Skip to content

Antispasmodics and peppermint oil

TL;DR — These are the oldest and most-prescribed IBS drugs, and their evidence base is the field's clearest example of a large positive meta-analytic signal resting on small, old, methodologically weak trials. In the network meta-analysis of 51 RCTs and 4,644 patients, peppermint oil ranked first for global symptoms (RR of not improving 0.63, 95% CI 0.48–0.83, P-score 0.84) and tricyclics second (0.66, 0.53–0.83) — but only 13 of 51 trials were at low risk of bias, and no active treatment differed significantly from any other on direct or indirect comparison (Black 2020, PMID 31859183). Peppermint oil's own updated meta-analysis (10 RCTs, 1,030 patients) gives RR of global symptoms not improving 0.65 (0.43–0.98), NNT 4 (2.5–71), and abdominal pain not improving 0.76 (0.62–0.93), NNT 7 (4–24), with more adverse events (RR 1.57, 1.04–2.37) and very low quality of evidence (Ingrosso 2022, PMID 35942669). The one adequately powered modern trial using regulatory endpoints was negative on both co-primary outcomes: in 189 Rome IV patients, abdominal-pain response was 46.8% with small-intestinal-release peppermint oil versus 34.4% placebo (p=0.170), and overall relief 9.7% vs 4.7% (p=0.317) — although secondary abdominal pain, discomfort and severity all improved (Weerts 2020, PMID 31470006). Among antispasmodics, otilonium (RR 0.55, 0.31–0.97) and hyoscine (0.63, 0.51–0.78) have the most consistent evidence (Ford 2008, PMID 19008265). Note the width of the NNT confidence interval for peppermint oil — 2.5 to 71 — which is the honest summary of what is known.

The comparative ranking

Black and colleagues pooled every RCT of soluble fibre, antispasmodics, peppermint oil and gut–brain neuromodulators (search to August 2019; 51 RCTs, 4,644 patients, 4–12 weeks of treatment) (Black 2020, PMID 31859183):

Endpoint Rank 1 RR (95% CI) P-score Rank 2 RR
Failure to improve global IBS symptoms Peppermint oil capsules 0.63 (0.48–0.83) 0.84 Tricyclic antidepressants 0.66 (0.53–0.83), P-score 0.77
Failure to improve abdominal pain Tricyclic antidepressants 0.53 (0.34–0.83) 0.87 — —
Adverse events Tricyclics more likely than placebo 1.59 (1.26–2.06) 0.16 — —

Four qualifications the authors themselves place on this table, all of which matter more than the ranking: 1. Only 13 of 51 trials were at low risk of bias. 2. For global symptoms, no active treatment differed significantly from any other on direct or indirect comparison — the ranking is a probability ordering, not a demonstrated hierarchy. 3. The tricyclic abdominal-pain result rests on four RCTs and 92 patients. 4. Treatment duration in most trials was 4–12 weeks; long-term relative efficacy is unknown.

