This blog follows the outline of a 2018 review of peppermint oil as a treatment of gastrointestinal disorders (Chumpitazi 2018). The FDA has sent warning letters to companies that claim the ability of peppermint to treat diseases. The message is that peppermint oil is in the process of being established as a medical food to treat diseases.
“This work was a publication of the USDA/ARS Children’s Nutrition Research Center …The contents do not necessarily reflect the views or policies of the USDA, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government”
1 Introduction
Chumpitazi briefly reviewed the history of peppermint oil use in folk medicines. To go beyond this history, peppermint oil is a mixture of menthol derivatives.
These images were modified from those available on PubChem. Oxygens are shown in red because these groups are important in metabolism. Many different enantomers of menthol exist in peppermint oil. Which are bioactive? What is the lot to lot variation of these peppermint oil components?
2 Methods
Chumpitazi and coworkers described how they performed their search of PubMed literature as well as how they reviewed peppermint oil clinical trials. Additional information has been included in this blog to make the Chumpitazi review easier to understand…. and to emphasize the medicinal potential of peppermint oil.
3.1 Pharmokinetics
Chumpitazi and coworkers mention absorption of menthol sprayed on the gastric mucosa reaching a peak concentration within one hour.
In the liver, menthol undergo metabolism by cytochrome P450s and other enzymes. The main metabolite is menthol glucuronide. How much is excreted in the feces versus the urine seems to be dependent on the formulation. The metabolism of menthol related compounds in peppermint oil may not be known at present. Some aspects of metabolism are being addressed in clinical trials in menthol’s journey to becoming a medical food.
3.2 Potential mechanism of actions
This is an aside from the Chumpitazi review. Menthol binds to the transient receptor potential sodium/calcium channel TRPM8. Neurons are activated when calcium and sodium flow through these channels. Low temperatures are a natural means of opening these channels. Menthol is a natural product ligand that effects a cool sensation because it gates the same ion channel as do cool temperatures. A related channel, TRPV1, is opened by high temperatures and capsaicin from chili peppers, hence the hot sensation of chili peppers. TRPA1 is a little more promiscuous in terms of natural food ligands. Menthol is considered a ligand as are cinnabichromene (cinnamon) and allylisothiocyante (mustard).
3.2.1 Effects on gastrointestinal tract neuromotor function
Menthol seems to act as a relaxer of GI smooth muscle by blocking L-type calcium channels in smooth muscle cell membranes. Voltage gated L-type calcium channels are opened by depolarization of electrically coupled neurons. Menthol opens calcium channels in the pace maker interstitial cells of Cajal (ICC). The TRPM8 channels did not appear to be involved in the mechanism reviewed by Chumpitazi and coworkers. Rather, menthol seems to be acting on TRPA1 on the ICC. What makes this discussion truly confusing is that transit of material through the gastrointestinal tract is mediated by coordination of relaxation and contraction of longitudinal and circular smooth muscle.
Note that when the action potentials, in this case occur on top of the depolarization crests of the slow waves, the mechanical recording increases. Many other ion channels are involved in proper gastrointestinal locomotion. They have been reviewed by Radulovic and coworkers (2018) in a paper describing pharmaceutical intervention in patients suffering reduced GI motility resulting from spinal cord injuries.
Slow waves underlying pace maker action potentials
Kim and coworkers (2016) discuss the input of G protein coupled receptors (GPCR) on the slow waves in cultured interstitial cells of Cajal. Kim and coworkers used whole cell patch clamping. ICC were cultured in a smooth muscle cell growth medium. Both the acetylcholine and epinepthrine (adrenaline) receptors are GPCR. The difference is that they signal through different alpha subunits of heterotrimeric G proteins. GPCR ligands, if present, were not mentioned.
From Fig 1, Kim (2016). “In current clamp mode, cells in cultured ICC clusters had a mean resting membrane potential of -57.3 ± 2.2 mV and produced pacemaker potentials (PPs) of amplitude 24.5 ± 3.2 mV (n = 62) at 30°C. Initially, we examined the effects of menthol on PPs. Menthol (1, 5 or 10 μM) ”
3.2.2 Effects on gastrointestinal visceral sensation
In a paper reviewed by Chumpitazi and coworkers, lower concentrations of menthol activated TRPA1 currents whereas higher micromolar concentrations blocked the same channels.
