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Efficacy and safety of peppermint oil in IBS 145 7 capsules, coated with a Colopulse coating layer 1,27 ), or placebo (microcrystalline cellulose) intake orally. Randomization was done with ALEA (Abcoude, The Netherlands) Screening and Enrolment Application Software using the minimization method, accounted for inclusion center, IBS subtypes (diarrhea, mixed, constipation, undefined), sex, and age. All study medication was over-encapsulated with identical hard gelatin capsules and packaged in identical blisters to ensure allocation concealment by Tiofarma S.A. (Oud-Beijerland, the Netherlands). Patients were instructed to self- administer three capsules daily, 30 min before breakfast, lunch, and dinner, during eight weeks. An eight-week treatment period was chosen as we expected the clinical effect to occur within this period based on previous studies. 17,21 This treatment duration was also selected to mitigate potential hazardous effects of long-term peppermint administration related to certain constituents. 26 Nevertheless, safety issues were later refuted by the EMA. 28 To decrease possible AEs, in particular heartburn and belching, a gradual titration schedule was followed in the first week of 1-1-2-2-2-3-3 capsules per day, respectively. Patients, investigators and health care providers were blinded to treatment allocation. Patients were instructed to refrain from lifestyle changes ( e.g. a change in diet or exercise routine) throughout the study. Rescue medication, i.e. acetaminophen alone or a combination with NSAIDs, PPIs, antacids, Histamine H2-receptor antagonists, loperamide, polyethylene glycol and psyllium, were allowed after consultation with the investigator (ZW). All rescue medication had to be documented in the digital diary. Study visits were conducted at the start of the pre-treatment period (screening), at randomization, and at the end of the treatment period (end-visit). Throughout the pre- treatment and eight-week treatment periods, patients had to complete daily questions on worst abdominal pain (scored on an 11-point NRS, 0=no pain, 10=worst possible pain), stool evacuation frequency and consistency assessed by the Bristol Stool Form Scale (BSFS), and presence of AEs in a digital diary. Relief of IBS symptoms (scored on a 7-point NRS ,1=no relief, 7=completely relieved), and abdominal discomfort, abdominal bloating, abdominal cramping, belching, nausea, and urgency (all scored on an 11-point NRS, 0=no symptoms, 10=worst possible symptoms) were assessed once weekly. In addition, at week 1, 2, 4, 6, and 8, and at month 3 and 6 of follow-up after the treatment period, patients were asked to complete several web-based questionnaires, including the IBS Severity Scoring System (IBS-SSS) 29 ; the Irritable Bowel Syndrome Quality of Life (IBS-QoL) 30 , the EuroQoL-5D (EQ-5D-5L) 31,32 , the Generalized Anxiety Disorder-7 (GAD-7) 33 , and the Patient Health Questionnaire-9 (PHQ-9). 34 At the beginning of week 2, 4, and 6, patients were contacted by telephone for follow-up and