Peppermint oil

Source Design Result
Pittler 1998, PMID 9672344 Early critical review and meta-analysis The first synthesis; flagged methodological weakness of the underlying trials
Ford 2008, PMID 19008265 4 trials, 392 patients RR of persistent symptoms 0.43 (0.32–0.59)
Khanna 2014, PMID 24100754 9 studies, 726 patients; RCTs ≥2 weeks Global improvement RR 2.23 (1.78–2.81) (5 studies, 392 patients); abdominal pain RR 2.14 (1.64–2.79) (5 studies, 357 patients). Adverse events more frequent but mild and transient; commonest was heartburn
Alammar 2019, PMID 30654773 Pooled clinical data Additional synthesis reaching a favourable conclusion
Weerts 2020, PMID 31470006 (NCT02716285) 190 randomised / 189 ITT Rome IV patients, 4 Dutch hospitals, 8 weeks, 3 arms: 182 mg small-intestinal-release vs 182 mg ileocolonic-release vs placebo; 57.7% recruited in primary care Both co-primary endpoints negative. FDA-defined abdominal-pain response: 29/62 (46.8%) small-intestinal-release, p=0.170; 26/63 (41.3%) ileocolonic-release, p=0.385; 22/64 (34.4%) placebo. EMA-defined overall relief: 9.7% (p=0.317) and 1.6% (p=0.351) vs 4.7%. Secondary endpoints did favour small-intestinal-release: abdominal pain p=0.016, discomfort p=0.020, IBS severity p=0.020. Adverse events mild but more common in both oil arms (p<0.005). Authors: findings "do not support further development of ileocolonic-release peppermint oil"
Ingrosso 2022, PMID 35942669 Updated meta-analysis, 10 RCTs, 1,030 patients, search to April 2022 — explicitly undertaken because "recent studies have cast doubt" Global symptoms RR of not improving 0.65 (0.43–0.98), NNT 4 (2.5–71); abdominal pain 0.76 (0.62–0.93), NNT 7 (4–24); any adverse event RR 1.57 (1.04–2.37). "Quality of evidence was very low. Adequately powered RCTs of peppermint oil as first-line treatment for IBS are needed"
Weerts 2021, PMID 34468079 Trial-based economic evaluation of the above RCT, societal perspective, n=126 Peppermint oil dominant in 46% of bootstrap replications; 56% probability of cost-effectiveness at €10,000/QALY; using FDA abdominal-pain response as the outcome, dominant in 51% of replications and 89% probability of cost-effectiveness

The peppermint-oil story is worth stating plainly because it recurs across this condition: a treatment ranked first in the most comprehensive network meta-analysis failed its co-primary regulatory endpoints in the largest and most rigorous single trial ever run on it, while improving the same symptoms measured as continuous secondaries. Both results are in the table above; neither cancels the other. The most defensible summary is that peppermint oil produces a small real effect that is not reliably detectable with dichotomous regulatory responder definitions in a population with a 34% placebo response rate — see placebo-response-and-trial-design.

Note also that Ingrosso 2022 (PMID 35942669) includes the Weerts trial and still reports a significant pooled effect; the NNT interval extending to 71 is where the uncertainty lives.

Antispasmodics

Agent Evidence Source
All antispasmodics pooled 22 trials, 1,778 patients; RR of persistent symptoms 0.68 (0.57–0.81) Ford 2008, PMID 19008265
Otilonium bromide 4 trials, 435 patients; RR 0.55 (0.31–0.97) Ford 2008, PMID 19008265
Hyoscine (butylbromide) 3 trials, 426 patients; RR 0.63 (0.51–0.78) Ford 2008, PMID 19008265
All antispasmodics pooled (Mexican formulary review) 23 trials, 2,585 patients; global improvement OR 1.55 (1.33–1.83); pain OR 1.52 (1.28–1.80) in 2,394 patients; agents included pinaverium, mebeverine, otilonium, trimebutine, alverine, hyoscine, fenoverine, dicyclomine Martínez-Vázquez 2012, PMID 22672854
Alverine/simethicone and pinaverium/simethicone combinations Significant global improvement (alverine/simethicone) and bloating improvement (pinaverium/simethicone) Martínez-Vázquez 2012, PMID 22672854
Mebeverine No individually significant signal in Ford 2008 Ford 2008, PMID 19008265

Mechanism: why "antispasmodic" is a misnomer for at least two of these drugs

  • Peppermint oil / menthol. Proposed mechanisms are multiple and not confined to smooth muscle: calcium-channel blockade or direct enteric nervous system effects producing smooth-muscle relaxation; visceral sensitivity modulation via transient receptor potential cation channels; antimicrobial activity; anti-inflammatory activity; and modulation of psychosocial distress. Effects have been documented on oesophageal, gastric, small-bowel, gall-bladder and colonic physiology (Chumpitazi 2018, PMID 29372567). Direct study of menthol on human colonic circular smooth muscle has characterised the relaxant mechanism (Amato 2014, PMID 25046841). If the visceral-sensitivity component is real, peppermint oil is closer to a neuromodulator than to a spasmolytic — which would explain why it ranks alongside tricyclics rather than alongside the anticholinergics (Black 2020, PMID 31859183).
  • Otilonium bromide. A quaternary ammonium derivative that concentrates in the large-bowel wall and acts locally. Its pharmacodynamics are deliberately described as complex: blockade of L-type and T-type calcium channels, interference with intracytoplasmic calcium mobilisation, interference with muscarinic responses, and direct or indirect interaction with tachykinin receptors on smooth muscle cells and on primary afferent neurons — the last of which is a sensory rather than motor action (Evangelista 2018, PMID 29732965; Santicioli 1999, PMID 10498293; Martínez-Cutillas 2013, PMID 23941257).