3.2.3 Antimicrobial actions
Chumpitazi and coworkers reported antimicrobial activity of peppermint oil (menthol) for the following microorganisms:
- Helicobacter pylori
- Escherichia coli,
- Staphylococcus aureus,
- Klebsiella sp.
- Salmonella typhi
- Shigella boydii
- Shigella flexneri
- some fungal pathogens
If most of menthol is excreted in the feces as menthol glucuronide, does this conjugation enhance or diminish antimicrobial activity? What does menthol/peppermint oil do to the beneficial intestinal microbiome? If intestinal motility is altered, does this also have a impact on the microbiome?
3.2.4 Effects on inflammation
Mention was made of colitis and immune cells such as monocytes expressing the transient receptor potential (TRP) family of cation channels. Monocytes may differentiate into macrophages and antigen presenting dendritic cells. Khalil and coworkers (2018) published an excellent review on the topic.
G proteins coupled receptors often communicate with the TRP family of calcium/sodium channels. Bertram and coworkers (2018) examined the role of monocyte G protein coupled bradykinin receptors 1 and 2, intracellular calcium and cell migration. The potential role of peppermint oil in modulating production of prostaglandins and leukotienes is an unknown.
3.2.5 Effects on behavior
Chumpitazi and coworkers cite references on peppermint constituents menthol, menthone, and pulegone. Some behavior aspects cited include
- attention
- dose dependent anxiolytic effects
- involvement of dopamine pathways
Very recent work of Zhang and coworkers (2018) suggest that while menthol had no affect on dopamine release from the nucleus accumbens in rats, nicotine did increase the release of dopamine from this “reward and reenforcement” region of the brain. Menthol enhanced the nicotine induced release of dopamine. The rationale of doping cigarettes with menthol becomes obvious as something beyond a flavor enhancing agent.
3.3 Peppermint oil effects on gastrointestinal physiology
Chumpitazi and coworkers issued the caveat of peppermint oil on gastrointestinal physiology
- Older studies used drops rather than a quantified dose.
- Concentration may vary with botanical source as well as the method of preparation.
Other caveats not mentioned include
- Pub Chem lists six menthol related compounds in peppermint oil. There may be more or less. Proportions may vary.
- Similar compounds may have different enantiomer forms.
- The method of extract may inadvertently add additional compounds such as residual solvents.
- Menthols, may react with other dietary components.
- Menthols may be metabolized by intestinal microorganisms.
- Glucuronide conjugates, secreted in the bile, may have their own biological activity.
3.3.1 Peppermint oil effects on the esophagus.
Peppermint oil may decrease spasms, gastric reflux, and sphincter pressure. Has this to do with the enteric nervous system or the smooth muscle? Note that there are layers of circular and longitudinal smooth muscle act in a coordinated manner.
3.3.2 Peppermint oil effects on gastric physiology and gastric emptying
References were cited claiming a decrease in spasms of the lower stomach. Peppermint oil/menthol sprayed on the mucosa may decrease gastric peristalsis and increase pyloric ring diameter.
3.3.3 Peppermint oil effects on small bowel physiology and transit time
Most of the studies cited by the Chumpitazi concerned the duodenum. Cho (2014) found TRPA1 channels in the enteroendocrine cells (EEC) of the mouse duodenum and jejunum. These channels were less abundant in EEC of the ileum, the stomach, and colon. The TRPA1 expressing EEC also contained the neurotrnasmitters CCK and 5-HT (seotonin). The authors suggested that foods that contain TRPA1 stimulants aid in digestion by the release of CCK and subsequent effect of CCK on the release of digestive enzymes and bile.
EEC of the small intestine produce 90% of the serotonin in our bodies. Serotonin controls intestinal motility via the enteric nervous system.
3.3.4 Peppermint oil effects on gall-bladder emptying
Pasternak and coworkers demonstrated a decrease in of number of ICC cells in the wall
of gallbladders of patients suffering from gallstone disease in comparison to the controls. They hypothesized that such decrease could influence the emptying of the gall bladder. This emptying relates to gallstone disease. One has to wonder if the affect is really via the EEC of the duodenum rather than a direct effect on the gall bladder as menthol or the menthol glucoronide.
