Clinical pharmacology of peppermint oil
Nine studies involving 269 healthy subjects or patients confirmed the antispasmodic a fact of peppermint oil and gastrointestinal smooth muscle. “There is reasonable evidence that PO exerts a spasmolytic effect on the smooth vasculature of the intestinal tract. The duration of effect is limited to approximately 20 min.” The authors suggest that enteric coated peppermint oil can extend the duration of action and reduce side effects.
[c] 2005 Published by Elsevier GmbH.
Keywords: Peppermint oil; Pharmacodynamics; Pharmacokinetics; Galenic formulations; Irritable bowel syndrome
Introduction
Peppermint oil (Menthae piperitae aetheroleum, PO) is obtained from the fresh leaves of peppermint, Mentha piperita L. by steam distillation. The major constituents of the oil include the terpenes (-)-menthol (30-55%), (-)-menthone (14-32%), (+)-isomenthone (1.5-10%), (-)-menthyl acetate (2.8-10%), (+)-menthofuran (1.0-9.0%) and 1,8-cineol (3.5-14%). Due to its calcium antagonistic properties (-)-menthol has been made responsible spasmolytic effect of PO (Hawthorn et al., 1988). The Food and Drug Administration lists peppermint and PO as “generally recognized as safe” (GRAS; Food and Drugs, 1998).
The purpose of this review is to analyze in detail the pharmacodynamic effects of PO on the gastrointestinal tract with a focus on its use in irritable bowel syndrome (IBS; ESCOP, 1997) as well as oral pharmacokinetics.
Pharmacodynamics
In Table 1 pharmacodynamic studies and results thereof relevant to the use of PO in the gastrointestinal tract are summarized. In nine studies 269 subjects underwent exposure to PO either by topical intraluminal (stomach or colon) or oral administration by single doses or 2 weeks (Wildgrube, 1988) treatment. Methods used to detect effects were oro-cecal transit time by hydrogen expiration, total gastrointestinal transit time by carmine red method, gastric emptying time by radiolabelled test meal or sonography, direct observation of colonic motility or indirect recording through pressure changes or relieve of colonic spasms during barium enema examination. The dose range covered in single dose studies is 0.1-0.24 ml of PO/subject. With the exception of the findings by Rogers et al. (1988 [dose 0.1 ml]), which show an unexplained potentiation of neostigmine stimulated colon activity, all other studies result in comparable data indicating a substantial spasmolytic effect of PO.
This effect commences as early as 0.5 min after topical (intestinal tract) application and may last up to 23 min. This is evidently a too short time period to treat e.g. IBS. To expose the target organ, i.e. the large bowel to a constant concentration of PO to maintain the short lasting effect a sustained release formulation is needed to secure constant exposure of the organ to constant concentrations of PO.
Oro-cecal transit time is prolonged after both acute and chronic use. A low dose of the oil (90 mg; approximately 0.1 ml) has no influence on gastric emptying (Georg and Spilker, 1998), after 0.2 ml a significant reduction is found (Dalvi et al., 1991). The findings are in line with the antispasmodic effect. Also, as an additive to a barium sulphate suspension PO exerts a spasmolytic effect on the colon in patients undergoing barium enema examination (Sparks et al., 1995).
Heartburn, one of the major adverse events of oral PO may be caused to a large extent by inappropriate release of the oil in the upper GI tract (Sigmund and McNally, 1969) resulting in relaxation of the lower esophageal sphincter thus facilitating reflux. To minimize these adverse events an appropriate delayed release formulation may be useful.
Pharmacokinetics
In rats PO is relatively rapidly absorbed and eliminated mainly via the bile. The major biliary metabolite is menthol glucuronide, which undergoes enterohepatic circulation. The urinary metabolites result from hydroxylation at the C-7 methyl group at C-8 and C-9 of the isopropyl moiety, forming a series of mono- and dihydroxymenthols and carboxylic acids, some of which are excreted in part as glucuronic acid conjugates (Yamaguchi et al., 1994).