The practical consequence is that pooling "antispasmodics" as one class in meta-analysis mixes drugs with anticholinergic, calcium-channel, tachykinin-antagonist and afferent-modulating actions, which is one reason class-level estimates sit on such wide heterogeneity.

Mebeverine: the negative case, and an experiment on labelling

Mebeverine is the most widely used antispasmodic in several health systems and has the weakest evidence of any agent on this page. A systematic review of eight randomised trials (555 patients, 63% women) found pooled RR for clinical improvement 1.13 (0.59–2.16, p=0.71) and for relief of abdominal pain 1.33 (0.92–1.93, p=0.13) — neither significant — with no dose advantage of 200 mg over 135 mg (Darvish-Damavandi 2010, PMID 20128021).

A 2025 Dutch 2×2 factorial trial then did something unusual and highly informative. Two hundred and sixty-nine adolescents (12–17 years) with IBS or functional abdominal pain received mebeverine 200 mg twice daily or placebo for 8 weeks, and independently were told their treatment was either "mebeverine or placebo" (blinded trial label) or "mebeverine" (open label) (Rexwinkel 2025, PMID 40074185):

Contrast Treatment success (>50% reduction in pain intensity and frequency) OR (95% CI) p
Drug mebeverine vs placebo 31 (23.4%) vs 30 (22.0%) 1.08 (0.59–1.99) 0.81
Label "mebeverine" vs "mebeverine or placebo" 42 (31.6%) vs 19 (14.1%) 2.84 (1.52–5.34) 0.001
Adequate relief, drug contrast 55 (41.0%) vs 61 (45.5%) 0.83 (0.51–1.35) 0.46
Adequate relief, label contrast 67 (50.4%) vs 49 (36.3%) 1.78 (1.1–2.9) 0.02

The drug did nothing; the label roughly doubled the response rate. This is a direct, randomised measurement of the informational component of treatment effect in a functional bowel disorder, and it belongs beside the open-label placebo literature on placebo-response-and-trial-design. It also constrains how the older antispasmodic meta-analyses should be read: trials conducted with strong expectation of benefit and weak blinding will overstate drug effect in exactly this way. The trial was in adolescents, so extrapolation to adults is an assumption, not a finding.

For completeness, peppermint oil has also been tested in paediatric IBS and functional abdominal pain (Vermeijden 2026, PMID 41610933; Shulman 2022, PMID 34528282; Shulman 2025, PMID 40390282); this knowledge base is adult-scoped and those trials are noted rather than synthesised.

Antispasmodics are heterogeneous — anticholinergics (hyoscine, dicyclomine), calcium-channel blockers acting on smooth muscle (otilonium, pinaverium), and direct smooth-muscle relaxants (mebeverine, alverine) — and pooling them into one class effect obscures large differences in mechanism, availability and licensing. Availability is jurisdictional: otilonium and pinaverium are not marketed in the USA, while dicyclomine and hyoscine are widely used, which means the "best-evidenced antispasmodic" is often not the one prescribed. Both syntheses report no significant excess of serious adverse events (Ford 2008, PMID 19008265; Martínez-Vázquez 2012, PMID 22672854), though anticholinergic side effects (dry mouth, blurred vision, urinary hesitancy) are class-expected and matter in older patients.

Other plant-based therapies

A 2026 systematic review and meta-analysis of plant-based therapy in IBS has been published (Meyer 2026, PMID 42572206), and an earlier synthesis covered Western herbal medicines (Hawrelak 2020, PMID 31987249). These are outside the scope of this page beyond noting that the same methodological pattern — many small trials, high heterogeneity, low certainty — applies.