3.4 Peppermint oil usage during endoscopic procedures
this one was a clinical trial. “The investigators hypothesize that spraying peppermint oil containing L-menthol onto the colonic mucosa during colonoscopy will relax smooth muscle allowing better colonic visualization.” link The study was completed in the US in November of 2017.
3.5 Peppermint oil for treatment of gastrointestinal disorders
3.5.1 Adult irritable bowel syndrome
This was a pilot study to compare the relative bioavailability between two peppermint oil formulations, namely a colon-targeted-delivery capsule (Tempocol-ColoPulse®) and an enteric-coated capsule (Tempocol®). This study is conducted as part of a future multicenter randomized controlled trial that will assess the therapeutic effect of the new peppermint oil formulation in IBS patients. site. This study was conducted in the Netherlands. Results were not listed on clinicaltrials.gov.
3.5.2 Pediatric functional abdominal pain
This continues as an ongoing PMO pediatric clinical trial that includes microbiome analysis of stool samples.
3.5.3 Functional dyspepsia
“This study aims to investigate changes in gastric motility (including gastric accommodation), nutrient volume tolerance, gastric emptying and gastrointestinal hormones in healthy volunteers after an acute intake of a combination of peppermint oil and caraway oil, compared to placebo. In addition, the effect of a combination of peppermint oil and caraway oil on appetite-related sensations and upper gastrointestinal symptoms will be assessed. These outcomes will be studied on 2 study days. On study day 1, gastric emptying rate will be assessed using a 13C breath test 30 minutes after intake of study medication. This test is followed by an intragastric pressure (IGP) measurement during which 350 mL of a nutrient drink will be intragastrically infused 30 minutes after intake of study medication. On the second study day, IGP will be measured in fasted state for 4 hours after intake of study medication. Hereafter, a second dose of study medication will be administered. Thirty minutes later, a nutrient drink will be infused until the participant is fully satiated. Appetite-related sensations and gastrointestinal symptoms will be rated during IGP measurements on a 100mm VAS. Blood samples will be collected to assess peptide hormone levels.” link
3.5.4 Post-operative nausea
“Healthy weight management and use of essential oils and aromatherapy as natural interventions to manage health-related issues are significantly growing interests. One frequent intervention for healthy weight management is bariatric surgery. In the post-operative period following bariatric surgery, nausea is a common consequence. Peppermint oil aromatherapy is an effective intervention for relieving nausea and other gastrointestinal symptoms in the bariatric and surgical population. This study has multiple aims. One is to determine effectiveness of peppermint oil aromatherapy in relieving post-operative nausea in the bariatric surgery patient population. A second aim is to establish relative cost-effectiveness of peppermint oil aromatherapy versus traditional anti-emetic drug therapies. A third is to determine whether peppermint oil aromatherapy increases patient satisfaction versus anti-emetic drug therapies. This is a randomized study with control and experimental groups. The control group will receive no peppermint oil aromatherapy and only traditional anti-emetics as needed. The experimental group will receive peppermint oil aromatherapy and traditional anti-emetics as needed.” link This study was conducted in Lancaster, UK. The results have not been posted on clinicaltrials.gov.
“The purpose of this pilot study is to determine if aromatherapy will prevent postoperative nausea and vomiting (PONV). Peppermint aromatherapy will be used preemptively to test for effectiveness, decreased PONV, and the ability to avoid anti-emetics. This study will seek to demonstrate that peppermint aromatherapy is a simple, cost effective way to prevent PONV after anesthesia. By decreasing the need for anti-emetics and incidence of PONV, patients may have a quicker recovery time and experience less side effects from anti-emetics, such as increased sedation. This problem is significant to patients and society as it may demonstrate that the inhalation of peppermint can ease PONV and decrease costs due to anti-emetics, wound dehiscence, and prolonged hospital stay. This study may lead to higher levels of patient satisfaction; if the patients are not nauseated they may be more satisfied with their care.” link This study will be completed in March 2019.
