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Efficacy and safety of peppermint oil in IBS 157 7 Discussion To our knowledge, this is the first randomized, double- blind, placebo-controlled clinical trial of peppermint oil in patients with Rome IV-defined IBS. It showed that neither small-intestinal release nor ileocolonic release peppermint oil led to a statistically significant reduction in abdominal pain or increase in global relief based on the pre- specified primary outcome measures as defined by FDA and EMA guidelines. Small- intestinal release peppermint oil, but not ileocolonic, however, did yield statistically significant improvements in exploratory secondary outcomes of IBS symptom severity, abdominal pain, and abdominal discomfort. AEs occurred more often in both peppermint oil groups compared to placebo, but were all mild and transient. The treatment effect of small-intestinal peppermint oil was not as pronounced as anticipated based on the results of previous meta-analyses 35,37 , which indicated a difference in dichotomous overall abdominal pain improvement of 30% between placebo and peppermint oil. 35 This discrepancy may relate to the more stringent criteria used in the current study, as our primary outcome measure required an abdominal pain reduction compared to baseline of at least 30% in at least four out of eight weeks treatment. In contrast to our study, none of the earlier trials investigating peppermint oil reported this endpoint. The most recent randomized trial investigated a sustained small- intestinal release peppermint formulation (182 mg) of which the pharmacokinetics are comparable to the one used in the current study, in 72 IBS (Rome III) patients. They used the change from baseline in the Total IBS Symptom Score as a primary endpoint and found a significantly greater reduction of 15.7% in the peppermint oil group compared to placebo. 17 In the current study, the placebo response rate according to the stringent FDA definition was 33%, which is similar to previous studies using this outcome measure. 38-40 The therapeutic gain of small-intestinal peppermint oil over placebo was 12.4%, corresponding to a NNT of 8. Albeit non-significant, this difference in response rate is numerically comparable to the previous studies in IBS reporting statistically significant differences between linaclotide 38 , and plecanatide 39 and placebo. Of note is that the recent ACG Monograph 18 mentions a NNT of 4 for peppermint oil (using the data hitherto available), which is considerable better than the NNT that we found, but also than the NNT for linaclotide (6), plecanatide (10), or eluxadoline (12.5). Since we powered the study for an expected 30% difference 35 , it seems plausible that a type II error may exist and a statistical significant difference between groups would have been identified had we included a larger number of patients. Another reason for the discrepancy may be differences in baseline characteristics of our study population compared with populations previously investigated. In contrast with earlier work, a large