Khat (Catha edulis) is a plant with psychoactive effects similar to those of amphetamine. Indeed, it is popularly known as the “natural amphetamine”. Specifically, this herb is one of the most widely consumed herbs in the whole world, with users usually chewing its leaves [85]. The mean age of khat users is approximately the second decade of life, with a significant predominance of the male gender [86]. Khat is a legal and socially accepted substance used recreationally in East African and Middle Eastern countries (mainly Somalia, Ethiopia and Yemen) [86]. It is estimated that it has a daily consumption by more than 20 million people [87]. However, Khat is considered a drug of abuse by the WHO, and its sale is forbidden in almost all Western countries, including the United States of America (USA) and European Union [86].

Khat is a well-established hepatotoxic agent, with case reports and case series implicating the herb in acute and chronic liver injury, and it is defined as category B in terms of its hepatotoxicity potential in LiverTox (this xenobiotic has been reported and is known or highly likely to cause idiosyncratic liver damage, with 12–50 previously published cases) [27,88]. Although it is not clear whether this toxic potential is due to its constituents or a direct effect of the pesticides/preservatives used for cultivating and transporting the herb [28]. The mechanism of khat-related liver injury remains to be elucidated. Animal model studies have shown that khat can cause acute hepatitis, and that chronic active hepatitis and fibrotic liver disease are linked to long-term khat exposure in rats [89]. On the other hand, vasoconstriction due to cathinone, one of its components, has been suggested as a plausible mechanism of the liver injury [90]. It is worth mentioning that, in humans, the pattern of liver damage associated with khat typically has autoimmune features, with frequent autoantibody presentation and, histologically, chronic hepatitis and fibrosis [29,30,31,32,91]. Indeed, a cross-sectional study carried out in Ethiopia—one of the countries with the highest prevalence of khat intake—showed, interestingly, an eye-catching ratio of cirrhosis of apparently unexplained causes (55%). The authors noted that the widespread consumption of khat in this area, together with histological features of toxic injury in the liver biopsy performed among a subgroup of patients without an established etiology, suggest a probable causal association [33]. Similar data have been published in other regions with a high prevalence of khat use, such as Somaliland [34]. Nonetheless, a careful review of all the published reports on khat-induced liver injury does not provide sufficient evidence to link khat consumption with the development of HCC [27,28,29,30,31,32,33,34,35,36,37,38].

Kava (or kava-kava) is a herb extracted from the roots of the plant named Piper methysticum. Kava has been taken as a recreational beverage in Oceania for centuries, and more recently, it has been used in its concentrated form or as an infusion to alleviate anxiety disorders [92,93].

The hepatotoxicity of kava has been recognized in recent decades, with an important fraction of sever and fatal cases, and it is thus included in category A (highest hepatotoxic potential) in LiverTox (the xenobiotic is well-known, with more than 50 cases published in the literature) [39,94]. Several experimental studies on in vivo mouse models have shown the liver oncogenic potential of kava. In 2011, Behl et al. found an increase in the incidence of hepatoblastoma (dose-dependent) in male mice and an increment in hepatocellular carcinoma and adenoma detection (non-dose-related) in female mice. Moreover, non-neoplastic lesions (such as hepatocellular hypertrophy) were detected in the livers of mice, and such findings were confirmed in an independent study, which also identified a considerable rise in the rates of liver cancer and non-malignant liver lesions in mice of both sexes after kava exposure [40,41]. In contrast, in humans, there is no convincing published evidence linking kava intake to HCC thus far [39,42,43,44,45,46,47,48,49,50,51,52,53]. This apparent discrepancy could be related to the low quality of the design of these studies (observational, lacking long-term follow-up) that precluded the drawing of firm conclusions.

Other herbs have been associated with chronic liver damage, even causing liver fibrosis and cirrhosis. In a recent review of the published case reports on herbal-induced liver injury in Latin America, a case of chronic hepatitis with a cholestatic and granulomatous pattern and cirrhotic processing due to Centella asiatica was identified [54,95]. Centella asiatica (or Gotu kola) is a traditional Chinese plant frequently used in Southeast Asia that occasionally is taken to facilitate weight loss, among other applications [96]. In the same systematic review, another case of herb-induced hepatotoxicity with a chronic course due to Crotalaria juncea was also included [54]. This herb is traditionally used as household remedy for several medical conditions, and it is known to cause sinusoidal obstruction syndrome [97]. Crotalaria juncea contains pyrrolizidine alkaloids among its components [54], which have been clearly related to veno-occlusive disease and, hence, to cirrhosis [54,55]. Nevertheless, there is no published evidence to associate these herbs with the risk of HCC.