists must address several challenges:
- First, the substance must undergo a process of standardization in its cultivation, harvest, and post-harvest handling, extraction, fractionation, and manufacturing for commercialization, preclinical animal investigation, and human clinical evaluations. Without it, many contradictory observations that were difficult to reconcile were reported, and raised concerns about product safety;
- Secondly, further systematic studies have to be conducted to fulfill the existing gaps in Kava’s pharmacodynamics and pharmacokinetics.
- Finally, human clinical trials have to be designed and conducted to better adapt Kava modalities for specific disease indications. [2]
References:
- A. R. Bilia, S. Gallori, and F. F. Vincieri, “Kava-kava and anxiety: Growing knowledge about the efficacy and safety”, 2002, Life Sciences, 70, pp. 2581–2597.
- T. Bian et al., “Kava as a clinical nutrient: Promises and challenges”, 2020, MDPI AG. doi: 10.3390/nu12103044.
- V. Lebot and J. Lèvesque, “THE ORIGIN AND DISTRIBUTION OF KAVA (PIPER METHYSTICUM FORST. F., PIPERACEAE): A PHYTOCHEMICAL APPROACH”, 1989, Allertonia, 5(2), pp. 223-281.
- E. Laporte, J. Sarris, C. Stough, and A. Scholey, “Neurocognitive effects of kava (Piper methysticum): A systematic review”, 2011, Wiley Online Library, pp 102-111. doi: 10.1002/hup.1180.
- P. A. Whitton, A. Lau, A. Salisbury, J. Whitehouse, and C. S. Evans, “Kava lactones and the kava-kava controversy”, 2003, Phytochemistry, 64(3), pp. 673–679, 2003, doi: 10.1016/S0031-9422(03)00381-9.
- Y. N. Singh and N. N. Singh, “Therapeutic Potential of Kava in the Treatment of Anxiety Disorders”, 2002, CNS Drugs
- C. S. Côté, C. Kor, J. Cohen, and K. Auclair, “Composition and biological activity of traditional and commercial kava extracts”, 2004, Biochem Biophys Res Commun, 322(1), pp. 147–152. doi: 10.1016/j.bbrc.2004.07.093.
