During the rash of liver issues in the time frame of 1998-2001 many culprits were considered as the cause. One of these alleged compounds is PM. Pipermethystine is found in the aerial (above ground) portions of the kava plant, and it is concentrated in the stem peelings and leaves [1] as well as in the lower stems, with negligible amounts found in the peeled stems. Although peeled stems contain little PM, it is still recommended that only the belowground portion of the plant be used for overall safety. PM is found in differing concentrations in different varieties of kava [2]. In vitro studies have shown that pipermethystine causes cell death in 24 h from various concentrations in solution compared with 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 kava in Fiji, Tonga, and Hawaii have revealed little to no PM in any root samples that were taken commercially or otherwise. Currently, PM may cause toxicity and cell death under in vitro conditions; studies have shown a total absence of toxicity and possibly even a hepatoprotective effect. High doses of PM in vivo at 10 mg/kg / day in rats did not elicit 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