Menthol (30-55% of natural PO) and other plant mono-terpenes in PO are highly fat soluble and therefore rapidly absorbed from the proximal gut (Somerville et al., 1984; White et al., 1987). Thus, to secure availability of unmetabolised PO at the target organ in IBS, i.e. the lumen of the lower intestinal tract, the oil requires an appropriate galenic formulation (sustained release in the lower intestinal tract) to reach the target. In addition, such a formulation may be useful to minimize one of the more frequent adverse events of PO, i.e. heartburn. The kinetic properties of such formulations (Colpermin[R] and Mintec[R]) were analyzed in two studies, comparing also soft gelantine capsules as a model formulation for upper gastrointestinal release of PO.
Somerville et al. (1984) investigated in a cross over study in six healthy volunteers urinary excretion of menthol in the form of its major metabolite menthol glucuronide after oral ingestion of either two capsules of Colpermin[R] or two soft gelatine capsules without enteric coating, containing each a total of 0.4 ml of PO. Urine was collected in 2-hourly intervals up to 14 h plus one 10 h sample up to 24 h.
In the pooled 24 h sample urinary menthol excretion was essentially identical for both groups (64 mg/74 mg). In Fig. 1 the fractionated menthol excretion is illustrated showing a sustained release pattern for Colpermin[R] as compared to the gelatine capsule. It is concluded that PO from Colpermin[R] is released to a significant extent in the lower digestive tract and in the colon, the target organ to exert antispasmodic effects. The gelantine capsule release pattern does not meet the therapeutic requirements.
The study was extended in six patients, each with an ileostoma. Urine was collected in a single 24h sample. Patients simultaneously collected their ileostoma fluid (n = 5 Colpermin[R], n = 6 gelatine capsules) over the study period. In both fluids the menthol content was analyzed.
Urinary menthol excretion after Colpermin[R] in ileostoma patients is by more than 50% reduced as compared to healthy subjects whereas after gelatine capsules the reduction is <30%. It is interesting to note that Rhodes (1976) describes a patient suffering from achlorhydria. After ingestion of enteric coated PO the patient complained of heartburn and eructation; investigations demonstrated that the capsule disintegrated in the stomach due to the high pH. McKenzie and Gallacher (1989) describe a patient who had only 10 cm of jejunum anastomosed to the left colon. Repeated ingestion of Colpermin[R] capsules resulted in them being passed unchanged per rectum. Both observations and the study by Somerville et al. (1984) underline that efficacy and tolerance may be dependent on effective enteric coating. >
White et al. (1987) studied in 13 healthy subjects in a randomized cross over study the urinary pharmacokinetic profiles of Colpermin[R] and Mintec[R], another enteric coated PO formulation, after ingestion of each three capsules (0.6 ml PO) each. Urine was collected in 2-hourly intervals up to 14 h and in a 10 h sample up to 24 h. Menthol and its glucuronide metabolite were determined in urine.
Mean total 24h menthol urinary excretion was 95.5 mg for Colpermin[R] and 130.9 mg for Mintec[R] (n.s.). The fractionated excretion pattern is shown in Fig. 2.
[FIGURE 1 OMITTED]
Peak excretion was approximately 30 mg menthol/h for Mintec[R] at 3h post dose with a sharp decline thereafter, whereas this rate was about 10 mg menthol/h for Colpermin[R] extending over at least 12 h.
This describes two distinct formulations. Lag time (1.07 h/0.5 h–Colpermin[R]/Mintec[R]) and time to peak (5h/2.8h–Colpermin[R]/Mintec[R]) are statistically different (p < 0.017 or p < 0.047) for the two formulations. Absorption half life, terminal elimination half life and AUC’s are not different. The difference in total urinary menthol excretion (~35%) may indicate that PO release from Colpermin[R] is not finalized within 24 h. It is interesting to note that five subjects had symptoms described as nausea and vague abdominal pain after Mintec[R], whereas no such events were reported after the comparator. This may underline the need for a release of PO in the lower gastrointestinal tract to ensure both efficacy and clinical tolerance, as e.g. demonstrated for the Colpermin[R] formulation.