Where these drugs sit in practice

Both classes are recommended as first- or second-line symptomatic treatment in most guidelines (guidelines), largely because they are cheap, familiar, available over the counter in several jurisdictions, and carry little serious risk. That positioning rests on the meta-analytic signal, not on any single adequately powered modern trial — for antispasmodics, no equivalent to the Weerts peppermint trial exists. The most consequential comparator is now dietary: in CARIBS, optimised medical treatment (which included antispasmodics among symptom-directed choices) achieved a 58% response versus 76% for low-FODMAP plus dietary advice (Nybacka 2024, PMID 38643782) — see dietary-therapy.

Open questions

  • Would an adequately powered modern antispasmodic trial using FDA/EMA endpoints replicate the meta-analytic effect, as the peppermint-oil trial failed to (Weerts 2020, PMID 31470006)? A targeted PubMed search on 2026-09-02 retrieved only the peppermint-oil trial and no qualifying modern antispasmodic trial.
  • Is the discrepancy between dichotomous regulatory endpoints and continuous symptom scales a property of peppermint oil or of the endpoints (Weerts 2020, PMID 31470006; Ingrosso 2022, PMID 35942669)?
  • Which antispasmodic is best? A targeted PubMed search on 2026-09-02 retrieved no direct comparison capable of ranking individual antispasmodics; the class is pooled despite three distinct mechanisms (Ford 2008, PMID 19008265; Martínez-Vázquez 2012, PMID 22672854).
  • Does adding simethicone genuinely improve antispasmodic performance, as two combination analyses suggest (Martínez-Vázquez 2012, PMID 22672854)?
  • What is the long-term (>12 weeks) efficacy of either class? A targeted PubMed search on 2026-09-02 retrieved no qualifying long-term efficacy trial; most contributing trials ran 4–12 weeks (Black 2020, PMID 31859183).
  • Should peppermint oil be first-line given cost-effectiveness data (Weerts 2021, PMID 34468079) despite a failed primary endpoint in the same trial?
  • If a drug label alone nearly doubles response (OR 2.84, 1.52-5.34; Rexwinkel 2025, PMID 40074185), how much of the historical antispasmodic meta-analytic effect is label rather than molecule? A targeted PubMed search on 2026-09-02 retrieved no adult replication of the labelling design.
  • Is peppermint oil acting as an antispasmodic or as a peripheral neuromodulator via TRP channels (Chumpitazi 2018, PMID 29372567)? The distinction would change where it belongs in a treatment sequence.
  • Should mebeverine continue to be prescribed at scale given a null pooled estimate (Darvish-Damavandi 2010, PMID 20128021) and a null adolescent trial (Rexwinkel 2025, PMID 40074185)?

