Re: A Review of the Physiological and Toxicological Effects of Peppermint Oil in Gastrointestinal Disorders

HerbClip Peppermint (Mentha × piperita, Lamiaceae) Irritable Bowel Syndrome Gastrointestinal Physiology Safety Date: 09-28-2018 HC# 031843-601 Chumpitazi BP, Kearns GL, Shulman RJ. Review article: the physiological effects and safety of peppermint oil and its efficacy in irritable bowel syndrome and other functional disorders. Aliment Pharmacol Ther. March 2018;47(6):738-752. doi: 10.1111/apt.14519. A centuries-old remedy for a variety of gastrointestinal complaints, data indicate that peppermint (Mentha × piperita, Lamiaceae) may be beneficial in clinical treatment. Peppermint is a generally sterile hybrid between water mint (M. aquatica) and spearmint (M. spicata) thought to have occurred naturally. Peppermint essential oil (PEO), obtained by distillation from fresh leaves, has been used for centuries for gastrointestinal (GI) ailments. The authors reviewed the literature on PEO's metabolism, effects on GI physiology, clinical use, efficacy, and safety. An electronic search found over 2800 articles published through July 15, 2017. Following review and searches of reference lists, 96 articles were selected for inclusion in this report. In evaluating interventions for clinical disorders, only randomized, placebo-controlled trials (RCTs) were considered. No language restrictions on their search were mentioned. Pharmacokinetic knowledge of PEO in humans is limited. PEO pharmacokinetics are highly dependent on formulation and method of use as well as developmental age. PEO is administered orally, by injection, topically, and by inhalation (aromatherapy). With more than 80 compounds, its major constituent and bioactive ingredient is menthol. PEO is absorbed quickly in rats and humans. Enteric-coated capsules allow 70% of PEO to reach the colon. Menthol is metabolized mainly in the liver via P450 enzymes and then undergoes transformation by UDP-glucuronosyltransferases. The enzymes CYP2A6 and UGT2B7 are particularly important to menthol clearance. PEO metabolites are excreted in urine. PEO's reported benefits in irritable bowel syndrome (IBS) are attributed mainly to its spasmolytic effect. The degree to which its other GI effects, including smooth muscle relaxation, modulation of visceral sensations, immunomodulation, and effects on the microbiome enhance its clinical utility is unclear. It apparently acts as a smooth muscle relaxer through calcium channel blockade. It may act directly on the enteric nervous system through transient receptor potential cation channel, subfamily A member 1 (TRPA1). Menthol is a well-known topical pain reliever. Studies suggest that it relieves visceral pain when used orally or interperitoneally. PEO has antimicrobial and antifungal effects and is active against obligate and facultative anaerobes, based on in vitro studies. It is bactericidal to ≥20 common enteric pathogens. Menthol may impair quorum-sensing in gram-negative bacteria. PEO suppresses inflammatory mediators. Rodent studies suggest that menthol has dose-dependent anxiolytic effects that may involve dopamine pathways. Psychosocial distress plays a role in functional GI pain disorders and this suggests another potential mechanism of action. PEO aromatherapy in humans improves attention, but other mood effects have not been demonstrated. PEO's physiological effects are presented in tables and text, organized by organ and function. Its spasmolytic effects are seen throughout the GI tract. For esophageal function, for example, studies report fewer esophageal spasms and contractions. No long-term studies have examined PEO in hypercontractile esophageal disorders. One esophageal study also reported fewer lower stomach spasms. PEO or menthol sprayed directly on gastric mucosa facilitated esophagogastroduodenoscopy, reducing peristalsis and increasing pyloric ring diameter. Manometry and/or barostatic studies report that PEO reduces intragastric pressure and gastric motility with no effect on gastric accommodation. PEO slows orocecal transit time. Studies report differing findings for its effect on gastric emptying, probably because of different study designs and test meals. In healthy subjects, PEO inhibited gall bladder emptying vs. placebo. PEO appears to reduce small bowel contractility and spasms of the duodenal bulb. During endoscopic retrograde cholangiopancreatography, instilling PEO into the duodenum reduced contractions. PEO decreases colon spasms during colonoscopy. More adenomas were detected during colonoscopies of individuals who had taken PEO vs. placebo. Studies of intraluminal PEO injection after intramuscular injection of neostigmine had contrasting results on contractility and motor activity in the sigmoid colon. PEO's effects in GI disorders are also presented in tables and text. Ten RCTs assessed PEO in adult IBS. All but one found it superior to placebo. Five meta-analyses also found it effective in IBS. While the authors did not rate RCT quality, they remark that the lack of negative results for IBS may suggest publication bias. Two trials of PEO in pediatric functional abdominal pain reported benefits. One included pediatric IBS patients. The other, a three-armed trial, compared PEO to a probiotic plus folic acid and to placebo, according to the accompanying table; the text is less certain. Three RCTs report PEO effective in functional dyspepsia when used with other herbs. Two used a PEO/caraway (Carum carvi, Apiaceae) seed oil combination; the other, a multi-herb product. No RCTs on PEO alone in this disorder were found. PEO with other herbs was superior to placebo for post-operative nausea in one RCT; ginger (Zingiber officinale, Zingiberaceae) EO alone was also effective. PEO was more effective than placebo in post-operative nausea in women who had Caesarean sections. The text cites two double-blind RCTs that did not find a PEO benefit in post-operative nausea over placebo or controlled breathing; however, the accompanying table lists only one single-blind trial testing PEO inhalation against the latter technique, with no difference seen in results. Menthol is Generally Recognized as Safe (GRAS) in the United States. However, pulegone and its metabolite menthofuran, found in PEO, are potentially toxic at high doses. According to one rat study, doses exceeding 80 mg/kg/d resulted in vacuolization of hepatocytes. The European Medicines Agency (EMA), while stressing that no cases of liver toxicity in humans are associated with PEO or EOs of other Mentha spp., suggests an acceptable exposure of 75 mg/d pulegone plus menthofuran, several hundred times more than would occur with maximum usual doses of PEO. Study is needed to clarify pediatric exposure concerns. One author, BP Chumpitazi, serves as a consultant for Mead Johnson Nutrition. Another author, RJ Shulman, is a consultant for Nutrinia Inc. —Mariann Garner-Wizard