Discussion
There is reasonable evidence that PO exerts a spasmolytic effect on the smooth vasculature of the intestinal tract. The duration of effect is limited to approximately 20 min. Furthermore, there is evidence that the typical adverse events of PO (e.g. heartburn) do occur if PO is released in the upper gastrointestinal tract. If the target organ like in IBS is the colon immediate release formulations are inadequate. A sustained release formulation is required which releases PO in the lower GI tract, thus also avoiding typical adverse events of PO. Such formulations are available as described in pharmacokinetic studies (Somerville et al., 1984; White et al., 1987). A sustained release formulation having its peak release at about 4h after ingestion with a release time of PO of up to 24h meet such requirements. A t.i.d. regimen is thus possible and it can be assumed that over a 24h period at the target site, i.e. the large bowel sufficient amount of PO is available to exert its pharmacological action(s).
[FIGURE 2 OMITTED]
References
Dalvi, S.S., Nadkarni, P.M., Pardesi, R., Gupta, K.C., 1991. Effect of peppermint oil on gastric emptying in man: a prelimary study using a radiolabelled solid test meal. Indian J. Physiol. Pharmacol. 35 (3), 212-214.
Duthie, H.L., 1981. The effect of peppermint oil on colonic motility in man. Br. J. Surg. 68, 820.
ESCOP (European Scientific Cooperative on Phytotherapy), 1997. Monograph: Menthae Piperitae Aetheroleum (Peppermint Oil). Exeter, UK.
Food and Drugs, 1998. Substances generally recognized as safe, 21 C.F.R. Sect. 182.10 and Sect. 182.20 (April 1, 1998).
Georg, K.J., Spilker, Th., 1998. Motilitatshemmende Wirkung von Kummel- und Pfefferminzol: simultane kombinierte Messung mit Sonographie und H2-Atemtest. (Motility inhibitory effect of caraway and peppermint oil: combined simultaneous measurement by sonography and H2-expiration test) Abstract Phytopharmakaforschung 2000, Bonn 27-28.11.98.
Hawthorn, M., Ferrante, J., Luchowski, E., et al., 1988. The actions of peppermint oil and menthol on calcium channel-dependent processes in intestinal, neuronal and cardiac preparations. Aliment Pharmacol. Therap. 2, 101-118.
Leicester, R.J., Hunt, R.H., 1982. Peppermint oil to reduce colonic spasm during endoscopy. Lancet, 989.
McKenzie, J., Gallacher, M., 1989. A sweet smelling success. Nur. Times 85, 48-49.
Rhodes, J., 1976. Open clinical study of peppermint oil in patients with colonic symptoms. Clinical trial report
Rogers, J., Tay, H.H., Misiewicz, J.J., 1988. Peppermint oil. Lancet, 98-99.
Sigmund, C.J., McNally, E.F., 1969. The action of a carminative on the lower esophageal sphincter. Gastroenterology 56, 13-18.
Somerville, K.W., Richmond, C.R., Bell, G.D., 1984. Delayed release peppermint oil capsules (Colpermin) for the spastic colon syndrome: a pharmacokinetic study. Br. J. Clin. Pharmacol. 18, 638-640.
Sparks, M.J.W., O’Sullivan, P., Herrington, A.A., Morcos, S.K., 1995. Does peppermint oil relieve spasm during barium enema? Br. J. Radiol. 68, 841-843.
Taylor, B.A., Duthie, H.L., Oliveira, R.B., Rhodes, J., 1983. Ultrasound used to measure the response of colonic motility to essential oils. Proceedings of the International Motility Symposium, Aix-en-Provence, France, pp. 441-448.
White, D.A., Thompson, S.P., Wilson, C.G., Bell, G.D., 1987. A pharmacokinetic comparison of two delayed-release peppermint oil preparations, Colpermin and Mintec, for treatment of the irritable bowel syndrome. Int. J. Pharmaceutics 40, 151-155.
Wildgrube, H.J., 1988. Untersuchung zur Wirksamkeit von Pfefferminzol auf Beschwerdebild und funktionelle Parameter bei Patienten mit Reizdarm-Syndrom (Studie) [Investigation of the efficacy of peppermint oil on the symptoms and functional parameters of patients with irritable bowel syndrome (study)]. Naturheilpraxis 41, 2-5.
Yamaguchi, T., Caldwell, J., Farmer, P.B., 1994. Metabolic fate of [[.sup.3]H]-l-menthol in the rat. Drug Metabol. Dispos. 22, 616-624.
