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Chapter 6 134 of the other ingredients mentioned above. Furthermore, the toxic compounds known to be present in peppermint oil in very low quantities – in equal dosages for ileocolonic release and small-intestinal release peppermint oil - were also not measured. Pulegone and menthofuran normally appear in peppermint oil in doses of between 1-9% and less than 4.0% 32 and could potentially harm chronic peppermint oil users. Some animal studies reported toxicity due to pulegone and menthofuran; high dosages in rats were associated with hepatocyte vacuolization, liver necrosis, and possibly cyst-like spaces in the cerebellum. 7 Nevertheless, when taken in the recommended dosages, the EMA and the FDA consider peppermint oil to be generally safe. Even if the EMA states that no confirmed cases of liver damage due to peppermint oil usage have been reported 51 , they do advise against the continuous use of peppermint oil for longer than three months. 52 It remains to be elucidated whether this advice is substantiated – no studies have assessed the long-term effect, thus no studies have revealed damage occurring after three months – but further research into this topic is certainly desired. Of note is that half of the participants were male, whereas the male/female ratio in IBS patients is usually estimated to be 1:2. 53 Ideally, future research should include IBS patients who may experience altered motility and/or altered transit times and should preferably also investigate relatively more females. Although large effects of sex on pharmacokinetic parameters are not expected, factors such as menstrual cycle and lower body weights, and thereby smaller distribution volumes, higher body fat percentages etc. could be of influence. 54 Conclusions A novel ileocolonic release peppermint oil formulation has been developed to decrease upper gastro-intestinal side effects associated with small-intestinal release peppermint oil. This study provides evidence that the ileocolonic release peppermint oil has a significantly delayed peak menthol-glucuronide concentration, pointing to a more delayed and therefore more distal intestinal release of peppermint oil. The ileocolonic release may enhance therapeutic efficacy as it results in increased exposure to the colonic mucosal afferents and decrease adverse events. A randomized placebo- controlled trial (RCT) investigating the efficacy of small-intestinal and ileocolonic release peppermint oil in IBS patients has been initiated and is currently ongoing. This RCT is based on the pharmacokinetic data from the present study.