During the rash of liver issues in the time frame of 1998-2001 many culprits were considered for the cause. One of these alleged compounds that was thought to be Pipermethystine (PM). Pipermethystine is found in the aerial (above ground) portions of the kava plant, and it is seen concentrated in the stem peelings and leaves [1] and also in the lower stems with negligible amounts found in the peeled stems. While peeled stems are being shown to contain little PM, it is still recommended that only the below ground portion of the plant be used for the sake of overall safety. PM is found in differing concentrations in different varieties of kava [2]. In vitro studies have shown pipermethystine causing cell death in 24 hours from various concentrations in solution in comparison to kavalactones which did not show loss of cell viability for 8 days [3]. It would stand to reason that we should look closely at this compound, however further studies and routine analysis of kavas in Fiji Tonga and Hawaii have revealed little to no PM in any root samples that were taken commercial or otherwise. Currently as it stands PM may cause toxicity and cell death under in vitro conditions, however further studies have shown a total absence of toxicity and possibly even hepaprotective effect. It was shown that high doses of PM in vivo at 10mg/kg per day in rats did not elicit any liver injury. To summarize, evidence to support hepatoxicity from pipermethystine has not been convincingly presented [4].

[1] Dragull, K., Yoshida, W. Y., & Tang, C. S. (2003). Piperidine alkaloids from piper methysticum. Phytochemistry, 63(2), 193–198.

https://doi.org/10.1016/S0031-9422(03)00111-0

[2] Olsen, L. R., Grillo, M. P., & Skonberg, C. (2011). Constituents in Kava extracts potentially involved in hepatotoxicity: A review. Chemical Research in Toxicology, 24(7), 992–1002.

https://doi.org/10.1021/tx100412m

[3] Nerurkar PV, Dragull K, Tang CS. In vitro toxicity of kava alkaloid, pipermethystine, in HepG2 cells compared to kavalactones. Toxicol Sci. 2004 May;79(1):106-11. doi: 10.1093/toxsci/kfh067. Epub 2004 Jan 21. PMID: 14737001.

https://doi.org/10.1093/toxsci/kfh067

[4] Teschke, R., Qiu, S. X., & Lebot, V. (2011). Herbal hepatotoxicity by kava: Update on pipermethystine, flavokavain B, and mould hepatotoxins as primarily assumed culprits. In Digestive and Liver Disease (Vol. 43, Issue 9, pp. 676–681).

https://doi.org/10.1016/j.dld.2011.01.018