H.-G. Grigoleit*, P. Grigoleit
Johann-Sebastian-Bach-str. 27, 65193 Wiesbaden, Germany
Received 13 September 2004; accepted 26 October 2004
*Corresponding author. Tel.: 
+49 611 520509
; fax: +49 611 5990443.
E-mail address: Dr.Grigoleit@t-online.de (H.-G. Grigoleit).
Table 1. Summary of pharmacodynamic studies relevant to the use of peppermint oil (PO) in the GI tract Design/no. of subjects/route ofDose PO/ Reference or application site comparator Method(s) Sigmund and Open/n = 34 healthy 15 drops ofManometrical McNally (1969) subjects/gastric essence of recording of lower lumenpeppermint/esophageal saline (n =(intrasphincteric) 7) and gastric pressure Duthie (1981) Open, randomized/n 0.2 ml/15 min after 0.5 mg = 6 healthy placeboi.m. neostigmine subjects/coloniccolonic motility lumen recording by triple lumen catheter Leicester and Open/n = 20 PO; dose not Visual observation Hunt (1982) patients undergoing given via colonoscope diagnostic or therapeutic coloscopy/colonic lumen Taylor et al. Open, randomized/n 0.2 ml/After 0.5 mg (1983) = 6 healthy placeboneostigmine i.m. subjects/ intraluminal rectosigmoidal pressure recording lumen Rogers et al. Open, randomized/n 0.1 ml/30 min after 0.5 mg (1988) = 5 healthy placeboneostigmine subjects/colonicintracolonic lumen pressure recording for 30 min Wildgrube Matched pairs/n =EntericOro-cecal transit (1988) 19 IBS patients/ coated PO/ time (hydrogen oral treatment 2 placeboexhalation) and weeks total gastrointestinal transit time (carmine red) Dalvi et al.Open/n = 20 healthy 0.2 ml versus Radiolabelled test (1991) subject; 10 younger no treatment meal and recording (21 yr), 10 older of gastric emptying (40 yr); n = 6 by gamma camera dyspepsia patients oral solution Sparks et al. Double blind/141 0.24 ml PO in X-ray films reviewed (1995) patients standardbarium by 2 independent contrast barium sulphate radiologists for enema examination; contrast colonic spasms n = 71 standard medium or barium preparation, without PO n = 70 standard plus PO/oral Georg and Multiple cross Oral 90 mg PO Gastric and gall Spilker (1998) over?/n = 12 or caraway bladder emptying healthy subjects/oiltime by sonography; oral encapsulated/ oro-cecal transit saline/time (hydrogen cisaprid/10expiration) mg/butyl- scopolamine rectal Reference ResultsComments/conclusions Sigmund and 25/27 1-7 min post It is concluded that heartburn McNally (1969) dose decrease in after PO is associated with the Intrasphincteric relaxation of lower esophageal pressure; no salinesphincter effect Duthie (1981) <2 min inhibition of motor activity up to 23 min (mean 12 min); p >< 0.05 PO/placebo Leicester and Within 30s relieve of PO is useful in reducing spasms Hunt (1982) colonic spasms thus allowing easier passage of instrument or assisting in polypectomy Taylor et al. Up to 20 min (1983) inhibition of colonic motor activity; placebo no effect Rogers et al. Significant increase Unexplained finding; in contrast (1988) in colonic motor to all other studies activity after PO Wildgrube Oro-cecal transit It is concluded that PO improves (1988) time doubles from 40 disturbed GI motility in IBS to 80 min (p < 0.05); patients total transit time increase from 39 to 46.5 h (p < 0.05) Dalvi et al.Basal emptying: 100It is concluded that the (1991) min young; 160 min spasmolytic property of PO is old; 227 min responsible for reduction of dyspepsia; after POemptying time significant shortening: young 81, old 110, dyspepsia 148 min Sparks et al. No residual spasm in It is concluded that PO added to (1995) 60% with PO versus barium suspension is a safe, 35% with out (p < simple and cheap method to relax 0.001) the colon during barium enema examination Georg and No influence of PO on Spilker (1998) gastric emptying time; oro-cecal transit time prolonged from 65 to 85 min (p < 0.05) by PO
From:
Phytomedicine: International Journal of Phytotherapy &Phytopharmacology
Date:
August 1, 2005
Author:
Grigoleit, H.-G.; Grigoleit, P.