3.6 Safety
Pulegone, the third compound from the top in Section 1 Introduction, was mentioned as a toxic compound in peppermint oil. A more recent publication ( Zárybnický 2018) also examined menthofuran, second compound on the bottom row. These authors used the R-enantomers of these compounds. Pulegone and menthofuran toxicity in human precision cut liver slices was compared to acetominophen (Tylenol). Liver samples were obtained from fie patients undergoing abdominal surgery for colon cancer. ATP was used to assess viability. Pulegone produced a decrease in ATP in all five samples, menthofuran in only two of the five patients’ liver slices, and acetominophen produced even more individual variability. “The EC50 of PUL and MF were approximately 293 µM (4.0 µg/mg of tissue) and >418 µM (>5.8 µg/mg of tissue), respectively. ” These authors looked at select miRNA, small pieces of RNA that prevent messenger RNA transcripts from being tanslated into protein. What they found was a lot of variation among individual liver slices. Pulegone, even at non-toxic concentrations, caused a decrease in miR155-1p in all five samples. It was not clear if there were also individual variations in metabolism of pulegone and menthofuran by these liver slices that could explain variation of miRNA. Whether these miRNA were released n exosomes to influence mRNA translation to protein in other tissues was not addressed. The miRNA responses appear to be influenced by starting miRNA and individual sources of the liver slices.
4 Summary
Chumpitazi and coworkers pointed to the promise and need for further study of peppermint oil (and its many constituents) as a regulator of GI function.
5. Looking at the biochemistry…
We don’t know if peppermint oil is working on voltage gated and/or TRPA1 calcium channels in smooth muscle, interstitial cells of Cajal, or enteroendrocrine cells.
Placanatide is used to treat irritable bowel syndrome with constipation and chronic idiopathic sonstipation. Placanatide is an analog of uroguanylin, a peptide hormone secreted by the enteroendocrine cells of the duodenum. Uroguanylin binds to the guanylate cyclase coupled receptor. Rifaximin is an antibiotic used to treat travelers’ diarrhea and irritable bowel syndrome with diarrhea.
Could peppermint oil be used treat both irritable bowl syndrome with constipation as well as IBS with diarrhea? Perhaps. Unsupervised self medication may not be a good idea.
References
Bertram CM, Baltic S, Misso NL, Bhoola KD, Foster PS, Thompson PJ, Fogel-Petrovic M. (2007) Expression of kinin B1 and B2 receptors in immature, monocyte-derived dendritic cells and bradykinin-mediated increase in intracellular Ca2+ and cell migration. J Leukoc Biol. 81(6):1445-54. free paper
Cho HJ, Callaghan B, Bron R, Bravo DM, Furness JB. (2014) Identification of enteroendocrine cells that express TRPA1 channels in the mouse intestine. Cell Tissue Res. 356(1):77-82.
Chumpitazi BP, Kearns GL, Shulman RJ. (2018) Review article: the physiological effects and safety of peppermint oil and its efficacy in irritable bowel syndrome and other functional disorders. Aliment Pharmacol Ther. 47(6):738-752. free link
Khlil M et all. (2018) Functional Role of Transient Receptor Potential Channels in Immune Cells and Epithelia. Front Immunol. 9:174. PubMed
Kim HJ, Wie J, So I, Jung MH, Ha KT, Kim BJ. (2016) Menthol Modulates Pacemaker Potentials through TRPA1 Channels in Cultured Interstitial Cells of Cajal from Murine Small Intestine. Cell Physiol Biochem. 38(5):1869-82. free paper
Pasternak A, Szura M, Mazur M, Mróz I, Matyja M, Matyja A.(2014) Number and distribution of interstitial cells of Cajal in human gallbladder. Folia Med Cracov. 2014;54(1):71-7. Review. free paper
Radulovic M, Anand P, Mark A Korsten MA, Gong B(2015)Targeting Ion Channels: An Important Therapeutic Implication in Gastrointestinal Dysmotility in Patients With Spinal Cord Injury. Journal of Neurogastroenterology and Motility 21(4): 494-502.
Zárybnický T, Matoušková P, Lancošová B, Šubrt Z, Skálová L, Boušová I.(2018) Inter-Individual Variability in Acute Toxicity of R-Pulegone and R-Menthofuran in Human Liver Slices and Their Influence on miRNA Expression Changes in Comparison to Acetaminophen. Int J Mol Sci. 19(6). free paper
Zhang M, Harrison E, Biswas L, Tran T, Liu X.(2018) Menthol facilitates dopamine-releasing effect of nicotine in rat nucleus accumbens. Pharmacol Biochem Behav. 175:47-52. PubMed