References

  1. Black CJ, Yuan Y, Selinger CP, Camilleri M, Quigley EMM, Moayyedi P, Ford AC. Efficacy of soluble fibre, antispasmodic drugs, and gut-brain neuromodulators in irritable bowel syndrome: a systematic review and network meta-analysis. Lancet Gastroenterol Hepatol. 2020;5(2):117-131. PMID 31859183
  2. Ingrosso MR, et al. Systematic review and meta-analysis: efficacy of peppermint oil in irritable bowel syndrome. Aliment Pharmacol Ther. 2022;56(6):932-941. PMID 35942669
  3. Weerts ZZRM, et al. Efficacy and Safety of Peppermint Oil in a Randomized, Double-Blind Trial of Patients With Irritable Bowel Syndrome. Gastroenterology. 2020;158(1):123-136. PMID 31470006
  4. Weerts ZZRM, et al. A trial-based economic evaluation of peppermint oil for the treatment of irritable bowel syndrome. United European Gastroenterol J. 2021;9(9):997-1006. PMID 34468079
  5. Ford AC, Talley NJ, Spiegel BM, Foxx-Orenstein AE, Schiller L, Quigley EM, Moayyedi P. Effect of fibre, antispasmodics, and peppermint oil in the treatment of irritable bowel syndrome: systematic review and meta-analysis. BMJ. 2008;337:a2313. PMID 19008265
  6. Khanna R, MacDonald JK, Levesque BG. Peppermint oil for the treatment of irritable bowel syndrome: a systematic review and meta-analysis. J Clin Gastroenterol. 2014;48(6):505-12. PMID 24100754
  7. Alammar N, et al. The impact of peppermint oil on the irritable bowel syndrome: a meta-analysis of the pooled clinical data. BMC Complement Altern Med. 2019;19:21. PMID 30654773
  8. Pittler MH, Ernst E. Peppermint oil for irritable bowel syndrome: a critical review and metaanalysis. Am J Gastroenterol. 1998;93(7):1131-5. PMID 9672344
  9. Martínez-Vázquez MA, et al. Effect of antispasmodic agents, alone or in combination, in the treatment of Irritable Bowel Syndrome: systematic review and meta-analysis. Rev Gastroenterol Mex. 2012;77(2):82-90. PMID 22672854
  10. 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. 2018;47(6):738-752. PMID 29372567
  11. Amato A, Liotta R, Mulè F. Effects of menthol on circular smooth muscle of human colon: analysis of the mechanism of action. Eur J Pharmacol. 2014;740:295-301. PMID 25046841
  12. Evangelista S, Traini C, Vannucchi MG. Otilonium Bromide: A Drug with a Complex Mechanism of Action. Curr Pharm Des. 2018;24(16):1772-1779. PMID 29732965
  13. Santicioli P, Zagorodnyuk V, Renzetti AR, Maggi CA. Antimuscarinic, calcium channel blocker and tachykinin NK2 receptor antagonist actions of otilonium bromide in the circular muscle of guinea-pig colon. Naunyn Schmiedebergs Arch Pharmacol. 1999;359(5):420-7. PMID 10498293
  14. Martínez-Cutillas M, et al. Mechanisms of action of otilonium bromide (OB) in human cultured smooth muscle cells and rat colonic strips. Neurogastroenterol Motil. 2013;25(12):e803-12. PMID 23941257
  15. Darvish-Damavandi M, Nikfar S, Abdollahi M. A systematic review of efficacy and tolerability of mebeverine in irritable bowel syndrome. World J Gastroenterol. 2010;16(5):547-53. PMID 20128021
  16. Rexwinkel R, et al. Mebeverine and the Influence of Labeling in Adolescents With Irritable Bowel Syndrome or Functional Abdominal Pain Not Otherwise Specified: A 2 x 2 Randomized, Placebo-Controlled Trial. Gastroenterology. 2025;169(1):94-103. PMID 40074185
  17. Vermeijden NK, et al. Peppermint Oil and Sweets in Pediatric Irritable Bowel Syndrome and Functional Abdominal Pain: A Randomized Trial. Clin Gastroenterol Hepatol. 2026;24(8):2286-2296. PMID 41610933
  18. Shulman RJ, et al. Randomised trial: Peppermint oil (menthol) pharmacokinetics in children and effects on gut motility in children with functional abdominal pain. Br J Clin Pharmacol. 2022;88(3):1321-1333. PMID 34528282
  19. Shulman RJ, et al. Randomized trial: Peppermint oil (menthol) pharmacokinetics in children and effects on gut motility in children with functional abdominal pain: 540 mg vs. 900 mg dose comparison. Br J Clin Pharmacol. 2025;91(9):2711-2724. PMID 40390282
  20. Meyer A, et al. Systematic Review and Meta-Analysis: Plant-Based Therapy for Irritable Bowel Syndrome. Phytother Res. 2026 Aug 9 (online ahead of print). PMID 42572206
  21. Hawrelak JA, Wohlmuth H, Pattinson M, et al. Western herbal medicines in the treatment of irritable bowel syndrome: A systematic review and meta-analysis. Complement Ther Med. 2020;48:102233. PMID 31987249
  22. Nybacka S, et al. A low FODMAP diet plus traditional dietary advice versus a low-carbohydrate diet versus pharmacological treatment in irritable bowel syndrome (CARIBS). Lancet Gastroenterol Hepatol. 2024;9(6):507-520. PMID 38643782